Leptin signaling in the hypothalamus: emphasis on energy homeostasis and leptin resistance

Frontiers in Neuroendocrinology Frontiers in Neuroendocrinology 24 (2004) 225–253 www.elsevier.com/locate/yfrne

Leptin signaling in the hypothalamus: emphasis on energy homeostasis and leptin resistance Abhiram Sahu* Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, S829 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USA

Abstract Leptin, the long-sought satiety factor of adipocytes origin, has emerged as one of the major signals that relay the status of fat stores to the hypothalamus and plays a significant role in energy homeostasis. Understanding the mechanisms of leptin signaling in the hypothalamus during normal and pathological conditions, such as obesity, has been the subject of intensive research during the last decade. It is now established that leptin action in the hypothalamus in regulation of food intake and body weight is mediated by a neural circuitry comprising of orexigenic and anorectic signals, including NPY, MCH, galanin, orexin, GALP, a-MSH, NT, and CRH. In addition to the conventional JAK2–STAT3 pathway, it has become evident that PI3K–PDE3B–cAMP pathway plays a critical role in leptin signaling in the hypothalamus. It is now established that central leptin resistance contributes to the development of diet-induced obesity and ageing associated obesity. Central leptin resistance also occurs due to hyperleptinimia produced by exogenous leptin infusion. A defective nutritional regulation of leptin receptor gene expression and reduced STAT3 signaling may be involved in the development of leptin resistance in DIO. However, leptin resistance in the hypothalamic neurons may occur despite an intact JAK2–STAT3 pathway of leptin signaling. Thus, in addition to defective JAK2–STAT3 pathway, defects in other leptin signaling pathways may be involved in leptin resistance. We hypothesize that defective regulation of PI3K–PDE3B–cAMP pathway may be one of the mechanisms behind the development of central leptin resistance seen in obesity. Ó 2003 Elsevier Inc. All rights reserved.

1. Introduction 1.1. Historical background Obesity is one of the major health hazards in humans, particularly in western society. Remarkably in most humans body weight is maintained in stable condition. Positive energy balance as a result of less energy expenditure as compared to energy intake leads to the storage of energy in the form of fat. Although cumulative evidence gathered mostly over the last two decades suggest that body weight is regulated by a complex circuitry involving both central and peripheral factors working primarily in the brain, particularly in the hypothalamus; the idea that some factors originating in the periphery relay the status of body fat stores to the brain has originated from the days of Kennedy, almost 50

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0091-3022/$ - see front matter Ó 2003 Elsevier Inc. All rights reserved. doi:10.1016/j.yfrne.2003.10.001

years ago [160]. In 1953, Kennedy hypothesized that the hypothalamus senses some peripheral factors that provide the information about the body fat stores, and the hypothalamus would then transduce this information to change food intake to compensate for changes in body fat content. Subsequent studies using parabiosis experiments in rats, Hervey showed that when one of the parabiotic partner made obese by a lesion in the ventromedial hypothalamus, the intact partner became anorexic and lean [132]. These results suggested that some blood-borne factor produced by the increased fat mass acted to induce satiety in the intact partner. Furthermore, its lack of effect in the lesioned animals also suggested that the action of this factor(s) in the hypothalamus is essential for the maintenance of normal body weight. In the 1970s, Douglas ColemanÕs finding that recessive mutations in the mouse ob and db genes resulted in obesity and diabetes [60], provided a critical clue about this peripheral factor that regulates body weight. Using parabiosis experiments with ob/ob and db/db mice,

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Coleman concluded that the blood-borne factor was encoded in the ob gene and the receptor for this factor was encoded in the db gene [60]. However, the product of the ob gene was not discovered until 1994, when Jeffrey FriedmanÕs team, using positional cloning, identified and characterized the ob gene and its product, leptin (from the Greek leptos ¼ thin). They identified leptin as a 16 kDa protein produced primarily in white adipose tissue [367]. Although subsequent studies have demonstrated that leptin is produced in small amount in other tissues such as the placenta [207], stomach [10], pituitary [148,251] and the hypothalamus [221], the role of this extra adipose tissue-derived leptin is not clearly understood. After the discovery of leptin receptor by TartagliaÕs group in 1995 [327], physiological role of leptin has been the subject of intensive investigation and has been appreciated not only in regulation of body weight, but also in a variety of physiological functions such as reproduction, bone formation, and cardiovascular systems, etc. 1.2. Leptin physiology As expected, cumulative evidence suggests that leptin signals nutritional status to key regulatory centers in the hypothalamus [92,153,294,357] and it has emerged as an important signal regulating body weight homeostasis and energy balance [42,102,124,243,347]. Mutations that result in leptin deficiency are associated with massive obesity in humans as well as rodents [102,220]. Central or peripheral administration of leptin decreases food intake and body weight in a variety of animals, including rats, mice, and monkeys [102,267,326]. In normal mice, leptin administration reduces weight and corrects diet-induced obesity [42,124,243]. Leptin treatment has been shown to normalize feeding, reduce body weight and initiate puberty in a leptin deficient girl [99]. It is well established that leptin plays an important role in the long-term maintenance of body weight. In addition, the evidence that leptin mRNA levels are decreased following food deprivation and return to normal after refeeding [200,277]; and a rapid decrease of plasma leptin levels after a short-term fast followed by a rapid recovery after refeeding in man [34,65,165,166]; the existence of diurnal rhythm of plasma leptin entrained to meal timing in man [288]; and the evidence that circulating leptin levels increase within 4 h of natural feeding in rat [359] suggest that leptin may be involved in daily food intake and short-term regulation of body weight. Paradoxically, in the majority of cases, human obesity cannot be attributed to defects in leptin or its receptor [58,65,66,115,209,220], and serum leptin levels are significantly higher in obese humans relative to non-obese humans [43,64,65,129,193,202,292], and leptin administration shows very limited effects in obese people [134], suggesting a state of leptin-resistant in obese individuals.

In addition to its role in normal regulation of food intake and body weight, leptin treatment corrects obesity related disorders, including hyperglycemia, hyperinsulinemia, and sterility in ob/ob mice [14,42,49,124,243], and blunts the starvation-induced abnormalities in the gonadal, adrenal, and thyroid axes in lean mice [1]. Furthermore, leptinÕs role in reproduction is becoming increasingly apparent. For examples, leptin has been shown to accelerate puberty in mice [2,50]. Also transgenic mice over expressing leptin display accelerated puberty [364]. Leptin reverses the suppression of sexual maturation induced by fasting in rodents [54], and the effects of fasting on pulsatile secretion of luteinizing hormone [226]. Leptin also stimulates gonadotropin-releasing hormone secretion in vivo [346]. However, leptinÕs role in primate puberty appears to be permissive, because there is no evidence of increased circulating leptin before the onset of puberty [247–250,274]. In a recent study, we have shown that continuous peripheral infusion of leptin failed to induce gonadotropin-releasing hormone secretion in prepubertal monkeys [15]. Other central action of leptin includes regulation of bone formation [83,157] and angiogenesis [36,309]. In most part, leptinÕs role in various physiological functions, including food intake and body weight regulation, reproduction, bone formation, and angiogenesis appears to be mediated through the hypothalamus. In this review, I will however focus on the mechanisms of leptin action in the hypothalamus with regard to food intake and body weight regulation, obesity, and leptin resistance.

2. Hypothalamus as the major site of leptin action From the lesion studies by Hetherington and Ranson [133], and by Anand and Brobeck [7], it has been established that lesion in the ventromedial hypothalamus causes hyperphagia and obesity, and lesion in the lateral hypothalamus causes aphagia and even death by starvation. These studies clearly suggested the hypothalamus as the primary center for regulation of food intake and body weight with the ventromedial nucleus as the ‘‘satiety center’’ and the lateral hypothalamus as the ‘‘feeding center.’’ Since then a large body of evidence suggest that neural circuitry comprising of orexigenic and anorectic signals reside in the hypothalamus, and intricate regulation of this circuitry is critical for normal food intake and body weight in the individual. It appears that this circuitry senses the status of body energy stores from peripheral signals, such as leptin and insulin, and modifies its activity accordingly. Along this line, accumulated evidence clearly indicates that hypothalamus is one of the major sites of leptin action. First, central injection of leptin is more

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potent than peripheral administration in reducing food intake and body weight [42]. Within the hypothalamus, leptin is most effective in the arcuate nucleus (ARC) and ventromedial nucleus (VMN) areas in reducing food intake and body weight [146,279]. Second, leptin receptors are present in the hypothalamus and choroid plexus [199,203,291,327]. In this regard, the long-form of the Ob receptor (Ob-Rb) that is thought to be crucial for intracellular leptin signal transduction [51,182,328] has been localized in various hypothalamic sites, including ARC, VMN, dorsomedial nucleus (DMN), lateral hypothalamus (LH) and paraventricular nucleus (PVN), which are known to regulate food intake and energy homeostasis [51,214]. Systemic or central injections of leptin also activate neurons in these hypothalamic sites [91,92,122,214,291]. Third, inhibition of leptin signaling in the hypothalamus due to mutation in leptin receptors is the cause of obesity in db/db mice [56,328] and Zucker fa/fa rats [56,246]. Fourth, leptin can cross the blood–brain barrier [12,292]. Fifth, lesions in the hypothalamus make the animal become obese and unresponsive to exogenous leptin [80,168,280]. Sixth, neuronal specific knockout of Ob-Rb results in obesity [59]. Finally, leptin receptor mutations (although rare) in humans lead to morbid obesity [58]. Thus, the leptin signal to the hypothalamus is obligatory for normal food intake and body weight regulation; and any alteration in leptin action in the hypothalamus due either to defect in leptin transport and or leptin resistance in leptin target neurons would lead to dysregulation of body weight seen in obesity.

3. Neuronal targets of leptin action The hypothalamus produces an array of orexigenic and anorectic peptides that constitute a major part of the neural circuitry regulating ingestive behavior and body weight [153,272,294,357]. Evidence accumulated during the last several years suggest that leptinÕs effects are mediated through the activity of several neuropeptidergic neurons of both orexigenic and anorectic in nature in specific site of the hypothalamus. Leptin sensitive neurons include those that produce neuropeptide Y (NPY), agouti-related protein (AgRP), melanin concentrating hormone (MCH), galanin, orexin, a-melanocyte stimulating hormone (a-MSH), neurotensin (NT), corticotropin-releasing hormone (CRH), and cocaine- and amphetamine-regulated transcript (CART), etc. 3.1. Orexigenic peptide-producing neurons as leptin targets Among the orexigenic neuronal systems, NPY has become a prime candidate implicated in mediating leptin

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action in the hypothalamus, because: (a) NPY is the most potent endogenous orexigenic signal in various mammals, including rat [152,153,263,272,357]; (b) NPY neuronal activity is enhanced in hyperphagia observed in experimental diabetes [264,266,348,349], as well as in several experimental and genetic models of obesity [153,278,294,357], and (c) continuous or repeated central administration of NPY produces hyperphagia, body weight gain and ultimately, obesity [47,315,366]. Accordingly, leptin decreases hypothalamic NPY gene expression [267,291,317] and NPY release from the hypothalamic explants [317], leptin opposes the action of NPY on feeding [268,310], and NPY may act antagonistically against anorectic effect of leptin [16,96]. Furthermore, NPY neurons express Ob-Rb [215] and signal transducer and activator of transcription 3 (STAT3) [121], suggesting a direct action of leptin on these neurons. Finally, genetic knockout of NPY reduces hyperphagia and obesity in ob/ob mice indicating that full response to leptin deficiency requires NPY signaling [97]. Interestingly, mice lacking NPY show no abnormality in food intake and body weight regulation, and in fact these mice are more sensitive to leptin [96], suggesting further the antagonism of leptin action by NPY. This also indicates redundant signaling mechanisms in the hypothalamus, such that, in the absence of NPY, leptin acts through other pathways to maintain normal food intake and body weight. NPY neurons also co-express AgRP [39,120]; and like NPY, AgRP over expression results in obesity [116] and AgRP is up-regulated in obese and diabetic mutant mice [308]. Importantly, AgRP is an endogenous melanocortin antagonist [239], and leptin decreases AgRP mRNA levels in the hypothalamus [84,167,218,355]. These findings suggest that AgRP inhibition may be an important mechanism by which leptin can enhance its anorectic effect in the hypothalamus. Recently, MCH (melanin-concentrating hormone) neurons have received significant attention with regard to feeding and body weight regulation, and therefore for a target of leptin signaling. MCH is primarily expressed in the lateral hypothalamus (LH). Central MCH administration stimulates feeding [258], MCH synthesis in the hypothalamus is elevated by both energy restriction and leptin deficiency [252], MCH-knockout mice are hypophagic and have increased metabolic rate, despite low leptin levels, and are excessively lean [304]. MCH overexpression in the hypothalamus causes obesity [197], and MCH knockout in ob/ob mice results in decreased body weight mainly due to increased energy expenditure without any change in food intake [298]. Along this line, our study shows that leptin not only decreases MCH gene expression but also reduces food intake induced by MCH in rat [267,268]. MCH is also a functional melanocortin antagonist in the hypothalamus [196]. Functional interactions between MCH, NPY, and

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anorectic peptides occurs in the hypothalamus [332]. Thus, MCH neurons appear to function as feeding stimulant downstream of leptin signaling. Among other orexigenic neurons, galanin, and orexin producing neurons have been shown to play important role in food intake and body weight regulation [183,276,319]. Galanin and orexin can both elicit strong feeding behavior when injected centrally [81,175,176,268,276,287,320] and are expressed in hypothalamic areas associated with feeding and metabolic regulations [48,78,13,183,245,276,301]. However, no or modest effect of orexin on feeding has also been reported [85,130]. While galanin-positive neurons are present in the PVN, PFH, LH, and ARC [48,301], orexin-positive cells are localized in the LH and zona incerta [78,138,245]. Similar to NPY neurons, orexin and galanin producing neurons exhibit reciprocal changes in their activities in response to fasting and refeeding [183,219,276]. Furthermore, galanin and orexin neurons express leptin receptors [122,123,138] and STAT3 [123]; and leptin administration decreases galanin and orexin mRNA in the hypothalamus [194,267]. Our study also shows that leptin not only decreases galanin gene expression [267], it also reduces food intake induced by galanin [268]. Other evidences, such as (a) orexin neurons establish synaptic contacts with NPY and POMC producing neurons in the ARC [38,88,118,138] and these ARC neurons establish reciprocal contact with the orexin cells [38,88]; (b) orexin and NPY interacts with each other in stimulating feeding [82,145,147,271,361], (c) orexin and MCH neurons make synaptic contacts in the LH [21]; and d) galanin stimulates NPY secretion from hypothalamic neurons [27], suggest that interactions between the neurons of the ARC, LHA, and PVN play a critical role in energy homeostasis, and consequently leptin signaling in the hypothalamus. There are some evidences that suggest a potential role of recently identified galanin-like peptide (GALP) in mediating leptin action in the hypothalamus. GALP, a 60 amino acid peptide, was isolated from porcine hypothalamus by Ohtaki et al. [237] on the basis of its ability to bind and activate galanin receptors in vitro. Amino acids 9–21 of GALP are 100% homologous to the biologically active N-terminal (1–13) portion of galanin [237]. The role of GALP in energy homeostasis has been recently revealed. GALP is highly expressed in the ARC [149,150,161,179,323]. Although central administration of GALP has been shown to increase food intake [180,208], and PVN GALP stimulates feeding [301] and increases NPY release [302], GALP is also reported to decrease food intake [170]. Nevertheless, GALP neurons express leptin receptor [73,323], leptin increases GALP-expressing cells in the ob/ob mice [150], fasting decreases the number of GALP-expressing neurons and leptin administration restores GALP expressing cells in fasted rats [149]. In addition, leptin induces

GALP mRNA levels in the hypothalamus [174], and GALP mRNA levels are decreased in Zucker rats and in db/db and ob/ob mice [174]. These findings clearly suggest that leptin modify GALP neuronal activity in the hypothalamus. Recent reports also suggest that GALP co-expresses with a-MSH [324] and orexin receptor-1 [325] in some of the ARC neurons. Thus, GALP may play an important role in regulation of feeding behavior, and therefore, regulation of GALP by leptin may be potentially important in energy homeostasis. Recent demonstrations that ghrelin, a 28-amino acid peptide produced predominantly in the stomach [229], is also produced in a group of neurons adjacent to the third ventricle between the dorsal, ventral, paraventricular, and ARC, and that these neurons send efferents onto NPY, AgRP, POMC, and CRH neurons suggest that central ghrelin may play an important role in the neural circuitry controlling energy homeostasis [71]. In addition, peripheral or central injection of ghrelin induces food intake [181,229,333,358], and ghrelin receptors are localized in the hypothalamus, particularly in the NPY neurons [353]. Ghrelin induces food intake by engaging NPY/AgRP neurons in that antibodies or antagonists of NPY or AgRP reverses the effect of ghrelin on feeding [155,229,306], and ghrelin induces NPY/AgRP gene expression [9,154,155,300] and c-Fos expression in the NPY neurons [345]. Recent evidence also suggest that orexin pathway may mediate ghrelinÕs action in the hypothalamus [331]. Importantly, ghrelin blocks the effects of leptin on feeding, and prior leptin administration attenuates the effect of ghrelin on feeding [306], suggesting a functional interaction between leptin and ghrelin. Furthermore, Kohno et al. [164] have demonstrated that ghrelin directly interacts with NPY neurons in the ARC to induce Ca2þ signaling, and leptin attenuates ghrelin-induced Ca2þ increase. Thus, it appears that the regulation of ghrelinÕs effect on hypothalamic neurons, particularly NPY/AgRP neurons, may be one of the important mechanisms by which leptin controls food intake and body weight. It is however unknown whether leptin modify ghrelin gene expression in the hypothalamus—another possible mechanism by which leptin may transduce its anorectic action in the hypothalamus. 3.2. Anorectic peptide-producing neurons as leptin targets One of the major neural systems involved in leptin signaling in the hypothalamus has been the melanocortin system. Because the CNS melanocortin system exerts effects of opposite to NPY, this system has been studied extensively with regard to food intake and body weight regulation and therefore to the leptin signaling [35,61,62, 69,70,98,153,217,293,329]. The endogenous melanocortin implicated most strongly in the control of food intake and body weight is a-MSH, a product of POMC neurons [61,294], which binds with high affinity to melanocortin

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receptor-3 (MC3) and MC4 [61,62]. Furthermore, MC3 and MC4 receptors are highly expressed in the hypothalamus [223], mice lacking MC4 receptor become obese [142], MC4 receptor mutation causes obesity [142,223,336,337,362], and MC4 antagonist reverses the effect of leptin on feeding [297]. The regulation of POMC neurons by leptin has been evident in rats and mice [293,294,329]. Accordingly, fasting that decreases leptin induces POMC gene expression [293,329], POMC mRNA levels are reduced in ob/ob mice and leptin administration to these animals reverses this effect [217]. However, a small decrease [267] or no change [339] in hypothalamic POMC mRNA levels following central administration of leptin has been reported in ad lib fed rats, although leptin increases POMC mRNA levels in FD rats [293]. Also, chronic sc leptin infusion had no effect on POMC mRNA levels in ad lib fed rats [3]. Because POMC gene produces both a-MSH and b-endorphin, which have opposite effects on feeding, one being anorectic and the other orexigenic, the effect of leptin on POMC mRNA could vary depending on the experimental situation. Nevertheless, POMC producing neurons express leptin receptor [53] and STAT3 [121], and leptin induces suppressor of cytokine signaling-3 (SOCS3) and c-Fos in these neurons [90], suggesting direct action of leptin on POMC neurons. One of the mechanisms by which leptin acts on the POMC neurons is by reducing inhibitory c-aminobutyric acid (GABA) release from the NPY neurons [70]. In addition, NPY/ GABA cells innervate POMC neurons [137], suggesting interaction between NPY/GABA and POMC neurons. As mentioned previously, since NPY neurons co-express AgRP [39,120], an endogenous melanocortin antagonist [239], it appears that stimulation of POMC neurons by leptin is a result of direct action as well as by inhibition of NPY/AgRP neurons. Because orexin also excites GABAergic neurons in the ARC [40], it is possible that leptinÕs effect on POMC could also be mediated indirectly by decreasing orexin neuronal activity. Recent studies further show that POMC neurons are glucose responsive and express K-ATP channels [144]; and leptin activates K-ATP channel in the POMC neurons [70]. These findings along with the demonstration that mutation in POMC gene results in obesity [173], provide further evidence in support of a significant role of POMC in mediating leptin action and energy homeostasis. The importance of leptin regulation of POMC neurons in the hypothalamus is further demonstrated by the fact that POMC neurons express CART, a potent inhibitor of food intake [89,172,178,341]. CART mRNA in the hypothalamus is reduced in the leptin-deficient ob/ ob mice [172] and fasted rats [172]; and leptin normalizes CART mRNA in these animals [172]. Leptin induces SOCS3 mRNA in CART neurons. CART neurons express leptin receptors [89]. Leptin induces Fos expression in the hypothalamic CART neurons [89]. Thus,

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these findings altogether suggest a major role of POMC/ CART neurons in mediating leptinÕs action in the hypothalamus. In a recent study, Xu et al. [360] have demonstrated that brain-derived neurotrophic factor (BDNF) regulates energy balance downstream of MC4 receptor. Because central BDNF administration decreases food intake [228], and because MC4 agonist, MT11, increases BDNF mRNA in the VMH of food deprived mice [360], it is likely that MC4 mediated leptin action may involve BDNF. Because NT is an important centrally acting anorectic signal [24,45,162,186,198,260,314,352,354] and it is localized in those areas of the hypothalamus that are implicated in food intake and body weight regulation [94,143,151], we investigated the role of NT neurons in mediating leptin action in the hypothalamus. We demonstrated that daily icv injection of leptin significantly increased NT gene expression in the hypothalamus [267]. We also observed that administration of NT-antibody or specific NT receptor antagonist, SR48692, reversed the suppressive effects of leptin on food intake in rats [269]. In a recent study, leptin has been shown to induce NT gene expression in a hypothalamic cell line [72]. These findings plus the observations of synergistic action between leptin and NT in feeding [25] strongly suggest that this anorectic peptide has a significant role in mediating leptin action on feeding in the hypothalamus. In addition, NT also stimulates activity of the neurons producing corticotrophin-releasing hormone (CRH) [231,261], a potent anorectic signal [222]. The role of CRH in mediating leptin action has been investigated [291,334]. CRH is localized in the PVN [63]. Central administration of CRH inhibits food intake [8,169]. The findings that leptin increases CRH mRNA expression [140] and CRH release in the PVN [140]; and leptinÕs satiety action is attenuated by pre-treatment with a-helical CRH (a-CRH), a specific CRH antagonist, or with anti-CRH antibody [105,238,334]; and the recent demonstrations that treatment with a-CRH markedly attenuated leptin-induced c-fos expression in the PVN and the VMH [206], and attenuated leptin-induced uncoupling protein-1 (UCP1) expression in the brown adipose tissue [206] clearly suggest that CRH is an important mediator of leptin signaling in the hypothalamus in regulation of food intake and energy expenditure. Although it remains to be established whether NT antagonist reverses the effects of leptin on CRH or CRH antagonist reverses the effects of leptin on NT neuronal activity, the reports that NT increases CRH release [261] and NT antagonist, SR48692, reduces CRH mRNA levels in the PVN [231], suggest that leptinÕs action on CRH may be a direct and/or indirectly through the activation of NT neurons in the hypothalamus. In total, accumulated evidence including those cited above strongly suggest that leptinÕs action is mediated through a large number of orexigenic and anorectic

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Fig. 1. Schematic presentation of leptin action on hypothalamic peptides governing feeding. In this model, decrease in circulating leptin levels during fasting or deficiency in leptin action due to absence of leptin, leptin receptor mutation or leptin resistance would increase gene expression, peptide release, and action of orexigenic neuropeptides, such as NPY, MCH, GAL, and orexin; and decrease synthesis, release of anorectic peptides, such as a-MSH, NT, CRH, etc. resulting in increased food intake. Similarly, increased circulating leptin levels would inhibit not only the synthesis and release of the orexigenic peptides, but it would modify the action of these peptides after being released, and enhance activity of anorectic peptides including synthesis, release, and postsynaptic action, resulting in decreased food intake. We hypothesize that acute inhibition of food intake that occurs within an hour of leptin injection may be due to modification of postsynaptic action of orexigenic and anorectic neuropeptides.

neurons that are localized in the arcuate, LH/PFH- and PVN areas of the hypothalamus. Furthermore, it appears that leptin not only modifies the synthesis and release of the peptides, it also modifies (antagonistic or synergistic effect) the action of the peptides after being secreted (Fig. 1). Because of the established morphological and functional communications among the orexigenic and anorectic signal-producing neurons in the ARC–PVN–LH/PFH axis, compromise in interactions between orexigenic peptides or in their effects on anorectic peptides could be one of the major mechanisms of leptin action in the hypothalamus. It is also important to consider the possibility of unidentified orexigenic and anorectic peptide-producing neurons that could be involved in mediating leptin action in the hypothalamus in regulation of food intake and body weight.

4. Leptin signal transduction pathways in the hypothalamus 4.1. Leptin receptor Leptin receptor is a member of the class I cytokine receptor family [327,328]. Of the several alternative spliced isoforms (a–f, as well as others) of the leptin receptor (Ob-R), the Ob-Rb, which has the longest cytoplasmic domain (302 amino acids), is expressed in high

levels in the hypothalamus [51,182,214,328], and has been clearly demonstrated to be capable of initiating signal transduction [51,102,107,182,213,335]. Other forms of the Ob-R appear to have no (Ob-Re) or short cytoplasmic domains, but share the common extracellular domain [51,102,328], and their role in leptin signaling is not clear. The hypothalamus has the highest ratio of Ob-Rb to Ob-Ra [107], consistent with its role in mediating the effects of leptin on feeding and energy balance. Ob-Ra and Ob-Rc are highly expressed in choroid plexus and microvessels [135], suggesting their role in blood–brain barrier transport. Hypothalamic leptin binding [17] and leptin receptor gene expression [16,190,273] are up regulated following fasting, suggesting that reduction in circulating leptin seen during fasting may be involved in modifying leptin receptor expression. However, although leptin decreases Ob-R mRNA expression in the ob/ob mice [16], icv administration of leptin [242] or hyperleptinemia produced by adenovirus [273] does not alter Ob-R mRNA expression in rats. Thus, besides leptin, there may be other signals that modulate leptin receptor expression. Available evidence suggests that insulin may be involved in leptin receptor regulation [46,75]. 4.2. JAK2–STAT3 pathway Early recognition of leptin receptor as a member of the class 1 cytokine receptor super-family [328] resulted in prompt identification of the JAK–STAT pathway as the major pathway of leptin signaling [20,28,107,108, 257,335,350, see Fig. 6]. In leptin-signaling cascade, the binding of leptin to the receptor results in phosphorylation and activation of JAK2. Activated JAK2, in turn, mediates phosphorylation at the specific receptor tyrosine residue, which then serves as a docking site for STAT3. STAT3 becomes phosphorylated, and phosphorylated STAT3 becomes dimerized and translocated to the nucleus where they bind and regulate expression from target promoter [76]. Although leptin induces JAK2 phosphorylation in BaF3 cells transfected with Ob-Rb [108], McCowen et al. [210] reported that a single iv injection of leptin, which induced STAT3 activation, failed to induce JAK2 phosphorylation in the rat hypothalamus. However, we observed an increased JAK2 phosphorylation in the hypothalamus following 2–4 days of continuous central leptin infusion [240]. Amongst several STAT proteins, leptin only activates STAT3 in the hypothalamus [210,335] including in the ARC, LH, VMN, and DMN areas [141]; indicating STAT3 as one of the major intracellular mediators of leptin signaling in the hypothalamus. Several leptin target neurons including NPY, POMC, galanin, and orexin neurons have been shown to express STAT3 [121,123], and it is likely that other leptin sensitive neurons that express leptin receptor do also express

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STAT3, unless leptin signaling is mediated by a mechanism that does not involve STAT3 activation in these neurons. Although Munzberg et al. [224] demonstrated leptin induction of STAT3 phosphorylation in hypothalamic POMC neurons, leptin-induced activation of STAT3 in other neurons including those producing NPY, MCH, orexin, and galanin is yet to be documented. It is also known that Tyr 1138 of Ob-Rb mediates activation of STAT3 during leptin action [11,20,313,350]. Recently, Bates et al. [19] have shown that Ob-Rb-STAT3 signaling is required for leptin regulation of energy balance but not reproduction. Specifically, these authors showed that in transgenic mice in which Tyr 1138 of Ob-Rb was replaced with a serine residue, STAT3 activation by leptin was impaired and caused obesity without affecting reproduction. Furthermore, disruption of Ob-Rb-STAT3 signaling resulted in dysregulation of leptin action on POMC neurons without compromising the effects of leptin on NPY neurons, suggesting the inhibition of NPY by leptin may be independent of STAT3 signaling [19]. Because leptin activates SOCS3 in the NPY neurons [90] and because induction of SOCS3 is dependent on STAT3 activation [11] and NPY neurons express STAT3 [121], it is critical to demonstrate whether leptin induces STAT3 in NPY neurons. Nevertheless, other pathways of leptin signaling (see below) including regulation of cAMP may play crucial role in leptinÕs action on NPY and possibly in many other neurons. Cumulative evidence suggests that JAK–STAT pathway of cytokine signaling is under the negative feedback control of a family of SOCS proteins [95,136,227,316]. The member of SOCS family of proteins contains an Src-homology (SH2) domain and a Cterminal SOCS box [136]. SOCS proteins are induced by a variety of cytokines and act as a negative regulator of cytokine signaling. Among eight SOCS proteins [171,230], leptin specifically induces SOCS3 mRNA levels in the hypothalamus [18,29,31,90] and activates SOCS3 expression in NPY and POMC neurons [18,90]. In mammalian cell lines, over expression of SOCS3 blocked leptin-induced signal transduction by inhibiting leptin-induced JAK2 phosphorylation [31,32]. Furthermore, SOCS3 also inhibits leptin signaling by binding to phosphorylated Tyr-985 [11]. SH2-containing phosphatase-2 (SHP-2), another mediator of leptin signaling [32], also competes with SOCS3 for p-Tyr-985 of Ob-Rb [31]. Thus, an alteration in any of these mechanisms could compromise inhibitory feedback action of SOCS3 during leptin signaling. 4.3. PI3K–PDE3B–cAMP pathway, an alternative pathway of leptin signaling Recent studies in peripheral tissues (pancreatic bcells, hepatocytes and adipocytes) have demonstrated

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that leptin induces an insulin-like signaling pathway involving PI3K-dependent activation of PDE3B and eventual reduction in cAMP levels [369,370]. Intracellular cAMP levels are regulated by adenylyl cyclase and cAMP phosphodiesterase (PDEs) [74,119]. Cyclic nucleotide PDEs are a large super family of enzymes consisting currently of 20 different genes sub-grouped into 11 different PDE families [23,67,79,204,311]. PDE3B, one of the two members of type 3 PDE family of genes [23], exhibits high affinities for both cAMP and cGMP, but prefer cAMP as the substrate [23,67,79,204]. In addition to its localization in several peripheral tissues such as adipose tissue, liver, pancreatic b-cells, kidney and testes, PDE3B is also localized in the CNS [211,216,225,255,322] including the hypothalamus. PDE3B plays a major role in regulation of intracellular cAMP levels by several hormones. For example, PDE3B is activated by insulin in adipocytes [368] and hepatocytes [79], resulting in decreased cAMP levels. Furthermore, the inhibition of glucagon-like peptide 1-stimulated insulin secretion by leptin in pancreatic b-cells, and the anti-glycogenolytic function of leptin in the rat primary hepatocytes are mediated through a P13K-dependent activation of PDE3B and subsequent reduction of cAMP [369,370]. The idea that regulation of hypothalamic cAMP levels could play a critical role in feeding and body weight regulation, and therefore in leptin signaling in the hypothalamus, is supported by the following evidence. First, central injection of either a cAMP analog, or the agents that increase endogenous cAMP, stimulates feeding in satiated rats [109–111]. Second, intracerebroventricular dibutyryl cAMP administration induces hypothalamic levels of NPY [5]. Finally, leptin also modifies cAMP response element (CRE)-mediated gene expression including that of NPY neurons in the hypothalamus [305]. Thus, we assessed whether PDE3B-activation dependent reduction in cAMP levels is involved in anorectic and body weight reducing effects of leptin [371]. First, we observed that while cilostamide, a specific PDE3 inhibitor [22], reversed the anorectic effect of central administration of leptin on food intake, R0-201724, a specific PDE4 inhibitor [22], failed to reverse this effect of leptin (Fig. 2). In addition, body weight reducing effect of daily leptin injection for three consecutive days was completely reversed by the PDE3 antagonist. Second, we demonstrated that within 45 min of leptin injection to the overnight fasted rats, PBE3B activity was significantly increased in association with a reduction in cAMP levels in the hypothalamus (Fig. 3). These findings suggested that activation of the PDE3B– cAMP pathway is an important mechanism of leptin signaling in the hypothalamus. If PDE3B–cAMP pathway plays a critical role in leptin signaling, then it was necessary to demonstrate whether this pathway interacts

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Fig. 2. Cilostamide, a PDE3 inhibitor, reverses the satiety action of leptin in male rats that are fed ad libitum, but RO-20-1724 (RO-20), a PDE4 inhibitor, does not. Rats were first injected ICV into the third ventricle with artificial cerebrospinal fluid (aCSF) or 4 lg of leptin and dimethyl sulphoxide (DMSO) or one of the PDE inhibitors; then were injected 1 h later with DMSO or the inhibitors. Data are means
SEM for the number (n) of animals in parentheses.  p < 0:05, relative to others except the groups with * or **. (Adapted from [371].)

with the JAK2–STAT3 pathway of leptin signaling in the hypothalamus. To demonstrate this we examined the effects of PDE3B inhibition by cilostamide on STAT3 activation in the hypothalamus. We reasoned that if these two pathways crosstalk then cilostamide should reverse the effects of leptin on STAT3 activation. We found indeed that this was the case, because cilostamide reversed the effects of leptin on p-STAT3 levels and DNA-binding activity of STAT3 in the hypothalamus (Fig. 4). These findings together with our unpublished observation that PDE3B is localized in the hypothalamus, particularly in the ARC, VMN, DMN, PVN, LH, and PFH areas (Fig. 5), which are implicated in food intake and body weight regulation, strongly suggest that the PDE3B–cAMP pathway plays a very important role in transducing leptin action in the hypothalamus. In various non-neuronal tissues, PI3K, in association with the insulin receptor substrate IRS1/2, is an upstream regulator of PDE3B [4,253,256,370]. We also observed an activation of IRS1-associated PI3K activity in the hypothalamus within 45 min of leptin injection [371, see Fig. 3]; an observation that was also supported by Niswender et al. [232]. These authors further showed that PI3K inhibitor reversed the effect of leptin on food intake [232]. While in non-neuronal tissues, PKB has been demonstrated to be an upstream regulator of PDE3B [79,370], it is yet to be examined whether this is true for the hypothalamus. Overall, these findings all together indicate that a PI3K–PDE3B–cAMP pathway interacting with the JAK2–STAT3 pathway constitutes a critical component

Fig. 3. Leptin activates PI3K (A), and PDE3B (B) and reduces cAMP (C) levels in rat hypothalamus. For PI3K activity, rats fasted for 24 h were injected ICV with 4 lg of leptin or vehicle (aCSF) and 45 min later, the medial basal hypothalamus (MBH) were processed for the assay of PI3-kinase activity. An aliquot of the hypothalamic homogenate (1 mg) was pre-cleared with 40 ll of 50% protein-G–agarose conjugate for 30 min before incubated under shaking with an antibody against IRS-1 overnight at 4 °C. The assay of PI3-kinase activity associated with the IRS-1 immunoprecipitate and subsequent thin-layer chromatography were carried out according to a previously described protocol (Avanti Polar Lipids, AL) with phosphatidylinositol as a substrate in the presence of [c-32 P]ATP. The phosphatidylinositol 3phosphate (PI–P3 ) and PI-P2 products were quantitated using densitometer and NIH image 1.6 software. PDE3B activity and cAMP levels were examined in the similar experiments. PDE3B activity was measured by previously described method [369,370], using 1 lM cAMP as a substrate; and the activity was adjusted to the quantity of immunoprecipitated PDE3B as shown on western blot, and expressed as pmol hydrolyzed cAMP/min/density unit of PDE3B. cAMP levels were measured by RIA kit (NEN) and expressed as relative (%) to vehicle group. Data are means
SEM for the number (n) of animals in parentheses.  p < 0:05 versus vehicle treated group. (Adapted from [371].)

of leptin signaling in the hypothalamus (Fig. 6). We hypothesize that PI3K–PDE3B–cAMP signaling pathway may mediate leptinÕs action in the hypothalamus in general. A further understanding of this signal transduction pathway would therefore be critical to unraveling the molecular mechanisms of hypothalamic action of leptin in normal states and during the development of leptin resistance seen in obesity and related disorders.

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tion in cAMP levels. As mentioned above, since cAMP stimulates food intake [109–111] and cAMP analog induces NPY gene expression in the hypothalamus [5], we hypothesize that PDE3B activation-dependent reduction in cAMP levels by leptin may be responsible for modifying NPY gene expression [267,317] and NPYÕs action on feeding [268]. Similarly, insulinÕs inhibitory action on NPY neuronal activity [265,289,290,342] may involve the activation of PI3K–PDE3B–cAMP pathway of intracellular signal transduction. 4.4. Other potential pathways

Fig. 4. Cilostamide reverses the effect of leptin on STAT3 activation in the hypothalamus. Fasted (24 h) rats were injected ICV with DMSO or cilostamide (10 lg) followed 30 min later by leptin (4 lg) or aCSF. (A) Top, western blot of STAT3 and p-STAT3 in the mediobasal hypothalamic (MBH) extracts. Bottom, densitometric analysis of the immunoreactive bands for p-STAT3 and expressed as relative (%) to vehicle group (DMSO + aCSF). (B) Top, DNA binding activity of STAT3 in the MBH as determined by an electrophoretic mobility shift assay using a 32 P-labeled M67-SIE oligonucleotide probe. Top right, DNA binding activity is specific to p-STAT3 because a ÔsupershiftÕ did not occur in the presence of anti-SOCS3 antibody. Bottom, results obtained by phosphor imaging and expressed as relative (%) to vehicle. Data are means
SEM for the number (n) of animals in parentheses.  p < 0:05 as compared to all other groups. The reversal of STAT3 activation by PDE3B inhibition implies a crosstalk between the JAK2STAT3 and PDE3B–cAMP pathways in transducing leptin action in the hypothalamus. (Adapted from [371].)

Because of the recent reports of stimulation of PI3K by insulin in the hypothalamus [235], reversal of insulinÕs anorectic action by PI3K inhibitor [235] and localization of PI3K immunoreactive neurons in the hypothalamus [233], it appears that stimulation of PI3K may be a common pathway for both leptin and insulin signaling in the hypothalamus [234]. In this regard, as seen in peripheral tissues [127,321], activation of PI3K has been proposed to mediate acute membrane effect of leptin and insulin [234] including the activation of ATP-sensitive potassium channel in the hypothalamus [128,253,312]. Since insulin stimulates STAT3 in the hypothalamus [46], it remains to be determined whether, like leptin signaling [371], insulin signaling through STAT3 pathway also requires PDE3B activation dependent reduc-

Among other potential pathways, an SHP2–GRB2 (growth receptor bound 2)-Ras–Raf–MAPK/ERK (mitogen-activated protein kinase/extracellular signal regulated kinase) pathway has been proposed in leptin receptor signaling [11,32]. In support of this pathway is the demonstration that leptin induces MAPK/ERK activity and egr-1 mRNA levels in the hypothalamus [32]. In addition, the findings that: (i) ERK activation is required for Ob-Rb mediated c-fos gene expression in cell line (11), (ii) central or peripheral administration of leptin induces c-fos in the hypothalamus [93,338,356, 363], and (iii) leptin induces c-fos in POMC neurons [89], suggest a potential role of this pathway in leptin signaling. Furthermore, an ERK dependent STAT3 Ser727 phosphorylation and DNA binding activity by leptin has been recently documented in macrophages [236]. It is however interesting to note that disruption of Ob-RbSTAT3 signaling does not compromise ERK activation in the hypothalamus, suggesting that ERK activation may be independent of STAT3 signaling [19]. Nevertheless, the physiological role of ERK-egr-1 activation in mediating leptin action in the hypothalamus is yet to be established. One other important issue is whether ERK activation in the hypothalamus is mediated by SHP2. In growth factor receptor signaling, such as platelet-derived growth factor receptor, tyrosine phosphorylated SHP2 acts as an adaptor molecule that recruits Grb2 and Sos, members of the Ras/MAPK/ERK signaling pathway. Using dominant negative SHP2 construct, Bjorbaek et al. [32] reported that SHP2 is essential for leptin-induced MAPK/ERK phosphorylation by Ob-Rb. However, Carpenter et al. [44] reported that activation of leptin receptor induces tyrosine phosphorylation of SHP2, but SHP2 appears to act as negative regulator of STAT3mediated transcription. Similarly, Li and Friedman [189] observed that activation of SHP2 by the leptin receptor resulted in decrease phosphorylation of JAK2, and thereby, SHP2 acts as negative regulator of leptin signaling. All these studies have been conducted in cell lines, therefore, although SHP2 has been found in the bovine and mouse hypothalamus [189], precise role of SHP2 in leptin signaling in the hypothalamus is yet to be resolved.

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Fig. 5. Bright-field photograph showing phosphodiesterase 3B (PDE3B) immunoreactive cells in rat hypothalamus. Adult male rat anesthetized with pentobarbital was perfused intracardially with 0.9% saline kept at room temperature, followed by ice-cold 4% paraformaldehyde in 0.1 M phosphate buffer, The brain was post-fixed in the same fixative for 4–5 h, and then kept in 25% sucrose solution at 4 °C until it sank. Thereafter, brain was frozen on dry ice and coronal 25 lm free-floating sections were cut through the hypothalamus on a freezing microtome, and stored in cryoprotectant at )20 °C until use. PDE3B-ir cells in the sections were detected by immunocytochemical (ICC) method, using tyramide amplification kit (NEN), primary PDE3B antibody (1:1000 dilution, SC-11838, Santa Cruz, CA), biotinylated anti-goat secondary antibody (1:200, BA-500, Vector Laboratories Inc, Burlingame, CA) and the avidin–biotin–horseradish peroxidase complex (Vector elite kit, Vector Laboratories), and were visualized with 5 min incubation with diaminobenzidine hydrochloride (Sigma) in the presence of hydrogen peroxide. (A) PBE3B-ir positive cells in the paraventricular nucleus (PVN), lateral hypothalamus (LH) and supraoptic nucleus (SON). (B) Immunocytochemical reaction without primary antibody in a section through the median eminence (ME)arcuate (ARC) area; (C) PDE3B-ir positive cells in the ARC, ventromedial nucleus (VMN), dorsomedial nucleus (DMN), and parafornical hypothalamic area (PFH). PDE3B-ir was completely blocked in the presence of PDE3B blocking peptide (SC-11838P, Santa Cruz) (data not shown). Localization of PDE3B in the ARC–VMN–DMN–PVN– LH axis along with activation of PDE3B in the hypothalamus (see Fig. 3) strongly suggests a physiological role of PDE3B in leptin signaling in the hypothalamus.

Protein tyrosine phosphatase 1B (PTP1B) has recently been shown to regulate leptin signal transduction in vivo [52,365] and in vitro [158,365]. It is suggested that PTP1B acts as a negative inhibitor of leptin receptor signaling primarily via dephosphorylation of JAK2 [52,365]. Because PTP1B is localized in the brain including the hypothalamic areas where Ob-Rb is localized [365], and because PTP1B knockout mice are resistant to diet-induce obesity [87,163] and become more sensitive to leptin [52], PTP1B appears to play a significant role in leptin signaling in the hypothalamus. It is interesting to note that SOCS3 is also a negative regulator of cytokine signaling, and as described above, SOCS3 inhibits leptin signaling by binding to JAK2 and leptin receptor [11,31,32] and SOCS3 also competes with SHP2 for its binding to Ob-Rb [31]. Thus, while SHP2, SOCS3, and PTP1B seem to play important role in regulation of leptin signaling, it is critical to understand the interactions among these and other unidentified negative regulator(s) of leptin signaling in the hypothalamus to further our understanding on leptin signaling in normal and

Fig. 6. Schematic of leptin intracellular signal transduction in the hypothalamus. Leptin binding to itÕs receptor (Ob-Rb) induces activation of Janus kinase (JAK), receptor dimerization, and JAK-mediated phosphorylation of the intracellular part of the receptor, followed by phosphorylation and activation of signal transducer and activators of transcription-3 (STAT3). Activated STAT3 dimerizes, translocates to the nucleus and tans-activates target genes, including suppressor of cytokine signaling-3 (SOCS3), neuropeptide Y (NPY) and proopiomelanocortin (POMC). Our evidence suggests that leptin also activates phosphatidylinositol 3-kinase (PI3K), and phosphodiesterase 3B (PDE3B) and reduces cAMP levels in the hypothalamus, and that the PI3K–PDE3B–cAMP pathway interacting with the JAK2–STAT3 pathway constitutes a critical component of leptin signaling in the hypothalamus. We hypothesize that defects in either one or both of the signaling pathways may be responsible for the development of leptin resistance seen in obesity. Other potential signaling pathways including the involvement of SHP2–GRB2–Ras–Raf–MAPK/ERK pathway and PTP1B in regulating leptin action in the hypothalamus are left out of this scheme to avoid complication in the figure. Furthermore, the role of SHP2–GRB2–Ras–Raf–MAPK/ERK pathway in leptin signaling in the hypothalamus is not clearly understood. Also the role of cofactors and co-activators, such as p300/CBP and NcoA/SRC1a, in STAT3 transcriptional activity is yet to be established in the hypothalamus.

during the development of leptin resistance. It is undoubtedly one of the most interesting areas of future investigation in leptin signal transduction mechanism. Thus, intracellular leptin signal transduction mechanism is much more complicated than it was originally thought.

5. Mechanisms underlying the central Leptin resistance Because human obesity, in the majority of cases, cannot be attributed to defects in leptin or its receptor [54,64,65,115,209], and because obese humans are hyperleptinimic [43,57,64,129,193,202,292], it is suggested

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that obese individuals are, in general, leptin-resistant [57,202]. Obese humans, and mice made obese by dietary manipulation, have elevated levels of circulating leptin but maintain a normal food intake [57,125,202]. Thus, it is likely that an extended period of exposure of the brain, especially the hypothalamus, to a high level of leptin may result in the development of central leptin resistance. 5.1. Defective leptin transport through blood–brain barrier (BBB) in obesity A defective leptin transport to the hypothalamus is thought to be one of the many defects in obesity. The evidence in support of this notion has come from the findings that: (i) the cerebrospinal fluid: plasma leptin ratio is lower in obese individuals compared to lean controls [43,292]; (ii) peripheral leptin administration to hyperleptinimic DIO mice does not have any effect on food intake or body weight, while central injection of leptin is effective in decreasing food intake and body weight in these mice [340], (iii) although peripheral administration of leptin to DIO mice does not activate STAT3 in the hypothalamus, icv administration does induce STAT3 activation, albeit 75% reduction than control [86], and (iv) leptin transport through BBB is reduced in several models of obesity including the DIO [13,41]. The molecular mechanism behind apparent defect in leptin access or transport is not clearly understood. While short isoforms of the leptin receptor have been implicated in leptin transport through BBB [30,114], and both Ob-Ra and Ob-Rc are highly expressed in cerebral microvessels, no change in mRNA levels in either of these isoforms has been reported in DIO mice [86,135]. However, in DIO rats, there is an increased expression of Ob-Ra mRNA levels in cerebral microvessels [33], Nevertheless, it is necessary to determine whether a decrease in brain uptake of leptin is the cause or consequence of obesity. Thus, a time course study in DIO animals before and during the development of obesity is of significant importance. 5.2. Central leptin resistance in DIO animals Using male Wistar rats, Widdowson et al. [351] demonstrated that while leptin injection into the lateral cerebroventricle resulted in a dose dependent decrease in food intake in the animals that were in normal laboratory diet, the anorectic effect of leptin was attenuated in the diet-induced obese rats. This is probably the first demonstration of the occurrence of central leptin insensitivity in DIO animals. Recently, reduced sensitivity to central leptin in decreasing food intake has also been reported in DIO prone Sprague–Dawley rats [185]. Halaas et al. [125] demonstrated that AKR/J mice, that are lean on a chow diet but have a heritable disposition

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toward developing obesity, when fed high-fat (HF) diet, were sensitive to peripheral leptin after 14 weeks on HF diet. These authors also demonstrated that AY mice develop central leptin resistance. In other studies, a reduced sensitivity to central leptin administration has been reported in mice that were on HF-diet for 19 weeks, but not during one or 8 weeks of HF dieting [192]. In a recent study, Bowen et al. [37] have demonstrated that 6- to 7-weeks-old mice that have been weaned onto a HF diet became obese and showed attenuated response to central effects of leptin on food intake and body weight without a compromise in peripheral effect of leptin. Furthermore, obesity due to HF diet decreases lumber sympathetic nerve activity and cardiovascular responses to intracerebroventricular leptin in female rats [195]. These findings strongly suggest that central leptin resistance also contributes to the development of diet-induced obesity and related disorders, and therefore understanding the mechanisms of central leptin resistance has been the subject of intensive research. One of the obvious assumptions is that leptin resistance is due to a defective leptin receptor signaling in the hypothalamus. As described above, Ob-Rb, the long signaling from of the leptin receptor, is highly expressed in the hypothalamus and modulated by nutritional status in that fasting increases Ob-Rb gene expression [16,190,273] and leptin binding in the hypothalamus [17]. Also hypothalamic leptin receptor mRNA levels are increased in ob/ob [16,139] and db/db [16] mice, models of obesity that are characterized by a lack of leptin and functional leptin receptors, respectively. Fasting effect on hypothalamic leptin receptor mRNA levels seen in lean mice is absent in the ob/ob mice [139,190], and leptin decreases hypothalamic leptin receptor mRNA expression in ob/ob mice [16]. Thus altered leptin levels and or defective leptin action are associated with changes in leptin receptor gene expression in the hypothalamus. However, the reports on leptin receptor gene expression in the hypothalamus during diet-induced obesity are variables. For example, El-Hasami et al. [86] reported that there was no change in leptin receptor gene expression in the mice feeding HF diet for 18 weeks. By contrast, Lin et al. [192] reported that the mice on HF diets for 19 weeks had less OB-Rb mRNA levels but those on HF diets for only 8 weeks had increased Ob-Rb mRNA levels in the ARC. We have also shown that leptin receptor gene expression does not change in rats on HF diets for 9 weeks [273]. However, despite unaltered Ob-R gene expression in the hypothalamus, there have been reports of decreased receptor protein levels in DIO rats [201] and reduced leptin signaling in DIO mice [86]. The discrepancies seen in data for leptin receptor gene expression in DIO animals in different studies could be due to the techniques used for mRNA measurement (in situ hybridization,

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RT-PCR, ribonuclease protection assay), strain difference, period of treatment, or due to the data collected for whole hypothalamus versus specific hypothalamic nuclei. Because these studies examined changes in Ob-R gene expression in DIO animals in the fed state [86,192,201] and because leptin receptor gene expression is modified by nutritional status [16,190,273], we examined whether there is any defect in nutritional regulation of leptin receptor in DIO. We observed that rats fed with HF diets for 9 weeks had similar levels of hypothalamic ObRb mRNA and Ob-Rtot (all receptor isoforms) mRNA levels in the fed state, as reported by others [86,201,242]. However, in the fasted (18-h) state, Ob-Rb mRNA levels were significantly increased in standard chow fed rats as compared to DIO rats (Fig. 7). This difference was due to a failure of Ob-RB mRNA to increase in response to an overnight fast in DIO [273]. Thus the finding that fasting was unable to induce leptin receptor gene expression in the hypothalamus of DIO animals suggests a defective leptin signaling in the hypothalamus of these animals. This notion is supported by the study of El-Hasami et al. [86] demonstrating approximately 75% reduction in hypothalamic STAT3 DNA binding activity in response to icv administration of leptin in overnight fasted DIO mice. While it is not clear whether

Fig. 7. Diet-induced obesity (DIO) is associated with a defective nutritional regulation of leptin receptor gene expression. Male Wistar rats were fed a standard chow diet (SC) or were fed a high fat diet for 9 weeks to induce DIO. At the end of this period, animals underwent an 18-h overnight fast (SC-FAST) and DIO-FAST) or continued feeding ad libitum (SC-FED and DIO-FED). Subsequently, all animals were killed and the hypothalami were processed for ribonuclease protection assay. Representative phosphor images showing the level of Ob-Rb mRNA, Ob-Rtot mRNA (all isoforms of the leptin receptor) and bactin mRNA in the hypothalamus of SC-FED and SC-FAST (A) and DIO-FED and DIO-FAST (C). Graphical representation of the total dataset showing the fold difference of Ob-Rtot mRNA and Ob-Rb mRNA between SC-FAST and SC-FED (B) and between DIO-FAST and DIO-FED (D). Data are means
SEM for the number of animals shown in parentheses.  p < 0:05 between the SC-FAST and SC-FED. Note that while fasting induced Ob-Rb gene expression in SC rats, it failed to induce Ob-Rb gene expression in DIO rats, suggesting a nutritional defect in leptin receptor gene expression in DIO, and this may contribute to central leptin resistance. (Adapted from [273].)

increased hypothalamic leptin binding seen in normal animals after fasting [17] is also altered in DIO animals, our study clearly suggests that leptin resistance in the DIO animals may be due to insensitivity of leptin receptor gene expression to fasting. Although there is no definitive study addressing whether nutritional regulation of leptin receptor gene expression plays any physiological role in mediating leptin action on food intake and body weight, in ad lib fed rats leptin receptor mRNA levels in the hypothalamus increase at the time of lights off (onset of ingestive behavior) and decreased gradually thereafter [359]. These results suggest that increased leptin receptor gene expression before the onset of feeding in normal ad lib fed animals may play an important role in mediating action of postprandial increased leptin [359]. Thus, impaired nutritional regulation of leptin receptor gene expression could alter food intake and body weight in DIO. Since STAT3 activation is one of the important mechanisms of leptin signaling, the demonstration of 75% reduction in leptin-induced STAT3 activation in DIO mice reported by El-Hasami et al. [86] suggests that a defective STAT3 signaling in the hypothalamus may be responsible for central leptin resistance in DIO. Although a defective nutritional regulation of leptin receptor gene expression [273] may be one of the reasons of reduced STAT3 signaling [86], it is not clear whether there is a defect in leptin receptor phosphorylation and or JAK2 activity. While overexpression of SOCS3 in mammalian cells antagonizes proximal leptin signaling [31], and protein inhibitor of activated STAT (PIAS3) antagonizes STAT3 DNA binding activity [57], ElHasami et al. [86] reported no increase in either SOCS3 or PIAS3 mRNA levels in the hypothalamus following 18 weeks of HF dieting. Similarly, Peiser et al. [242] reported no change in either SOCS3 or PIAS3 gene expression in rats on HF diet for 15 weeks. However, it remains to be determined whether there is any change in protein levels of SOCS3 or PIAS3 in the hypothalamus of DIO animals. It is quite possible that interactions among several negative regulators of STAT3 signaling, such as SOCS3, PIAS3, PTP1B, and SHP2, could be altered and thus may produce reduced leptin response in the hypothalamus without noticeable change in their protein levels. Because leptin resistance may be due to a defect in leptin signaling in leptin target neurons, many studies have examined changes, if any, in various leptin target neurons in DIO animals. Levin and Dunn-Meynell [184,185] reported that DIO-prone SD rats maintained on high-energy (HE, 31% fat) diet had significantly increased levels of ARC NPY mRNA within 2 weeks despite hyperleptinemia. However, after 12 weeks on HE diet, when the rats were more obese, ARC NPY mRNA levels were decreased. The authors suggested that the elevated ARC NPY expression in DIO-prone

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rats predisposes them to become obese in the presence of HE diet, but decrease ARC NPY expression may play a role in defending the body weight once they become obese. Ziotopoulou et al. [372] demonstrated that during the first 2 days of HF (42% fat) feeding, C57BL/6J mice showed hyperphagia and hyperleptinimia in association with a decrease in hypothalamic NPY and AgRP mRNA levels. However, after 1 week, both NPY and AgRP mRNA levels were comparable to control mice. Furthermore, while there was no change in POMC mRNA levels during the first week of HF feeding; after 2 weeks, POMC mRNA levels were increased in association with an increased calorie intake [372]. Again these authors also concluded that increase in POMC mRNA levels might be a second defense against obesity. Lin et al. [192] reported that at 8 weeks of HF (59% fat) feeding, ARC NPY mRNA levels were significantly decreased, without any change in POMC mRNA levels; however at 19 weeks, both NPY and POMC mRNA levels were significantly decreased. In another study, Wang et al. [343] showed that SD rats fed 60% fat diet for 8 weeks had significantly increased CART mRNA levels in the hypothalamus. Furthermore, increase circulating leptin levels with adenovirus-leptin treatment did not alter CART mRNA levels or food intake in these HF rats. Since CART is an anorectic signal [172,178], and CART is known to be up-regulated by leptin [89,172] and is also co-localized with POMC in the ARC [89,341], increased CART mRNA levels in DIO rats could also be involved in second defense against obesity. It is to be noted that the diet used in these studies had variable amount of fat (31–60%), which may modify gene expression of NPY/AGRP or POMC/CART independent of circulating leptin levels. Increase in NPY and AgRP mRNA levels, but not in MCH mRNA, in association with hyperleptinemia has also been reported in DIO rats on HF diet for 6 months [103]. In another study, rats on HF diets for 2–8 weeks had increased AgRP levels in the hypothalamus without any change in a-MSH or POMC levels [126]. Torri et al. [330] reported that DIO as a result of feeding cafeteria diet was associated with increased hypothalamic POMC mRNA in rats. Furthermore, Bergen et al. [26] showed that the mice (A/J mice) that are resistance to DIO, when subjected to 14 weeks of HF feeding, had increased POMC mRNA and decreased NPY mRNA levels; however, HF feeding for 14 weeks had no effect on either NPY or POMC gene expression in C57BL/6J mice. Overall, it appears that changes in NPY/AGRP and POMC neurons are dependent on species, strain and duration of dieting. Furthermore, the changes seen following HF diet are most likely due to several factors, including circulating levels of leptin, insulin, ghrelin and other factors and fat content in the food and duration of exposure to HF. While all these studies have examined the

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effects of DIO on some of the orexigenic and anorectic neuropeptides, and there may be changes in other neuropeptidergic neurons; it is important to demonstrate whether leptin sensitivity to these neurons are altered, and how and when does it occur during the development of DIO. 5.3. Leptin resistance following chronic central leptin infusion The increase in leptin levels as early as day-1 of high fat feeding [372], suggests that hypothalamus is subjected to gradual increase in circulating leptin levels during the development of DIO. Thus, central leptin resistance seen in various studies [37,125,185,191, 195,351] could be due to a consequence of chronic exposure of high levels of leptin to the hypothalamus, in addition to a defect in leptin transport. To address this issue, we developed a rat model of chronic central leptin infusion [270]. This was based on a mouse model developed by FriedmanÕs group at the Rockefeller University [125]. As shown in mice [125], we observed that in rats chronic central leptin infusion (160 ng/h) via Alzet pump resulted in an initial marked decrease in food intake followed by a recovery to the normal levels by two weeks of infusion, and food intake remained normalized throughout the rest of the 4 weeks of leptin infusion. These results suggest that rats develop resistance to the satiety action of leptin. In contrast, body weight was gradually decreased to reach a nadir by 10– 12 days of infusion and thereafter, it remained stabilized at reduced level despite the normalization in food intake. However, withdrawal of chronic leptin infusion resulted in hyperphagia, and body weight was mostly normalized by 22 days post leptin (Fig. 8). Although, the stabilization of body weight at a reduced level in the face of normal food intake is of considerable interest, the underlying mechanism behind this remains to be determined. Because chronic leptin infusion resulted in the development of resistance to the satiety action of this peptide, we reasoned that this rat model could be used to decipher some of the underlying mechanisms of central leptin resistance. Because NPY plays an important role in food intake and body weight regulation, and because NPY is one of the primary targets of leptin action in the hypothalamus, we tested the hypothesis that resistance to the satiety action of leptin seen during chronic central leptin infusion was due to the development of leptin resistance in the NPY neurons. This hypothesis predicted that NPY gene expression should be decreased during early period of leptin infusion when food intake remained decreased, and normalization of food intake on days 14–16 of infusion should be accompanied by unaltered NPY gene expression. Indeed, we observed that NPY gene expression was decreased

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Fig. 8. Effect of chronic central leptin infusion followed by leptin withdrawal on body weight (upper panel) and food intake (lower panel) in rats. Rats were infused with artificial cerebrospinal fluid (aCSF) via Alzet osmotic minipump (1 ll/h) for 7 days before infusion with either recombinant mouse leptin in phosphate-buffered saline (PBS) at a dose of 160 ng/0.5 ll or PBS alone for 28 days (experimental period). Thereafter, leptin was withdrawn and aCSF was infused for approximately 3 weeks. Note that after the initial decrease in food intake, rats developed resistance to the satiety action of leptin, and withdrawal of the chronic leptin infusion resulted in hyperphagia. Using this rat model, we have demonstrated that NPY neurons develop leptin resistance (see Fig. 9) despite a sustained elevation of the JAK–STAT pathway of leptin signaling throughout 16 days of chronic leptin infusion (see Fig. 10). Thus, this rat model can be used to decipher some of the underlying mechanisms of central leptin resistance. (Adapted from [273].)

on days 3–4 of leptin infusion, and this decrease was primarily in the rostral and middle part of the arcuate nucleus. On the other hand, on days 13–16 of leptin infusion, NPY gene expression in the hypothalamus was not significantly different from that observed in the control rats (Fig. 9). This effect of leptin on NPY gene expression was also not due to a reduced food intake, because the rats that were paired-fed to those of the leptin group exhibited increased NPY gene expression. Furthermore, our preliminary study [241] shows that hypothalamic POMC and NT gene expression is increased on day 4 of leptin infusion, but remains unaltered as compared to those of control on day 16 of leptin infusion. Thus, normalization of food intake following chronic leptin infusion may be due to relative increase in NPY gene expression and or a relative decrease in POMC and NT gene expression. These results clearly suggest the development of leptin resistance in the hypothalamus, particularly in the NPY, POMC, and NT neurons following chronic central leptin infusion and support that this rat model may be used to further our understanding on central leptin resistance.

To understand the mechanisms of leptin resistance in the hypothalamus, we next tested whether a defect in hypothalamic leptin receptor activity and associated signal transduction through JAK2–STAT3 pathway underlies the development of leptin resistance in NPY, POMC NT and other leptin sensitive neurons following chronic central leptin infusion, that could contribute to normalization in food intake after an initial decrease. However, we found that JAK2–STAT3 pathway of leptin signaling was operative normally during chronic leptin infusion [240] in that phosphorylated leptin receptor and phosphorylated STAT3 remained elevated in association with a sustained elevation in DNA-binding activity of STAT3 in the hypothalamus throughout 16day period of leptin infusion (Fig. 10). In addition, phosphorylated JAK2 levels were increased during initial period but not day 16 of leptin infusion. Although SOCS3 has been thought to be involved in leptin resistance [29,31], we observed that while hypothalamic SOCS3 mRNA levels were increased throughout leptin infusion (Fig. 11), SOCS3 leptin levels were increased on day 16 of leptin infusion. These findings clearly suggest a

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Fig. 9. Representative dark-field photographs (left panel) of coronal sections through rostral part of the hypothalamic arcuate nucleus of rats show changes in NPY mRNA expression (determined by in situ hybridization and denoted by silver grains) following continuous central leptin infusion. Note that while neuropeptide Y mRNA expression was decreased on day 3 of leptin infusion, mRNA expression remained unchanged on day 13 of leptin infusion compared to that of control. Relative optical density of NPY mRNA (as determined by in situ hybridization) in rostral, middle and caudal division of the arcuate nucleus after 3 or 13 days of leptin infusion (right panel). Data are means
SEM of five rats in each group and are represented relative to aCSF controls.  p < 0:05 versus aCSF control group. (Adapted from [270].)

Fig. 10. DNA-binding activity of STAT3 in the hypothalamus is increased after 2, 4, or 16 days of central leptin infusion in rat. (A) DNAbinding activity of STAT3 in the MBH extracts as determined by an EMSA using a 32 P-labeled M67-SIE oligonucleotide probe. (B) results obtained by phosphorimaging and expressed as relative to aCSF group. Values represent the mean
SEM for the number of animals indicated in parentheses.  p < 0:01 vs. all other groups; a, p < 0:01 vs. d 2 and d 4 leptin groups. PF, pair fed. (Adapted from [240].)

sustained elevation in hypothalamic leptin receptor signaling through JAK–STAT pathway despite an increased expression of SOCS3 during chronic central leptin infusion [240]. Because increased SOCS3 was unable to inhibit JAK2–STAT3 pathway, it appears that continuous exposure of leptin may modify the mechanism, such as SOCS3 binding to Ob-Rb [11] and JAK2 [31,32], by

Fig. 11. SOCS3 gene expression (as determined by ribonuclease protection assay) in the hypothalamus is increased after 2, 4, or 16 days of central leptin infusion in rat. (A) representative phosphor images showing the level of SOCS3 mRNA and b-actin mRNA in the MBH. (B) results obtained by phosphorimaging showing the changes in SOCS3 mRNA levels. The values are first normalized to b-actin mRNA and then expressed as relative to aCSF group. Values represent the mean
SEM for the number of animals indicated in the parentheses.  p < 0:01 vs. corresponding aCSF groups. C, aCSF control, PF, pair fed; L, leptin. (Adapted from [240].)

which SOCS3 regulates JAK2–STAT3 pathway of leptin signaling in the hypothalamus. Furthermore, leptin resistance in the NPY, POMC, and NT neurons in the

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presence of elevated JAK2-STAT3 signaling during chronic leptin infusion provides evidence in support of a critical role of other pathways including the PI3K– PDE3B–cAMP pathway [371] in transducing leptin action in these neurons. In this regard, our preliminary study [275] shows that continuous central leptin infusion resulted in decreased hypothalamic cAMP levels in association with an increased PDE3B activity on day 2 of infusion, when NPY, NT or POMC neurons were responsive to central leptin infusion; but this effect was abolished on day 16 of infusion in association with the development of resistance in these neurons. This finding, although preliminary, suggests a defective regulation of PDE3B–cAMP pathway of leptin signaling following continuous exposure of the hypothalamus to leptin, and this may be responsible for the development of resistance in NPY, POMC or NT neurons. However, it is also critical to identify if STAT3 transcriptional activity is altered after chronic leptin infusion and may be involved in leptin resistance. In this regard, recent evidence suggests that upon reaching the nucleus transcriptional activity of STAT proteins may be dependent on its interaction with other DNA-binding protein or co-activators [187]. Furthermore, STAT3 transcriptional activity can be regulated by other factors (co-activator), such as p300/CBP (cAMP response element binding protein-binding protein) and steroid receptor co-activators 1 (NcoA/SRC1a) [77,112,113,254]. Because both CBP and SRC1 are localized in the hypothalamus [212,318], any alteration in these coactivators could compromise STAT3 mediated leptin action despite an activation of STAT3. This is an interesting possibility and requires future investigation. Although this rat model of chronic leptin infusion may not necessarily be comparable to that of DIO, our evidence of the development of leptin resistance in the NPY, POMC and NT neurons following only 2 weeks of leptin infusion strongly suggests that this rat model provides an interesting opportunity to decipher the mechanisms of leptin resistance in the hypothalamus. In addition, since leptin withdrawal resulted in hyperphagia, this rat model can be used to examine the hypothalamic mechanism behind this phenomenon. 5.4. Central leptin resistance in ageing associated obesity Late-onset obesity is characterized by a steady increase in body weight and adiposity as adults age until early senescence, after which body weight declines [295]. This aging-associated obesity is different from DIO in that the later occurs rapidly with HF diet, while the former occurs slowly but steadily over a long period. Using F-344BN rats, Scarpace and colleagues have provided very strong evidence in support of the development of both central and peripheral leptin resistance during age-related obesity [282]. Adiposity and serum

leptin levels are increased with age; and like late-onset obesity in humans, F-344BN rats exhibit a steady increase in body fat into early senescence, followed by decline [188,281,303]. Although subcutaneous leptin infusion for 7 days decreased food consumption by 50% in young rats as compared to the saline control, but it only decreased 20% of food intake in aged rats; oxygen consumption was increased by leptin in young but not in old rats; and hypothalamic NPY mRNA levels were decreased by leptin in young but not in old rats [281]. These results clearly suggest the development of leptin resistance in aged-rats. The effects of central leptin injection on food intake, UCP1 gene expression in the BAT and hypothalamic NPY mRNA levels were significantly reduced in aged rats as compared to that in young rats, demonstrating resistance to the anorexic and thermogenic effects of centrally administered leptin [303]. In addition, STAT3-DNA binding activity in response to central leptin was greatly reduced in aged rats as compared to young rats; and old rats had reduced protein levels of the long-form of the leptin receptor, suggesting that diminished leptin receptor protein may be involved in reduced STAT3 activation in the hypothalamus of aged rats [283]. In a recent study, Scarpace et al. [284] reported that both the anorexic and thermogenic responses to rAAV mediated central leptin gene delivery were completely attenuated in aged-obese rats sometime after day 9 of 46-day period of the experiment without compromising leptin signal transduction through STAT3 activation. In addition, even on day 9 when food intake was reduced, NPY and POMC neurons did not respond to central leptin gene therapy in the aged obese rats [284]. Furthermore, despite a resistance to anorexic action of leptin, body weight in the obese rats remained lowered after 20 days of central gene delivery. This is somewhat similar to our finding of the maintenance of reduced body weight despite normalization in food intake in a rat model of chronic central leptin infusion [270]. However, in young rats, leptin signaling through STAT3 activation remained elevated, albeit at reduced level, at both day 9 and day 46 of leptin gene delivery; and leptin action on NPY and POMC neurons, and anorexic (although reduced by 50%) and thermogenic responses to leptin were not desensitized with prolonged elevated central leptin [284]. In another study, this group showed that in 18-monthold mildly obese rats, the anorexic and energy-expenditure responses were attenuated at 25 and 83 days, respectively, and STAT3 remained elevated following 138 days of central leptin gene therapy [285]. Thus, these studies altogether suggest that in rats the development of leptin-induced leptin resistance is accelerated by the extent of obesity [285]. Central leptin gene therapy for 138 days has been reported to increase hypothalamic SOCS3 gene expression

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in 18-month-old mildly obese rats, although STAT3 activation was normal in these rats [285]. We also observed an increase in both STAT3 activation and SOCS3 gene expression following chronic central leptin infusion in rat [240]. Thus, the role of SOCS3 in the development of leptin resistance in the hypothalamus is yet to be demonstrated. Similar to F344BN rats, in old Wistar rats, anorectic and body weight-reducing responses to central leptin injections are attenuated [101], suggesting the development of central leptin resistance. Also leptin uptake in the hypothalamus is reduced in association with decreased hypothalamic Ob-Rb mRNA and protein levels in 24-month-old Wistar rats [100]. Food restriction decreases adiposity and recovers leptin responsiveness in these aged rats. Aging also increases SOCS3 expression in the hypothalamus, and food restriction partially reverts the increases in SOCS3 mRNA levels associated with aging [244]. Increased SOCS3 expression has also been reported in 18-month-old lean wild type (+/+) Zucker diabetic fatty rats [344]. Because in these studies STAT3 activation was not examined, it is not clear whether increased SOCS3 is involved in central leptin resistance in these aged rats. Overall, age-associated obesity appears to be, at least partly, due to the development of central leptin resistance. This is most likely due to decreased leptin uptake, and down regulation of leptin receptor signaling through the JAK–STAT pathway in the hypothalamus. Although SOCS3 is increased in aged rats, the role of SOCS3 in hypothalamic leptin resistance during aging is not clear and should be explored more mechanistically. 5.5. Leptin resistance during pregnancy During pregnancy, leptin levels are elevated in serum during human and rodent gestation [55,106,159, 177,207]. The source of increased circulating leptin during pregnancy may be an increased leptin production in adipose tissue and/or placenta, or increased level of leptin-binding protein [6,106,159, 207,299]. However, food intake either increases [259] or remains unchanged [307] during pregnancy despite hyperleptinimia, suggesting that the pregnancy induces a state of leptin resistance most likely in the hypothalamus. Leptin signaling in the hypothalamus during pregnancy is incompletely understood. Garcia et al. [104] reported a decrease in Ob-Rb mRNA levels in the hypothalamus of pregnant rats on day 18 of gestation as compared to non-pregnant animals. Seeber et al. [296] reported that hypothalamic Ob-Rb mRNA expression was elevated on day 7 of pregnancy but returned to pre-pregnancy levels by mid gestation and remained stable thereafter. Because the status of leptin receptor phosphorylation or STAT3 activation was not examined in either of these studies, the interpretation of small changes in OB-Rb

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levels becomes difficult. Nevertheless, better understanding of the mechanism of leptin signaling during hyperleptinimia seen in pregnancy may shed some light on the mechanism of central leptin resistance. 5.6. Selective leptin resistance Recently, Mark et al. [205] have proposed an interesting concept of ‘‘selective leptin resistance.’’ This has come from their findings that while agouti yellow obese (Ay) mice develop resistance to the satiety and weightreducing effects of central and peripheral treatment of leptin, the sympathoexcitatory action of leptin is preserved in these animals [68]. Similar preservation of sympathetic activation despite the resistance to metabolic action of leptin has also been reported in DIO mice by these authors [205]. Since intracerebroventricular administration of leptin, like peripheral administration, produces regional sympathetic stimulation, and lesions in the arcuate nucleus prevent the sympathetic responses to peripheral leptin administration, it is suggested that the sympathoexcitatory action of leptin originates in the hypothalamus [131]. Although human obesity is associated with hyperleptinimia, suggesting leptin resistance, but it is often associated with hypertension [156] and increased sympathetic activity [117,262,286]. It will be interesting whether the concept of ‘‘selective leptin resistance’’ is applicable to human obesity. In this regard, it is to be noted that in Wistar rat obesity due to HF diet decreases the sympathetic nervous and cardiovascular responses to icv leptin [195], suggesting resistance also at the level of sympathetic activity. Nevertheless, the concept of selective leptin resistance is very interesting and should be carefully interpreted and requires further investigation in different models of obesity.

6. Summary and conclusion In this review, available data on the mechanisms of leptin signaling in the hypothalamus in regulation of food intake and body weight in normal condition and that during the development of leptin resistance in DIO, ageing-associated obesity and following continuous central leptin infusion have been summarized. It appears that in addition to the conventional JAK2–STAT3 pathway, an alternative insulin-like signaling pathway, involving activation of PI3K and PDE3B and reduction in cAMP levels, mediates leptin intracellular signal transduction in the hypothalamus. A crosstalk between the JAK2–STAT3 and PI3K–PDE3B–cAMP pathways may be critical for normal leptin signaling in the hypothalamus. At the neuronal level, leptin action is mediated by orexigenic and anorectic signal producing neurons in the ARC–PVN–LH/PFH axis. Because of morphological connections between the neurons in this

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axis, and the evidence of functional interactions among these neurons, it is no wonder that pharmacological intervention of activity of any one of them, in most cases, reverses the anorectic effect of leptin on food intake. While it is clear that NPY/AgRP and POMC/ CART neurons may represent the major neuronal systems for mediating leptin action on food intake and body weight, it is important to consider the contribution of other members of the neural circuitry that regulates energy homeostasis. Furthermore, one of the important mechanisms by which leptin acts in the hypothalamus may be by modifying the action of the neural signal after it is being produced, and therefore action at the postsynaptic level could still occur without having any effect on gene expression. This mechanism is most likely involved in mediating effect of leptin on food intake within hour of central injection, because leptinÕs effect on gene expression of target neurons cannot be achieved within this short time period. One of the other mechanisms by which leptin might be acting is by derailing the interactions among orexigenic signals and or enhancing interactions among anorectic signals in the hypothalamus. It has been a matter of debate whether obesity is associated with central leptin resistance. The evidence presented in this review clearly suggests that central leptin resistance contributes to the development of DIO and aging-associated obesity. Among the possible mechanisms, a defective nutritional regulation of leptin receptor, defective STAT3 signaling and or a defect at down stream of leptin receptor signaling in specific neurons such as NPY, POMC or NT have been implicated for central leptin resistance. Interestingly, leptin responsive neurons (e.g., NPY and POMC) develop leptin resistance in response to central leptin infusion despite sustained activation of the JAK2–STAT3 pathway. Thus, we hypothesize that besides the JAK2– STAT3 pathway, defect in other pathways of leptin signaling, such as PI3K–PDE3B–cAMP pathway, could play very important role in the development of leptin resistance in the hypothalamus. Furthermore, sustained elevation of JAK2-STAT3 signaling in the presence of increased SOCS3 expression and the development of leptin resistance in leptin-sensitive neurons during chronic central leptin infusion challenge the role of SOCS3 in central leptin resistance. However, if SOCS3 is involved in leptin resistance, it can be predicted that ablation of SOCS3 in the hypothalamus will result in decreased body weight, and the animals will be hypersensitive to leptin and would become resistant to DIO as seen in PTP1B knockout mice. It is also likely that cooperation between different negative regulators of cytokine signaling such as SHP2, PTP1B, and SOCS3 is critical in proper leptin signaling in the hypothalamus. An important caution about the concept of leptin resistance in DIO, whether it is central or peripheral, that these animals are fertile, and sympathoexcitatory effect

of leptin is preserved. Therefore, some action of leptin is still intact in the hypothalamus, and it is possible that partial leptin signaling seen in these animals could be responsible for transducing these effects. In conclusion, PI3K–PDE3B–cAMP pathway interacting with the JAK2–STAT3 pathway of signal transduction constitutes a critical component of leptin signaling in the hypothalamus, engaging various orexigenic and anorectic signal-producing neurons in the ARC–PVN–LH/PFH axis. Resistance or attenuated response to specific action of leptin, particularly food intake and body weight regulation, may occur due to defect in any of the steps in the signal transduction mechanism and or a defect at downstream of signaling, such as other co-factors/co-activators, resulting in the development of leptin resistance in target neurons. Understanding the key signaling mechanisms that are being altered during the development of leptin resistance is critical for the drug discovery to treat and or prevent obesity and related disorders.

Acknowledgments The author is indebted to Drs. Allan Zhao and Robert OÕDoherty for their collaboration in some studies. This work was supported by US Public Health Service Grants DK 54484 and DK 61499.

References [1] R.S. Ahima, D. Prabakaran, C. Mantzoros, D. Qu, B. Lowell, E. Maratos-Flier, J.S. Flier, Role of leptin in the neuroendocrine response to fasting, Nature 382 (1996) 250–252. [2] R.S. Ahima, J. Dushay, S.N. Flier, D. Prabakaran, J.S. Flier, Leptin accelerates the onset of puberty in normal female mice, J. Clin. Invest. 99 (1997) 391–395. [3] R.S. Ahima, J. Kelly, J.K. Elmquist, J.S. Flier, Distinct physiologic and neuronal responses to decreased leptin and mild hyperleptinemia, Endocrinology 140 (1999) 4923–4931. [4] M. Ahmad, P.R. Flatt, B.L. Furman, N.J. Pyne, The role of the cyclic GMP-inhibited cyclic AMP-specific phosphodiesterase (PDE3) in regulating clonal BRIN-BD11 insulin secreting cell survival, Cell Signal. 12 (2000) 541–548. [5] A. Akabayashi, C.T. Zaia, S.M. Gabriel, I. Silva, W.K. Cheung, S.F. Leibowitz, Intracerebroventricular injection of dibutyryl cyclic adenosine 30 ,50 -monophosphate increases hypothalamic levels of neuropeptide Y, Brain Res. 660 (1994) 323– 328. [6] J.A. Amico, A. Thomas, R.S. Crowley, L.A. Burmeister, Concentrations of leptin in the serum of pregnant, lactating, and cycling rats and of leptin messenger ribonucleic acid in rat placental tissue, Life Sci. 63 (1998) 1387–1395. [7] B.K. Anand, J.R. Brobeck, Localization of a feeding center in the hypothalamus of the rat, Proc. Soc. Exp. Biol. Med. 77 (1951) 323–324. [8] K. Arase, D.A. York, H. Shimizu, N. Shargill, G.A. Bray, Effects of corticotropin-releasing factor on food intake and

A. Sahu / Frontiers in Neuroendocrinology 24 (2004) 225–253

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

[22]

[23] [24]

[25]

[26]

brown adipose tissue thermogenesis in rats, Am. J. Physiol. 255 (1988) E255–E259. A. Asakawa, A. Inui, T. Kaga, H. Yuzuriha, T. Nagata, N. Ueno, S. Makino, M. Fujimiya, A. Niijima, M.A. Fujino, M. Kasuga, Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin, Gastroenterology 120 (2001) 337–345. A. Bado, S. Levasseur, S. Attoub, S. Kermorgant, J.P. Laigneau, M.N. Bortoluzzi, L. Moizo, T. Lehy, M. Guerre-Millo, Y. Le Marchand-Brustel, M.J. Lewin, The stomach is a source of leptin, Nature 394 (1998) 790–793. A.S. Banks, S.M. Davis, S.H. Bates, M.G. Myers Jr., Activation of downstream signals by the long form of the leptin receptor, J. Biol. Chem. 275 (2000) 14563–14572. W.A. Banks, A.J. Kastin, W. Huang, J.B. Jaspan, L.M. Maness, Leptin enters the brain by a saturable system independent of insulin, Peptides 17 (1996) 305–311. W.A. Banks, Leptin transport across the blood–brain barrier: implications for the cause and treatment of obesity, Curr. Pharm. Des. 7 (2001) 125–133. I.A. Barash, C.C. Cheung, D.S. Weigle, H. Ren, E.B. Kabigting, J.L. Kuijper, D.K. Clifton, R.A. Steiner, Leptin is a metabolic signal to the reproductive system, Endocrinology 137 (1996) 3144–3147. M.L. Barker-Gibb, A. Sahu, C.R. Pohl, T.M. Plant, Elevating circulating leptin in prepubertal male rhesus monkeys (Macaca mulatta) does not elicit precocious gonadotropin-releasing hormone release, assessed indirectly, J. Clin. Endocrinol. Metab. 87 (2002) 4976–4983. D.G. Baskin, R.J. Seeley, J.L. Kuijper, S. Lok, D.S. Weigle, J.C. Erickson, R.D. Palmiter, M.W. Schwartz, Increased expression of mRNA for the long form of the leptin receptor in the hypothalamus is associated with leptin hypersensitivity and fasting, Diabetes 47 (1998) 538–543. D.G. Baskin, J.F. Breininger, S. Bonigut, M.A. Miller, Leptin binding in the arcuate nucleus is increased during fasting, Brain Res. 828 (1999) 154–158. D.G. Baskin, J.F. Breininger, M.W. Schwartz, SOCS-3 expression in leptin-sensitive neurons of the hypothalamus of fed and fasted rats, Regul. Pept. 92 (2000) 9–15. S.H. Bates, W.H. Stearns, T.A. Dundon, M. Schubert, A.W. Tso, Y. Wang, A.S. Banks, H.J. Lavery, A.K. Haq, E. MaratosFlier, B.G. Neel, M.W. Schwartz, M.G. Myers Jr., STAT3 signalling is required for leptin regulation of energy balance but not reproduction, Nature 421 (2003) 856–859. H. Baumann, K.K. Morella, D.W. White, M. Dembski, P.S. Bailon, H. Kim, C.F. Lai, L.A. Tartaglia, The full-length leptin receptor has signaling capabilities of interleukin 6-type cytokine receptors, Proc. Natl. Acad. Sci. USA 93 (1996) 8374–8378. L. Bayer, G. Mairet-Coello, P.Y. Risold, B. Griffond, Orexin/ hypocretin neurons: chemical phenotype and possible interactions with melanin-concentrating hormone neurons, Regul. Pept. 104 (2002) 33–39. J.A. Beavo, D.H. Reifsnyder, Primary sequence of cyclic nucleotide phosphodiesterase isozymes and the design of selective inhibitors, Trends Pharmacol. Sci. 11 (1990) 150–155. J.A. Beavo, Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms, Physiol. Rev. 75 (1995) 725–748. B. Beck, A. Burlet, J.P. Nicolas, C. Burlet, Neurotensin in microdissected brain nuclei and in the pituitary of the lean and obese Zucker rats, Neuropeptides 13 (1989) 1–7. B. Beck, A. Stricker-Krongrad, S. Richy, C. Burlet, Evidence that hypothalamic neurotensin signals leptin effects on feeding behavior in normal and fat-preferring rats, Biochem. Biophys. Res. Commun. 252 (1998) 634–638. H.T. Bergen, T. Mizuno, J. Taylor, C.V. Mobbs, Resistance to diet-induced obesity is associated with increased proopiomela-

[27]

[28]

[29]

[30]

[31]

[32]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

[40]

[41]

[42]

[43]

[44]

243

nocortin mRNA and decreased neuropeptide Y mRNA in the hypothalamus, Brain Res. 851 (1999) 198–203. G.E. Bergonzelli, F.P. Pralong, M. Glauser, C. Cavadas, E. Grouzmann, R.C. Gaillard, Interplay between galanin and leptin in the hypothalamic control of feeding via corticotropin-releasing hormone and neuropeptide Y, Diabetes 50 (2001) 2666–2672. C. Bjorbaek, S. Uotani, B. Da Silva, J.S. Flier, Divergent signaling capacities of the long and short isoforms of the leptin receptor, J. Biol. Chem. 272 (1997) 32686–32695. C. Bjorbaek, J.K. Elmquist, J.D. Frantz, S.E. Shoelson, J.S. Flier, Identification of SOCS-3 as a potential mediator of central leptin resistance, Mol. Cell. 1 (1998) 619–625. C. Bjorbaek, J.K. Elmquist, P. Michl, R.S. Ahima, A. Van Bueren, A.L. Mccall, J.S. Flier, Expression of leptin receptor isoforms in rat brain microvessels, Endocrinology 139 (1998) 3485–3491. C. Bjorbaek, K. El-Haschimi, J.D. Frantz, J.S. Flier, The role of SOCS-3 in leptin signaling and leptin resistance, J. Biol. Chem. 274 (1999) 30059–30065. C. Bjorbaek, R.M. Buchholz, S.M. Davis, S.H. Bates, D.D. Pierroz, H. Gu, B.G. Neel, M.G. Myers Jr., J.S. Flier, Divergent roles of SHP-2 in ERK activation by leptin receptors, J. Biol. Chem. 276 (2001) 4747–4755. R.J. Boado, P.L. Golden, N. Levin, W.M. Pardridge, Upregulation of blood–brain barrier short-form leptin receptor gene products in rats fed a high fat diet, J. Neurochem. 71 (1998) 1761–1764. G. Boden, X. Chen, M. Mozzoli, I. Ryan, Effect of fasting on serum leptin in normal human subjects, J. Clin. Endocrinol. Metab. 81 (1996) 3419–3423. B.A. Boston, K.M. Blaydon, J. Varnerin, R.D. Cone, Independent and additive effects of central POMC and leptin pathways on murine obesity, Science 278 (1997) 1641–1644. A. Bouloumie, H.C. Drexler, M. Lafontan, R. Busse, Leptin, the product of Ob gene, promotes angiogenesis, Circ. Res. 83 (1998) 1059–1066. H. Bowen, T.D. Mitchell, R.B. Harris, Method of leptin dosing, strain, and group housing influence leptin sensitivity in high-fatfed weanling mice, Am. J. Physiol. Regul. Integr. Comp. Physiol. 284 (2003) R87–R100. C. Broberger, L. De Lecea, J.G. Sutcliffe, T. Hokfelt, Hypocretin/orexin- and melanin-concentrating hormone-expressing cells form distinct populations in the rodent lateral hypothalamus: relationship to the neuropeptide Y and agouti gene-related protein systems, J. Comp. Neurol. 402 (1998) 460–474. C. Broberger, J. Johansen, C. Johansson, M. Schalling, T. Hokfelt, The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice, Proc. Natl. Acad. Sci. USA 95 (1998) 15043–15048. D. Burdakov, B. Liss, F.M. Ashcroft, Orexin excites GABAergic neurons of the arcuate nucleus by activating the sodium–calcium exchanger, J. Neurosci. 23 (2003) 4951–4957. B. Burguera, M.E. Couce, G.L. Curran, M.D. Jensen, R.V. Lloyd, M.P. Cleary, J.F. Poduslo, Obesity is associated with a decreased leptin transport across the blood–brain barrier in rats, Diabetes 49 (2000) 1219–1223. L.A. Campfield, F.J. Smith, Y. Guisez, R. Devos, P. Burn, Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks, Science 269 (1995) 546–549. J.F. Caro, J.W. Kolaczynski, M.R. Nyce, J.P. Ohannesian, I. Opentanova, W.H. Goldman, R.B. Lynn, P.L. Zhang, M.K. Sinha, R.V. Considine, Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance, Lancet 348 (1996) 159–161. L.R. Carpenter, T.J. Farruggella, A. Symes, M.L. Karow, G.D. Yancopoulos, N. Stahl, Enhancing leptin response by preventing

244

[45]

[46]

[47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

[55]

[56]

[57]

[58]

[59]

[60]

[61]

A. Sahu / Frontiers in Neuroendocrinology 24 (2004) 225–253 SH2-containing phosphatase 2 interaction with Ob receptor, Proc. Natl. Acad. Sci. USA 95 (1998) 6061–6066. R. Carraway, S.E. Leeman, The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalami, J. Biol. Chem. 248 (1973) 6854–6861. J.B. Carvalheira, R.M. Siloto, I. Ignacchitti, S.L. Brenelli, C.R. Carvalho, A. Leite, L.A. Velloso, J.A. Gontijo, M.J. Saad, Insulin modulates leptin-induced STAT3 activation in rat hypothalamus, FEBS Lett. 500 (2001) 119–124. C. Catzeflis, D.D. Pierroz, F. Rohner-Jeanrenaud, J.E. Rivier, P.C. Sizonenko, M.L. Aubert, Neuropeptide Y administered chronically into the lateral ventricle profoundly inhibits both the gonadotropic and the somatotropic axis in intact adult female rats, Endocrinology 132 (1993) 224–234. S. Ceccatelli, M. Eriksson, T. Hokfelt, Distribution and coexistence of corticotropin-releasing factor-, neurotensin-, enkephalin-, cholecystokinin-, galanin- and vasoactive intestinal polypeptide/peptide histidine isoleucine-like peptides in the parvocellular part of the paraventricular nucleus, Neuroendocrinology 49 (1989) 309–323. F.F. Chehab, M.E. Lim, R. Lu, Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin, Nat. Genet. 12 (1996) 318–320. F.F. Chehab, K. Mounzih, R. Lu, M.E. Lim, Early onset of reproductive function in normal female mice treated with leptin, Science 275 (1997) 88–90. H. Chen, O. Charlat, L.A. Tartaglia, E.A. Woolf, X. Weng, S.J. Ellis, N.D. Lakey, J. Culpepper, K.J. Moore, R.E. Breitbart, G.M. Duyk, R.I. Tepper, J.P. Morgenstern, Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice, Cell 84 (1996) 491–495. A. Cheng, N. Uetani, P.D. Simoncic, V.P. Chaubey, A. Lee-Loy, C.J. Mcglade, B.P. Kennedy, M.L. Tremblay, Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B, Dev. Cell 2 (2002) 497–503. C.C. Cheung, D.K. Clifton, R.A. Steiner, Proopiomelanocortin neurons are direct targets for leptin in the hypothalamus, Endocrinology 138 (1997) 4489–4492. C.C. Cheung, J.E. Thornton, J.L. Kuijper, D.S. Weigle, D.K. Clifton, R.A. Steiner, Leptin is a metabolic gate for the onset of puberty in the female rat, Endocrinology 138 (1997) 855–858. E.K. Chien, M. Hara, M. Rouard, H. Yano, M. Phillippe, K.S. Polonsky, G.I. Bell, Increase in serum leptin and uterine leptin receptor messenger RNA levels during pregnancy in rats, Biochem. Biophys. Res. Commun. 237 (1997) 476–480. S.C. Chua Jr., W.K. Chung, X.S. Wu-Peng, Y. Zhang, S.M. Liu, L. Tartaglia, R.L. Leibel, Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor, Science 271 (1996) 994–996. C.D. Chung, J. Liao, B. Liu, X. Rao, P. Jay, P. Berta, K. Shuai, Specific inhibition of Stat3 signal transduction by PIAS3, Science 278 (1997) 1803–1805. K. Clement, C. Vaisse, N. Lahlou, S. Cabrol, V. Pelloux, D. Cassuto, M. Gourmelen, C. Dina, J. Chambaz, J.M. Lacorte, A. Basdevant, P. Bougneres, Y. Lebouc, P. Froguel, B. Guy-Grand, A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction, Nature 392 (1998) 398–401. P. Cohen, C. Zhao, X. Cai, J.M. Montez, S.C. Rohani, P. Feinstein, P. Mombaerts, J.M. Friedman, Selective deletion of leptin receptor in neurons leads to obesity, J. Clin. Invest. 108 (2001) 1113–1121. D.L. Coleman, Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice, Diabetologia 14 (1978) 141– 148. R.D. Cone, D. Lu, S. Koppula, D.I. Vage, H. Klungland, B. Boston, W. Chen, D.N. Orth, C. Pouton, R.A. Kesterson,

[62] [63]

[64]

[65]

[66]

[67]

[68]

[69]

[70]

[71]

[72]

[73]

[74] [75]

[76] [77] [78]

The melanocortin receptors: agonists, antagonists, and the hormonal control of pigmentation, Recent Prog. Horm. Res. 51 (1996) 287–317, discussion 318. R.D. Cone, The central melanocortin system and energy homeostasis, Trends Endocrinol. Metab. 10 (1999) 211–216. R.D. Cone, The corticotropin-releasing hormone system and feeding behavior—a complex web begins to unravel, Endocrinology 141 (2000) 2713–2714. R.V. Considine, E.L. Considine, C.J. Williams, M.R. Nyce, S.A. Magosin, T.L. Bauer, E.L. Rosato, J. Colberg, J.F. Caro, Evidence against either a premature stop codon or the absence of obese gene mRNA in human obesity, J. Clin. Invest. 95 (1995) 2986–2988. R.V. Considine, M.K. Sinha, M.L. Heiman, A. Kriauciunas, T.W. Stephens, M.R. Nyce, J.P. Ohannesian, C.C. Marco, L.J. Mckee, T.L. Bauer, et al., Serum immunoreactive-leptin concentrations in normal-weight and obese humans, N. Engl. J. Med. 334 (1996) 292–295. R.V. Considine, E.L. Considine, C.J. Williams, T.M. Hyde, J.F. Caro, The hypothalamic leptin receptor in humans: identification of incidental sequence polymorphisms and absence of the db/db mouse and fa/fa rat mutations, Diabetes 45 (1996) 992–994. M. Conti, G. Nemoz, C. Sette, E. Vicini, Recent progress in understanding the hormonal regulation of phosphodiesterases, Endocr. Rev. 16 (1995) 370–389. M.L. Correia, W.G. Haynes, K. Rahmouni, D.A. Morgan, W.I. Sivitz, A.L. Mark, The concept of selective leptin resistance: evidence from agouti yellow obese mice, Diabetes 51 (2002) 439– 442. M.A. Cowley, N. Pronchuk, W. Fan, D.M. Dinulescu, W.F. Colmers, R.D. Cone, Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat, Neuron 24 (1999) 155–163. M.A. Cowley, J.L. Smart, M. Rubinstein, M.G. Cerdan, S. Diano, T.L. Horvath, R.D. Cone, M.J. Low, Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus, Nature 411 (2001) 480–484. M.A. Cowley, R.G. Smith, S. Diano, M. Tschop, N. Pronchuk, K.L. Grove, C.J. Strasburger, M. Bidlingmaier, M. Esterman, M.L. Heiman, L.M. Garcia-Segura, E.A. Nillni, P. Mendez, M.J. Low, P. Sotonyi, J.M. Friedman, H. Liu, S. Pinto, W.F. Colmers, R.D. Cone, T.L. Horvath, The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis, Neuron 37 (2003) 649–661. H. Cui, D.D. Belsham, Regulation of neurotensin gene expression by leptin in a novel immortalized mouse neuronal hypothalamic cell line, in: Proceedings of the 85th Annual Meeting of the Endocrine Society, June 19–22, 2003, Philadelphia, PA, Abstract #P3-114. M.J. Cunningham, J.M. Scarlett, R.A. Steiner, Cloning and distribution of galanin-like peptide mRNA in the hypothalamus and pituitary of the macaque, Endocrinology 143 (2002) 755–763. P.B. Daniel, W.H. Walker, J.F. Habener, Cyclic AMP signaling and gene regulation, Annu. Rev. Nutr. 18 (1998) 353–383. J.A. Daniel, M.G. Thomas, C.S. Hale, J.M. Simmons, D.H. Keisler, Effect of cerebroventricular infusion of insulin and (or) glucose on hypothalamic expression of leptin receptor and pituitary secretion of LH in diet-restricted ewes, Domest. Anim. Endocrinol. 18 (2000) 177–185. J.E. Darnell Jr., STATs and gene regulation, Science 277 (1997) 1630–1635. J.E. Darnell Jr., Transcription factors as targets for cancer therapy, Nat. Rev. Cancer 2 (2002) 740–749. L. De Lecea, T.S. Kilduff, C. Peyron, X. Gao, P.E. Foye, P.E. Danielson, C. Fukuhara, E.L. Battenberg, V.T. Gautvik, F.S.

A. Sahu / Frontiers in Neuroendocrinology 24 (2004) 225–253

[79]

[80]

[81]

[82]

[83]

[84]

[85]

[86]

[87]

[88]

[89]

[90]

[91]

[92]

[93]

[94]

Bartlett II, W.N. Frankel, A.N. Van Den Pol, F.E. Bloom, K.M. Gautvik, J.G. Sutcliffe, The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity, Proc. Natl. Acad. Sci. USA 95 (1998) 322–327. E. Degerman, P. Belfrage, V.C. Manganiello, Structure, localization, and regulation of cGMP-inhibited phosphodiesterase (PDE3), J. Biol. Chem. 272 (1997) 6823–6826. M.G. Dube, B. Xu, P.S. Kalra, C.A. Sninsky, S.P. Kalra, Disruption in neuropeptide Y and leptin signaling in obese ventromedial hypothalamic-lesioned rats, Brain Res. 816 (1999) 38–46. M.G. Dube, S.P. Kalra, P.S. Kalra, Food intake elicited by central administration of orexins/hypocretins: identification of hypothalamic sites of action, Brain Res. 842 (1999) 473– 477. M.G. Dube, T.L. Horvath, P.S. Kalra, S.P. Kalra, Evidence of NPY Y5 receptor involvement in food intake elicited by orexin A in sated rats, Peptides 21 (2000) 1557–1560. P. Ducy, M. Amling, S. Takeda, M. Priemel, A.F. Schilling, F.T. Beil, J. Shen, C. Vinson, J.M. Rueger, G. Karsenty, Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass, Cell 100 (2000) 197–207. K. Ebihara, Y. Ogawa, G. Katsuura, Y. Numata, H. Masuzaki, N. Satoh, M. Tamaki, T. Yoshioka, M. Hayase, N. Matsuoka, M. Aizawa-Abe, Y. Yoshimasa, K. Nakao, Involvement of agouti-related protein, an endogenous antagonist of hypothalamic melanocortin receptor, in leptin action, Diabetes 48 (1999) 2028–2033. C.M. Edwards, S. Abusnana, D. Sunter, K.G. Murphy, M.A. Ghatei, S.R. Bloom, The effect of the orexins on food intake: comparison with neuropeptide Y, melanin-concentrating hormone and galanin, J. Endocrinol. 160 (1999) R7–R12. K. El-Haschimi, D.D. Pierroz, S.M. Hileman, C. Bjorbaek, J.S. Flier, Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity, J. Clin. Invest. 105 (2000) 1827–1832. M. Elchebly, P. Payette, E. Michaliszyn, W. Cromlish, S. Collins, A.L. Loy, D. Normandin, A. Cheng, J. Himms-Hagen, C.C. Chan, C. Ramachandran, M.J. Gresser, M.L. Tremblay, B.P. Kennedy, Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene, Science 283 (1999) 1544–1548. C.F. Elias, C.B. Saper, E. Maratos-Flier, N.A. Tritos, C. Lee, J. Kelly, J.B. Tatro, G.E. Hoffman, M.M. Ollmann, G.S. Barsh, T. Sakurai, M. Yanagisawa, J.K. Elmquist, Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area, J. Comp. Neurol. 402 (1998) 442–459. C.F. Elias, C. Lee, J. Kelly, C. Aschkenasi, R.S. Ahima, P.R. Couceyro, M.J. Kuhar, C.B. Saper, J.K. Elmquist, Leptin activates hypothalamic CART neurons projecting to the spinal cord, Neuron 21 (1998) 1375–1385. C.F. Elias, C. Aschkenasi, C. Lee, J. Kelly, R.S. Ahima, C. Bjorbaek, J.S. Flier, C.B. Saper, J.K. Elmquist, Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area, Neuron 23 (1999) 775–786. J.K. Elmquist, R.S. Ahima, E. Maratos-Flier, J.S. Flier, C.B. Saper, Leptin activates neurons in ventrobasal hypothalamus and brainstem, Endocrinology 138 (1997) 839–842. J.K. Elmquist, E. Maratos-Flier, C.B. Saper, J.S. Flier, Unraveling the central nervous system pathways underlying responses to leptin, Nat. Neurosci. 1 (1998) 445–450. J.K. Elmquist, R.S. Ahima, C.F. Elias, J.S. Flier, C.B. Saper, Leptin activates distinct projections from the dorsomedial and ventromedial hypothalamic nuclei, Proc. Natl. Acad. Sci. USA 95 (1998) 741–746. P.C. Emson, M. Goedert, P.W. Mantyh, Neurotensin-containing neurons, in: A. Bjorklund, T. Hockfelt (Eds.), Handbook of

[95]

[96]

[97]

[98]

[99]

[100]

[101]

[102] [103]

[104]

[105]

[106]

[107]

[108]

[109]

[110]

[111]

245

Chemical Neuroanatomy, vol. 4, Elsevier Science, New York, 1985, pp. 355–402. T.A. Endo, M. Masuhara, M. Yokouchi, R. Suzuki, H. Sakamoto, K. Mitsui, A. Matsumoto, S. Tanimura, M. Ohtsubo, H. Misawa, T. Miyazaki, N. Leonor, T. Taniguchi, T. Fujita, Y. Kanakura, S. Komiya, A. Yoshimura, A new protein containing an SH2 domain that inhibits JAK kinases, Nature 387 (1997) 921–924. J.C. Erickson, K.E. Clegg, R.D. Palmiter, Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y, Nature 381 (1996) 415–421. J.C. Erickson, G. Hollopeter, R.D. Palmiter, Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y, Science 274 (1996) 1704–1707. W. Fan, B.A. Boston, R.A. Kesterson, V.J. Hruby, R.D. Cone, Role of melanocortinergic neurons in feeding and the agouti obesity syndrome, Nature 385 (1997) 165–168. I.S. Farooqi, S.A. Jebb, G. Langmack, E. Lawrence, C.H. Cheetham, A.M. Prentice, I.A. Hughes, M.A. Mccamish, S. OÕrahilly, Effects of recombinant leptin therapy in a child with congenital leptin deficiency, N. Engl. J. Med. 341 (1999) 879– 884. C. Fernandez-Galaz, T. Fernandez-Agullo, F. Campoy, C. Arribas, N. Gallardo, A. Andres, M. Ros, J.M. Carrascosa, Decreased leptin uptake in hypothalamic nuclei with ageing in Wistar rats, J. Endocrinol. 171 (2001) 23–32. C. Fernandez-Galaz, T. Fernandez-Agullo, C. Perez, S. Peralta, C. Arribas, A. Andres, J.M. Carrascosa, M. Ros, Long-term food restriction prevents ageing-associated central leptin resistance in wistar rats, Diabetologia 45 (2002) 997–1003. J.M. Friedman, J.L. Halaas, Leptin and the regulation of body weight in mammals, Nature 395 (1998) 763–770. J. Gao, L. Ghibaudi, M. Van Heek, J.J. Hwa, Characterization of diet-induced obese rats that develop persistent obesity after 6 months of high-fat followed by 1 month of low-fat diet, Brain Res. 936 (2002) 87–90. M.D. Garcia, F.F. Casanueva, C. Dieguez, R.M. Senaris, Gestational profile of leptin messenger ribonucleic acid (mRNA) content in the placenta and adipose tissue in the rat, and regulation of the mRNA levels of the leptin receptor subtypes in the hypothalamus during pregnancy and lactation, Biol. Reprod. 62 (2000) 698–703. J.D. Gardner, N.J. Rothwell, G.N. Luheshi, Leptin affects food intake via CRF-receptor-mediated pathways, Nat. Neurosci. 1 (1998) 103. O. Gavrilova, V. Barr, B. Marcus-Samuels, M. Reitman, Hyperleptinemia of pregnancy associated with the appearance of a circulating form of the leptin receptor, J. Biol. Chem. 272 (1997) 30546–30551. N. Ghilardi, S. Ziegler, A. Wiestner, R. Stoffel, M.H. Heim, R.C. Skoda, Defective STAT signaling by the leptin receptor in diabetic mice, Proc. Natl. Acad. Sci. USA 93 (1996) 6231–6235. N. Ghilardi, R.C. Skoda, The leptin receptor activates janus kinase 2 and signals for proliferation in a factor-dependent cell line, Mol. Endocrinol. 11 (1997) 393–399. E.R. Gillard, A.M. Khan, H. Ahsan Ul, R.S. Grewal, B. Mouradi, B.G. Stanley, Stimulation of eating by the second messenger cAMP in the perifornical and lateral hypothalamus, Am. J. Physiol. 273 (1997) R107–R112. E.R. Gillard, A.M. Khan, R.S. Grewal, B. Mouradi, S.D. Wolfsohn, B.G. Stanley, The second messenger cAMP elicits eating by an anatomically specific action in the perifornical hypothalamus, J. Neurosci. 18 (1998) 2646–2652. E.R. Gillard, A.M. Khan, B. Mouradi, O. Nalamwar, B.G. Stanley, Eating induced by perifornical cAMP is behaviorally selective and involves protein kinase activity, Am. J. Physiol. 275 (1998) R647–R653.

246

A. Sahu / Frontiers in Neuroendocrinology 24 (2004) 225–253

[112] S. Gingras, J. Simard, B. Groner, E. Pfitzner, p300/CBP is required for transcriptional induction by interleukin-4 and interacts with Stat6, Nucleic Acids Res. 27 (1999) 2722–2729. [113] S. Giraud, F. Bienvenu, S. Avril, H. Gascan, D.M. Heery, O. Coqueret, Functional interaction of STAT3 transcription factor with the coactivator NcoA/SRC1a, J. Biol. Chem. 277 (2002) 8004–8011. [114] P.L. Golden, T.J. Maccagnan, W.M. Pardridge, Human blood– brain barrier leptin receptor. Binding and endocytosis in isolated human brain microvessels, J. Clin. Invest. 99 (1997) 14–18. [115] T. Gotoda, B.S. Manning, A.P. Goldstone, H. Imrie, A.L. Evans, A.D. Strosberg, P.M. Mckeigue, J. Scott, T.J. Aitman, Leptin receptor gene variation and obesity: lack of association in a white British male population, Hum. Mol. Genet. 6 (1997) 869– 876. [116] M. Graham, J.R. Shutter, U. Sarmiento, I. Sarosi, K.L. Stark, Overexpression of Agrt leads to obesity in transgenic mice, Nat. Genet. 17 (1997) 273–274. [117] G. Grassi, G. Seravalle, B.M. Cattaneo, G.B. Bolla, A. Lanfranchi, M. Colombo, C. Giannattasio, A. Brunani, F. Cavagnini, G. Mancia, Sympathetic activation in obese normotensive subjects, Hypertension 25 (1995) 560–563. [118] J.L. Guan, T. Saotome, Q.P. Wang, H. Funahashi, T. Hori, S. Tanaka, S. Shioda, Orexinergic innervation of POMC-containing neurons in the rat arcuate nucleus, Neuroreport 12 (2001) 547–551. [119] J.F. Habener, C.P. Miller, M. Vallejo, cAMP-dependent regulation of gene transcription by cAMP response element-binding protein and cAMP response element modulator, Vitam. Horm. 51 (1995) 1–57. [120] T.M. Hahn, J.F. Breininger, D.G. Baskin, M.W. Schwartz, Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons, Nat. Neurosci. 1 (1998) 271–272. [121] M.L. Hakansson, B. Meister, Transcription factor STAT3 in leptin target neurons of the rat hypothalamus, Neuroendocrinology 68 (1998) 420–427. [122] M.L. Hakansson, H. Brown, N. Ghilardi, R.C. Skoda, B. Meister, Leptin receptor immunoreactivity in chemically defined target neurons of the hypothalamus, J. Neurosci. 18 (1998) 559–572. [123] M. Hakansson, L. De Lecea, J.G. Sutcliffe, M. Yanagisawa, B. Meister, Leptin receptor- and STAT3-immunoreactivities in hypocretin/orexin neurones of the lateral hypothalamus, J. Neuroendocrinol. 11 (1999) 653–663. [124] J.L. Halaas, K.S. Gajiwala, M. Maffei, S.L. Cohen, B.T. Chait, D. Rabinowitz, R.L. Lallone, S.K. Burley, J.M. Friedman, Weight-reducing effects of the plasma protein encoded by the obese gene, Science 269 (1995) 543–546. [125] J.L. Halaas, C. Boozer, J. Blair-West, N. Fidahusein, D.A. Denton, J.M. Friedman, Physiological response to long-term peripheral and central leptin infusion in lean and obese mice, Proc. Natl. Acad. Sci. USA 94 (1997) 8878–8883. [126] J.A. Harrold, G. Williams, P.S. Widdowson, Changes in hypothalamic agouti-related protein (AGRP), but not alphaMSH or pro-opiomelanocortin concentrations in dietary-obese and food-restricted rats, Biochem. Biophys. Res. Commun. 258 (1999) 574–577. [127] J. Harvey, M.L. Ashford, Insulin occludes leptin activation of ATP-sensitive Kþ channels in rat CRI-G1 insulin secreting cells, J. Physiol. 511 (Pt 3) (1998) 695–706. [128] J. Harvey, M.L. Ashford, Leptin in the CNS: much more than a satiety signal, Neuropharmacology 44 (2003) 845–854. [129] S.G. Hassink, D.V. Sheslow, E. De Lancey, I. Opentanova, R.V. Considine, J.F. Caro, Serum leptin in children with obesity: relationship to gender and development, Pediatrics 98 (1996) 201–203. [130] A.C. Haynes, B. Jackson, P. Overend, R.E. Buckingham, S. Wilson, M. Tadayyon, J.R. Arch, Effects of single and chronic

[131]

[132] [133] [134]

[135]

[136]

[137]

[138]

[139]

[140]

[141]

[142]

[143]

[144]

[145]

[146]

intracerebroventricular administration of the orexins on feeding in the rat, Peptides 20 (1999) 1099–1105. W.G. Haynes, Interaction between leptin and sympathetic nervous system in hypertension, Curr. Hypertens. Rep. 2 (2000) 311–318. G. Hervey, The effects of lesions in the hypothalamus in parabiotic rats, J. Physiol. 145 (1959) 3336–3352. A.W. Hetherington, S.W. Ranson, Hypothalamic lesions and adiposity in the rat, Anat. Rec. 78 (1940) 149–172. S.B. Heymsfield, A.S. Greenberg, K. Fujioka, R.M. Dixon, R. Kushner, T. Hunt, J.A. Lubina, J. Patane, B. Self, P. Hunt, M. Mccamish, Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial, JAMA 282 (1999) 1568–1575. S.M. Hileman, D.D. Pierroz, H. Masuzaki, C. Bjorbaek, K. ElHaschimi, W.A. Banks, J.S. Flier, Characterizaton of short isoforms of the leptin receptor in rat cerebral microvessels and of brain uptake of leptin in mouse models of obesity, Endocrinology 143 (2002) 775–783. D.J. Hilton, R.T. Richardson, W.S. Alexander, E.M. Viney, T.A. Willson, N.S. Sprigg, R. Starr, S.E. Nicholson, D. Metcalf, N.A. Nicola, Twenty proteins containing a C-terminal SOCS box form five structural classes, Proc. Natl. Acad. Sci. USA 95 (1998) 114–119. T.L. Horvath, F. Naftolin, S.P. Kalra, C. Leranth, Neuropeptide-Y innervation of beta-endorphin-containing cells in the rat mediobasal hypothalamus: a light and electron microscopic double immunostaining analysis, Endocrinology 131 (1992) 2461–2467. T.L. Horvath, S. Diano, A.N. Van Den Pol, Synaptic interaction between hypocretin (orexin) and neuropeptide Y cells in the rodent and primate hypothalamus: a novel circuit implicated in metabolic and endocrine regulations, J. Neurosci. 19 (1999) 1072–1087. X.F. Huang, S. Lin, R. Zhang, Upregulation of leptin receptor mRNA expression in obese mouse brain, Neuroreport 8 (1997) 1035–1038. Q. Huang, R. Rivest, D. Richard, Effects of leptin on corticotropin-releasing factor (CRF) synthesis and CRF neuron activation in the paraventricular hypothalamic nucleus of obese (ob/ ob) mice, Endocrinology 139 (1998) 1524–1532. T. Hubschle, E. Thom, A. Watson, J. Roth, S. Klaus, W. Meyerhof, Leptin-induced nuclear translocation of STAT3 immunoreactivity in hypothalamic nuclei involved in body weight regulation, J. Neurosci. 21 (2001) 2413–2424. D. Huszar, C.A. Lynch, V. Fairchild-Huntress, J.H. Dunmore, Q. Fang, L.R. Berkemeier, W. Gu, R.A. Kesterson, B.A. Boston, R.D. Cone, F.J. Smith, L.A. Campfield, P. Burn, F. Lee, Targeted disruption of the melanocortin-4 receptor results in obesity in mice, Cell 88 (1997) 131–141. Y. Ibata, F. Kawakami, K. Fukui, H.L. Obata-Tsuto, M. Tanaka, T. Kubo, H. Okamura, N. Morimoto, C. Yanaihara, N. Yanaihara, Light and electron microscopic immunocytochemistry of neurotensin-like immunoreactive neurons in the rat hypothalamus, Brain Res. 302 (1984) 221–230. N. Ibrahim, M.A. Bosch, J.L. Smart, J. Qiu, M. Rubinstein, O.K. Ronnekleiv, M.J. Low, M.J. Kelly, Hypothalamic proopiomelanocortin neurons are glucose responsive and express K(ATP) channels, Endocrinology 144 (2003) 1331– 1340. T. Ida, K. Nakahara, T. Kuroiwa, K. Fukui, M. Nakazato, T. Murakami, N. Murakami, Both corticotropin releasing factor and neuropeptide Y are involved in the effect of orexin (hypocretin) on the food intake in rats, Neurosci. Lett. 293 (2000) 119–122. R.J. Jacob, J. Dziura, M.B. Medwick, P. Leone, S. Caprio, M. During, G.I. Shulman, R.S. Sherwin, The effect of leptin is

A. Sahu / Frontiers in Neuroendocrinology 24 (2004) 225–253

[147]

[148]

[149]

[150]

[151]

[152]

[153]

[154]

[155]

[156]

[157] [158]

[159]

[160]

[161]

[162]

[163]

enhanced by microinjection into the ventromedial hypothalamus, Diabetes 46 (1997) 150–152. M.R. Jain, T.L. Horvath, P.S. Kalra, S.P. Kalra, Evidence that NPY Y1 receptors are involved in stimulation of feeding by orexins (hypocretins) in sated rats, Regul. Pept. 87 (2000) 19–24. L. Jin, S. Zhang, B.G. Burguera, M.E. Couce, R.Y. Osamura, E. Kulig, R.V. Lloyd, Leptin and leptin receptor expression in rat and mouse pituitary cells, Endocrinology 141 (2000) 333–339. A. Jureus, M.J. Cunningham, M.E. Mcclain, D.K. Clifton, R.A. Steiner, Galanin-like peptide (GALP) is a target for regulation by leptin in the hypothalamus of the rat, Endocrinology 141 (2000) 2703–2706. A. Jureus, M.J. Cunningham, D. Li, L.L. Johnson, S.M. Krasnow, D.N. Teklemichael, D.K. Clifton, R.A. Steiner, Distribution and regulation of galanin-like peptide (GALP) in the hypothalamus of the mouse, Endocrinology 142 (2001) 5140–5144. D. Kahn, G.M. Abrams, E.A. Zimmerman, R. Carraway, S.E. Leeman, Neurotensin neurons in the rat hypothalamus: an immunocytochemical study, Endocrinology 107 (1980) 47–54. S.P. Kalra, M.G. Dube, A. Sahu, C.P. Phelps, P.S. Kalra, Neuropeptide Y secretion increases in the paraventricular nucleus in association with increased appetite for food, Proc. Natl. Acad. Sci. USA 88 (1991) 10931–10935. S.P. Kalra, M.G. Dube, S. Pu, B. Xu, T.L. Horvath, P.S. Kalra, Interacting appetite-regulating pathways in the hypothalamic regulation of body weight, Endocr. Rev. 20 (1999) 68–100. J. Kamegai, H. Tamura, T. Shimizu, S. Ishii, H. Sugihara, I. Wakabayashi, Central effect of ghrelin, an endogenous growth hormone secretagogue, on hypothalamic peptide gene expression, Endocrinology 141 (2000) 4797–4800. J. Kamegai, H. Tamura, T. Shimizu, S. Ishii, H. Sugihara, I. Wakabayashi, Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and Agouti-related protein mRNA levels and body weight in rats, Diabetes 50 (2001) 2438–2443. W.B. Kannel, N. Brand, J.J. Skinner Jr., T.R. Dawber, P.M. Mcnamara, The relation of adiposity to blood pressure and development of hypertension, The Framingham study, Ann. Intern. Med. 67 (1967) 48–59. G. Karsenty, Leptin controls bone formation through a hypothalamic relay, Recent Prog. Horm. Res. 56 (2001) 401–415. W. Kaszubska, H.D. Falls, V.G. Schaefer, D. Haasch, L. Frost, P. Hessler, P.E. Kroeger, D.W. White, M.R. Jirousek, J.M. Trevillyan, Protein tyrosine phosphatase 1B negatively regulates leptin signaling in a hypothalamic cell line, Mol. Cell Endocrinol. 195 (2002) 109–118. M. Kawai, M. Yamaguchi, T. Murakami, K. Shima, Y. Murata, K. Kishi, The placenta is not the main source of leptin production in pregnant rat: gestational profile of leptin in plasma and adipose tissues, Biochem. Biophys. Res. Commun. 240 (1997) 798–802. G.C. Kennedy, The role of depot fat in the hypothalamic control of food intake in the rat, Proc. Roy. Soc. Lond. 140 (1953) 579– 592. N.C. Kerr, F.E. Holmes, D. Wynick, Galanin-like peptide (GALP) is expressed in rat hypothalamus and pituitary, but not in DRG, Neuroreport 11 (2000) 3909–3913. P. Kitabgi, R. Carraway, S.E. Leeman, Isolation of a tridecapeptide from bovine intestinal tissue and its partial characterization as neurotensin, J. Biol. Chem. 251 (1976) 7053–7058. L.D. Klaman, O. Boss, O.D. Peroni, J.K. Kim, J.L. Martino, J.M. Zabolotny, N. Moghal, M. Lubkin, Y.B. Kim, A.H. Sharpe, A. Stricker-Krongrad, G.I. Shulman, B.G. Neel, B.B. Kahn, Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein–tyrosine phosphatase 1B-deficient mice, Mol. Cell. Biol. 20 (2000) 5479–5489.

247

[164] D. Kohno, H.Z. Gao, S. Muroya, S. Kikuyama, T. Yada, Ghrelin directly interacts with neuropeptide-Y-containing neurons in the rat arcuate nucleus: Ca2þ signaling via protein kinase A and N-type channel-dependent mechanisms and cross-talk with leptin and orexin, Diabetes 52 (2003) 948–956. [165] J.W. Kolaczynski, J.P. Ohannesian, R.V. Considine, C.C. Marco, J.F. Caro, Response of leptin to short-term and prolonged overfeeding in humans, J. Clin. Endocrinol. Metab. 81 (1996) 4162–4165. [166] J.W. Kolaczynski, R.V. Considine, J. Ohannesian, C. Marco, I. Opentanova, M.R. Nyce, M. Myint, J.F. Caro, Responses of leptin to short-term fasting and refeeding in humans: a link with ketogenesis but not ketones themselves, Diabetes 45 (1996) 1511–1515. [167] J. Korner, E. Savontaus, S.C. Chua Jr., R.L. Leibel, S.L. Wardlaw, Leptin regulation of Agrp and Npy mRNA in the rat hypothalamus, J. Neuroendocrinol. 13 (2001) 959–966. [168] K. Koyama, M. Shimabukuro, G. Chen, M.Y. Wang, Y. Lee, P.S. Kalra, M.G. Dube, S.P. Kalra, C.B. Newgard, R.H. Unger, Resistance to adenovirally induced hyperleptinemia in rats. Comparison of ventromedial hypothalamic lesions and mutated leptin receptors, J. Clin. Invest. 102 (1998) 728–733. [169] D.D. Krahn, B.A. Gosnell, A.S. Levine, J.E. Morley, Behavioral effects of corticotropin-releasing factor: localization and characterization of central effects, Brain Res. 443 (1988) 63–69. [170] S.M. Krasnow, G.S. Fraley, S.M. Schuh, J.W. Baumgartner, D.K. Clifton, R.A. Steiner, A role for galanin-like peptide in the integration of feeding, body weight regulation, and reproduction in the mouse, Endocrinology 144 (2003) 813–822. [171] D.L. Krebs, D.J. Hilton, SOCS: physiological suppressors of cytokine signaling, J. Cell Sci. 113 (Pt 16) (2000) 2813–2819. [172] P. Kristensen, M.E. Judge, L. Thim, U. Ribel, K.N. Christjansen, B.S. Wulff, J.T. Clausen, P.B. Jensen, O.D. Madsen, N. Vrang, P.J. Larsen, S. Hastrup, Hypothalamic CART is a new anorectic peptide regulated by leptin, Nature 393 (1998) 72–76. [173] H. Krude, H. Biebermann, W. Luck, R. Horn, G. Brabant, A. Gruters, Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans, Nat. Genet. 19 (1998) 155–157. [174] S. Kumano, H. Matsumoto, Y. Takatsu, J. Noguchi, C. Kitada, T. Ohtaki, Changes in hypothalamic expression levels of galaninlike peptide in rat and mouse models support that it is a leptintarget peptide, Endocrinology 144 (2003) 2634–2643. [175] S.E. Kyrkouli, B.G. Stanley, S.F. Leibowitz, Galanin: stimulation of feeding induced by medial hypothalamic injection of this novel peptide, Eur. J. Pharmacol. 122 (1986) 159–160. [176] S.E. Kyrkouli, B.G. Stanley, R.D. Seirafi, S.F. Leibowitz, Stimulation of feeding by galanin: anatomical localization and behavioral specificity of this peptideÕs effects in the brain, Peptides 11 (1990) 995–1001. [177] M. Lage, R.V. Garcia-Mayor, M.A. Tome, F. Cordido, F. ValleInclan, R.V. Considine, J.F. Caro, C. Dieguez, F.F. Casanueva, Serum leptin levels in women throughout pregnancy and the postpartum period and in women suffering spontaneous abortion, Clin. Endocrinol. (Oxf) 50 (1999) 211–216. [178] P.D. Lambert, P.R. Couceyro, K.M. Mcgirr, S.E. Dall Vechia, Y. Smith, M.J. Kuhar, CART peptides in the central control of feeding and interactions with neuropeptide Y, Synapse 29 (1998) 293–298. [179] J.A. Larm, A.L. Gundlach, Galanin-like peptide (GALP) mRNA expression is restricted to arcuate nucleus of hypothalamus in adult male rat brain, Neuroendocrinology 72 (2000) 67– 71. [180] C.B. Lawrence, F.M. Baudoin, S.M. Luckman, Centrally administered galanin-like peptide modifies food intake in the rat: a comparison with galanin, J. Neuroendocrinol. 14 (2002) 853–860.

248

A. Sahu / Frontiers in Neuroendocrinology 24 (2004) 225–253

[181] C.B. Lawrence, A.C. Snape, F.M. Baudoin, S.M. Luckman, Acute central ghrelin and GH secretagogues induce feeding and activate brain appetite centers, Endocrinology 143 (2002) 155– 162. [182] G.H. Lee, R. Proenca, J.M. Montez, K.M. Carroll, J.G. Darvishzadeh, J.I. Lee, J.M. Friedman, Abnormal splicing of the leptin receptor in diabetic mice, Nature 379 (1996) 632–635. [183] S.F. Leibowitz, Differential functions of hypothalamic galanin cell grows in the regulation of eating and body weight, Ann. N. Y. Acad. Sci. 863 (1998) 206–220. [184] B.E. Levin, A.A. Dunn-Meynell, Dysregulation of arcuate nucleus preproneuropeptide Y mRNA in diet-induced obese rats, Am. J. Physiol. 272 (1997) R1365–1370. [185] B.E. Levin, A.A. Dunn-Meynell, Reduced central leptin sensitivity in rats with diet-induced obesity, Am. J. Physiol. Regul. Integr. Comp. Physiol. 283 (2002) R941–R948. [186] A.S. Levine, J. Kneip, M. Grace, J.E. Morley, Effect of centrally administered neurotensin on multiple feeding paradigms, Pharmacol. Biochem. Behav. 18 (1983) 19–23. [187] D.E. Levy, J.E. Darnell Jr., Stats: transcriptional control and biological impact, Nat. Rev. Mol. Cell Biol. 3 (2002) 651– 662. [188] H. Li, M. Matheny, M. Nicolson, N. Tumer, P.J. Scarpace, Leptin gene expression increases with age independent of increasing adiposity in rats, Diabetes 46 (1997) 2035–2039. [189] C. Li, J.M. Friedman, Leptin receptor activation of SH2 domain containing protein tyrosine phosphatase 2 modulates Ob receptor signal transduction, Proc. Natl. Acad. Sci. USA 96 (1999) 9677–9682. [190] S. Lin, X.F. Huang, Fasting increases leptin receptor mRNA expression in lean but not obese (ob/ob) mouse brain, Neuroreport 8 (1997) 3625–3629. [191] S. Lin, T.C. Thomas, L.H. Storlien, X.F. Huang, Development of high fat diet-induced obesity and leptin resistance in C57Bl/6J mice, Int. J. Obes. Relat. Metab. Disord. 24 (2000) 639–646. [192] S. Lin, L.H. Storlien, X.F. Huang, Leptin receptor, NPY, POMC mRNA expression in the diet-induced obese mouse brain, Brain Res. 875 (2000) 89–95. [193] F. Lonnqvist, P. Arner, L. Nordfors, M. Schalling, Overexpression of the obese (ob) gene in adipose tissue of human obese subjects, Nat. Med. 1 (1995) 950–953. [194] M. Lopez, L. Seoane, M.C. Garcia, F. Lago, F.F. Casanueva, R. Senaris, C. Dieguez, Leptin regulation of prepro-orexin and orexin receptor mRNA levels in the hypothalamus, Biochem. Biophys. Res. Commun. 269 (2000) 41–45. [195] H. Lu, Z. Duanmu, C. Houck, K.L. Jen, A. Buison, J.C. Dunbar, Obesity due to high fat diet decreases the sympathetic nervous and cardiovascular responses to intracerebroventricular leptin in rats, Brain Res. Bull. 47 (1998) 331–335. [196] D.S. Ludwig, K.G. Mountjoy, J.B. Tatro, J.A. Gillette, R.C. Frederich, J.S. Flier, E. Maratos-Flier, Melanin-concentrating hormone: a functional melanocortin antagonist in the hypothalamus, Am. J. Physiol. 274 (1998) E627–E633. [197] D.S. Ludwig, N.A. Tritos, J.W. Mastaitis, R. Kulkarni, E. Kokkotou, J. Elmquist, B. Lowell, J.S. Flier, E. Maratos-Flier, Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance, J. Clin. Invest. 107 (2001) 379–386. [198] D. Luttinger, R.A. King, D. Sheppard, J. Strupp, C.B. Nemeroff, A.J. Prange Jr., The effect of neurotensin on food consumption in the rat, Eur. J. Pharmacol. 81 (1982) 499–503. [199] R.B. Lynn, G.Y. Cao, R.V. Considine, T.M. Hyde, J.F. Caro, Autoradiographic localization of leptin binding in the choroid plexus of ob/ob and db/db mice, Biochem. Biophys. Res. Commun. 219 (1996) 884–889. [200] O.A. Macdougald, C.S. Hwang, H. Fan, M.D. Lane, Regulated expression of the obese gene product (leptin) in white adipose

[201]

[202]

[203]

[204]

[205]

[206]

[207]

[208]

[209]

[210]

[211]

[212]

[213] [214]

[215]

[216]

tissue and 3T3-L1 adipocytes, Proc. Natl. Acad. Sci. USA 92 (1995) 9034–9037. A.M. Madiehe, A.O. Schaffhauser, D.H. Braymer, G.A. Bray, D.A. York, Differential expression of leptin receptor in high- and low-fat-fed Osborne-Mendel and S5B/Pl rats, Obes. Res. 8 (2000) 467–474. M. Maffei, J. Halaas, E. Ravussin, R.E. Pratley, G.H. Lee, Y. Zhang, H. Fei, S. Kim, R. Lallone, S. Ranganathan, et al., Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects, Nat. Med. 1 (1995) 1155–1161. K.F. Malik, W.S. Young III, Localization of binding sites in the central nervous system for leptin (OB protein) in normal, obese (ob/ob), and diabetic (db/db) C57BL/6J mice, Endocrinology 137 (1996) 1497–1500. C. Manganiello, E. Degerman, M. Taira, T. Kono, P. Belfrage, Type III cyclic nucleotide phosphodiesterases and insulin action, Curr. Top. Cell Regul. 34 (1996) 63–100. A.L. Mark, M.L. Correia, K. Rahmouni, W.G. Haynes, Selective leptin resistance: a new concept in leptin physiology with cardiovascular implications, J. Hypertens. 20 (2002) 1245– 1250. T. Masaki, G. Yoshimichi, S. Chiba, T. Yasuda, H. Noguchi, T. Kakuma, T. Sakata, H. Yoshimatsu, Corticotropin-releasing hormone-mediated pathway of leptin to regulate feeding, adiposity, and uncoupling protein expression in mice, Endocrinology 144 (2003) 3547–3554. H. Masuzaki, Y. Ogawa, N. Sagawa, K. Hosoda, T. Matsumoto, H. Mise, H. Nishimura, Y. Yoshimasa, I. Tanaka, T. Mori, K. Nakao, Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans, Nat. Med. 3 (1997) 1029– 1033. Y. Matsumoto, T. Watanabe, Y. Adachi, T. Itoh, T. Ohtaki, H. Onda, T. Kurokawa, O. Nishimura, M. Fujino, Galanin-like peptide stimulates food intake in the rat, Neurosci. Lett. 322 (2002) 67–69. N. Matsuoka, Y. Ogawa, K. Hosoda, J. Matsuda, H. Masuzaki, T. Miyawaki, N. Azuma, K. Natsui, H. Nishimura, Y. Yoshimasa, S. Nishi, D.B. Thompson, K. Nakao, Human leptin receptor gene in obese Japanese subjects: evidence against either obesity-causing mutations or association of sequence variants with obesity, Diabetologia 40 (1997) 1204–1210. K.C. McCowen, J.C. Chow, R.J. Smith, Leptin signaling in the hypothalamus of normal rats in vivo, Endocrinology 139 (1998) 4442–4447. E. Meacci, M. Taira, M. Moos Jr., C.J. Smith, M.A. Movsesian, E. Degerman, P. Belfrage, V. Manganiello, Molecular cloning and expression of human myocardial cGMP-inhibited cAMP phosphodiesterase, Proc. Natl. Acad. Sci. USA 89 (1992) 3721– 3725. O.C. Meijer, P.J. Steenbergen, E.R. De Kloet, Differential expression and regional distribution of steroid receptor coactivators SRC-1 and SRC-2 in brain and pituitary, Endocrinology 141 (2000) 2192–2199. B. Meister, Control of food intake via leptin receptors in the hypothalamus, Vitam. Horm. 59 (2000) 265–304. J.G. Mercer, N. Hoggard, L.M. Williams, C.B. Lawrence, L.T. Hannah, P. Trayhurn, Localization of leptin receptor mRNA and the long form splice variant (Ob-Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization, FEBS Lett. 387 (1996) 113–116. J.G. Mercer, N. Hoggard, L.M. Williams, C.B. Lawrence, L.T. Hannah, P.J. Morgan, P. Trayhurn, Coexpression of leptin receptor and preproneuropeptide Y mRNA in arcuate nucleus of mouse hypothalamus, J. Neuroendocrinol. 8 (1996) 733–735. T. Miki, M. Taira, S. Hockman, F. Shimada, J. Lieman, M. Napolitano, D. Ward, H. Makino, V.C. Manganiello,

A. Sahu / Frontiers in Neuroendocrinology 24 (2004) 225–253

[217]

[218]

[219]

[220]

[221]

[222] [223]

[224]

[225]

[226]

[227]

[228]

[229]

[230]

[231]

[232]

Characterization of the cDNA and gene encoding human PDE3B, the cGIP1 isoform of the human cyclic GMP-inhibited cyclic nucleotide phosphodiesterase family, Genomics 36 (1996) 476–485. T.M. Mizuno, S.P. Kleopoulos, H.T. Bergen, J.L. Roberts, C.A. Priest, C.V. Mobbs, Hypothalamic pro-opiomelanocortin mRNA is reduced by fasting and [corrected] in ob/ob and db/ db mice, but is stimulated by leptin, Diabetes 47 (1998) 294–297. T.M. Mizuno, C.V. Mobbs, Hypothalamic agouti-related protein messenger ribonucleic acid is inhibited by leptin and stimulated by fasting, Endocrinology 140 (1999) 814–817. M.S. Mondal, M. Nakazato, Y. Date, N. Murakami, M. Yanagisawa, S. Matsukura, Widespread distribution of orexin in rat brain and its regulation upon fasting, Biochem. Biophys. Res. Commun. 256 (1999) 495–499. C.T. Montague, I.S. Farooqi, J.P. Whitehead, M.A. Soos, H. Rau, N.J. Wareham, C.P. Sewter, J.E. Digby, S.N. Mohammed, J.A. Hurst, C.H. Cheetham, A.R. Earley, A.H. Barnett, J.B. Prins, S. OÕrahilly, Congenital leptin deficiency is associated with severe early-onset obesity in humans, Nature 387 (1997) 903– 908. B. Morash, A. Li, P.R. Murphy, M. Wilkinson, E. Ur, Leptin gene expression in the brain and pituitary gland, Endocrinology 140 (1999) 5995–5998. J.E. Morley, Neuropeptide regulation of appetite and weight, Endocr. Rev. 8 (1987) 256–287. K.G. Mountjoy, M.T. Mortrud, M.J. Low, R.B. Simerly, R.D. Cone, Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain, Mol. Endocrinol. 8 (1994) 1298–1308. H. Munzberg, L. Huo, E.A. Nillni, A.N. Hollenberg, C. Bjorbaek, Role of signal transducer and activator of transcription 3 in regulation of hypothalamic proopiomelanocortin gene expression by leptin, Endocrinology 144 (2003) 2121–2131. T. Nagaoka, T. Shirakawa, J. Kasuya, T.W. Balon, V.C. Manganiello, Y. Fujita-Yamaguchi, Cyclic nucleotide PDE-3. Quantitation of PDE-3A and -3B mRNAs in rat tissues by RNase protection assay, Cell Biochem. Biophys. 29 (1998) 49– 66. S. Nagatani, P. Guthikonda, R.C. Thompson, H. Tsukamura, K.I. Maeda, D.L. Foster, Evidence for GnRH regulation by leptin: leptin administration prevents reduced pulsatile LH secretion during fasting, Neuroendocrinology 67 (1998) 370– 376. T. Naka, M. Narazaki, M. Hirata, T. Matsumoto, S. Minamoto, A. Aono, N. Nishimoto, T. Kajita, T. Taga, K. Yoshizaki, S. Akira, T. Kishimoto, Structure and function of a new STATinduced STAT inhibitor, Nature 387 (1997) 924–929. T. Nakagawa, A. Tsuchida, Y. Itakura, T. Nonomura, M. Ono, F. Hirota, T. Inoue, C. Nakayama, M. Taiji, H. Noguchi, Brainderived neurotrophic factor regulates glucose metabolism by modulating energy balance in diabetic mice, Diabetes 49 (2000) 436–444. M. Nakazato, N. Murakami, Y. Date, M. Kojima, H. Matsuo, K. Kangawa, S. Matsukura, A role for ghrelin in the central regulation of feeding, Nature 409 (2001) 194–198. S.E. Nicholson, D.J. Hilton, The SOCS proteins: a new family of negative regulators of signal transduction, J. Leukoc. Biol. 63 (1998) 665–668. A. Nicot, W.B. Rowe, E.R. De Kloet, C. Betancur, D.S. Jessop, S.L. Lightman, R. Quirion, W. Rostene, A. Berod, Endogenous neurotensin regulates hypothalamic–pituitary–adrenal axis activity and peptidergic neurons in the rat hypothalamic paraventricular nucleus, J. Neuroendocrinol. 9 (1997) 263–269. K.D. Niswender, G.J. Morton, W.H. Stearns, C.J. Rhodes, M.G. Myers Jr., M.W. Schwartz, Intracellular signalling. Key enzyme in leptin-induced anorexia, Nature 413 (2001) 794–795.

249

[233] K.D. Niswender, B. Gallis, J.E. Blevins, M.A. Corson, M.W. Schwartz, D.G. Baskin, Immunocytochemical detection of phosphatidylinositol 3-kinase activation by insulin and leptin, J. Histochem. Cytochem. 51 (2003) 275–283. [234] K.D. Niswender, M.W. Schwartz, Insulin and leptin revisited: adiposity signals with overlapping physiological and intracellular signaling capabilities, Front. Neuroendocrinol. 24 (2003) 1–10. [235] K.D. Niswender, C.D. Morrison, D.J. Clegg, R. Olson, D.G. Baskin, M.G. Myers Jr., R.J. Seeley, M.W. Schwartz, Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus: a key mediator of insulin-induced anorexia, Diabetes 52 (2003) 227–231. [236] L. OÕrourke, P.R. Shepherd, Biphasic regulation of extracellularsignal-regulated protein kinase by leptin in macrophages: role in regulating STAT3 Ser727 phosphorylation and DNA binding, Biochem. J. 364 (2002) 875–879. [237] T. Ohtaki, S. Kumano, Y. Ishibashi, K. Ogi, H. Matsui, M. Harada, C. Kitada, T. Kurokawa, H. Onda, M. Fujino, Isolation and cDNA cloning of a novel galanin-like peptide (GALP) from porcine hypothalamus, J. Biol. Chem. 274 (1999) 37041–37045. [238] S. Okamoto, K. Kimura, M. Saito, Anorectic effect of leptin is mediated by hypothalamic corticotropin-releasing hormone, but not by urocortin, in rats, Neurosci. Lett. 307 (2001) 179–182. [239] M.M. Ollmann, B.D. Wilson, Y.K. Yang, J.A. Kerns, Y. Chen, I. Gantz, G.S. Barsh, Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein, Science 278 (1997) 135–138. [240] R. Pal, A. Sahu, Leptin signaling in the hypothalamus during chronic central leptin infusion, Endocrinology 144 (2003) 3789– 3798. [241] R. Pal, A. Sahu, Chronic central leptin infusion results in the development of leptin resistance in proopiomelanocortin and neurotensin neurons in the hypothalamus, in: Proceedings of the 85th Annual Meeting of the Endocrine Society, June 19–22, 2003, Philadelphia, PA, Abstract # P1-255. [242] C. Peiser, G.P. Mcgregor, R.E. Lang, Leptin receptor expression and suppressor of cytokine signaling transcript levels in high-fatfed rats, Life Sci. 67 (2000) 2971–2981. [243] M.A. Pelleymounter, M.J. Cullen, M.B. Baker, R. Hecht, D. Winters, T. Boone, F. Collins, Effects of the obese gene product on body weight regulation in ob/ob mice, Science 269 (1995) 540–543. [244] S. Peralta, J.M. Carrascosa, N. Gallardo, M. Ros, C. Arribas, Ageing increases SOCS-3 expression in rat hypothalamus: effects of food restriction, Biochem. Biophys. Res. Commun. 296 (2002) 425–428. [245] C. Peyron, D.K. Tighe, A.N. Van Den Pol, L. De Lecea, H.C. Heller, J.G. Sutcliffe, T.S. Kilduff, Neurons containing hypocretin (orexin) project to multiple neuronal systems, J. Neurosci. 18 (1998) 9996–10015. [246] M.S. Phillips, Q. Liu, H.A. Hammond, V. Dugan, P.J. Hey, C.J. Caskey, J.F. Hess, Leptin receptor missense mutation in the fatty Zucker rat, Nat. Genet. 13 (1996) 18–19. [247] T.M. Plant, A.R. Durrant, Circulating leptin does not appear to provide a signal for triggering the initiation of puberty in the male rhesus monkey (Macaca mulatta), Endocrinology 138 (1997) 4505–4508. [248] T.M. Plant, Leptin, growth hormone, and the onset of primate puberty, J. Clin. Endocrinol. Metab. 86 (2001) 458–460. [249] T.M. Plant, Neurobiological bases underlying the control of the onset of puberty in the rhesus monkey: a representative higher primate, Front. Neuroendocrinol. 22 (2001) 107–139. [250] T.M. Plant, Neurophysiology of puberty, J. Adolesc. Health 31 (2002) 185–191. [251] V. Popovic, S. Damjanovic, C. Dieguez, F.F. Casanueva, Leptin and the pituitary, Pituitary 4 (2001) 7–14.

250

A. Sahu / Frontiers in Neuroendocrinology 24 (2004) 225–253

[252] D. Qu, D.S. Ludwig, S. Gammeltoft, M. Piper, M.A. Pelleymounter, M.J. Cullen, W.F. Mathes, R. Przypek, R. Kanarek, E. Maratos-Flier, A role for melanin-concentrating hormone in the central regulation of feeding behaviour, Nature 380 (1996) 243–247. [253] T. Rahn, M. Ridderstrale, H. Tornqvist, V. Manganiello, G. Fredrikson, P. Belfrage, E. Degerman, Essential role of phosphatidylinositol 3-kinase in insulin-induced activation and phosphorylation of the cGMP-inhibited cAMP phosphodiesterase in rat adipocytes. Studies using the selective inhibitor wortmannin, FEBS Lett. 350 (1994) 314–318. [254] S. Ray, C.T. Sherman, M. Lu, A.R. Brasier, Angiotensinogen gene expression is dependent on signal transducer and activator of transcription 3-mediated p300/cAMP response element binding protein-binding protein coactivator recruitment and histone acetyltransferase activity, Mol. Endocrinol. 16 (2002) 824–836. [255] R.R. Reinhardt, E. Chin, J. Zhou, M. Taira, T. Murata, V.C. Manganiello, C.A. Bondy, Distinctive anatomical patterns of gene expression for cGMP-inhibited cyclic nucleotide phosphodiesterases, J. Clin. Invest. 95 (1995) 1528–1538. [256] C.M. Rondinone, E. Carvalho, T. Rahn, V.C. Manganiello, E. Degerman, U.P. Smith, Phosphorylation of PDE3B by phosphatidylinositol 3-kinase associated with the insulin receptor, J. Biol. Chem. 275 (2000) 10093–10098. [257] C.I. Rosenblum, M. Tota, D. Cully, T. Smith, R. Collum, S. Qureshi, J.F. Hess, M.S. Phillips, P.J. Hey, A. Vongs, T.M. Fong, L. Xu, H.Y. Chen, R.G. Smith, C. Schindler, L.H. Van Der Ploeg, Functional STAT 1 and 3 signaling by the leptin receptor (OB-R); reduced expression of the rat fatty leptin receptor in transfected cells, Endocrinology 137 (1996) 5178– 5181. [258] M. Rossi, S.J. Choi, D. OÕshea, T. Miyoshi, M.A. Ghatei, S.R. Bloom, Melanin-concentrating hormone acutely stimulates feeding, but chronic administration has no effect on body weight, Endocrinology 138 (1997) 351–355. [259] P. Rosso, Regulation of food intake during pregnancy and lactation, Ann. N. Y. Acad. Sci. 499 (1987) 191–196. [260] C. Rovere, A. Viale, J. Nahon, P. Kitabgi, Impaired processing of brain proneurotensin and promelanin-concentrating hormone in obese fat/fat mice, Endocrinology 137 (1996) 2954–2958. [261] W. Rowe, V. Viau, M.J. Meaney, R. Quirion, Stimulation of CRH-mediated ACTH secretion by central administration of neurotensin: evidence for the participation of the paraventricular nucleus, J. Neuroendocrinol. 7 (1995) 109–117. [262] M.S. Rumantir, M. Vaz, G.L. Jennings, G. Collier, D.M. Kaye, D.R. Seals, G.H. Wiesner, H.P. Brunner-La Rocca, M.D. Esler, Neural mechanisms in human obesity-related hypertension, J. Hypertens. 17 (1999) 1125–1133. [263] A. Sahu, P.S. Kalra, S.P. Kalra, Food deprivation and ingestion induce reciprocal changes in neuropeptide Y concentrations in the paraventricular nucleus, Peptides 9 (1988) 83–86. [264] A. Sahu, C.A. Sninsky, C.P. Phelps, M.G. Dube, P.S. Kalra, S.P. Kalra, Neuropeptide Y release from the paraventricular nucleus increases in association with hyperphagia in streptozotocininduced diabetic rats, Endocrinology 131 (1992) 2979–2985. [265] A. Sahu, M.G. Dube, C.P. Phelps, C.A. Sninsky, P.S. Kalra, S.P. Kalra, Insulin and insulin-like growth factor II suppress neuropeptide Y release from the nerve terminals in the paraventricular nucleus: a putative hypothalamic site for energy homeostasis, Endocrinology 136 (1995) 5718–5724. [266] A. Sahu, C.A. Sninsky, S.P. Kalra, Evidence that hypothalamic neuropeptide Y gene expression and NPY levels in the paraventricular nucleus increase before the onset of hyperphagia in experimental diabetes, Brain Res. 755 (1997) 339–342. [267] A. Sahu, Evidence suggesting that galanin (GAL), melaninconcentrating hormone (MCH), neurotensin (NT), proopiomelanocortin (POMC) and neuropeptide Y (NPY) are targets of

[268]

[269]

[270]

[271]

[272]

[273]

[274]

[275]

[276]

[277]

[278]

[279]

[280]

[281] [282]

[283]

[284]

leptin signaling in the hypothalamus, Endocrinology 139 (1998) 795–798. A. Sahu, Leptin decreases food intake induced by melaninconcentrating hormone (MCH), galanin (GAL) and neuropeptide Y (NPY) in the rat, Endocrinology 139 (1998) 4739–4742. A. Sahu, R.E. Carraway, Y.P. Wang, Evidence that neurotensin mediates the central effect of leptin on food intake in rat, Brain Res. 888 (2001) 343–347. A. Sahu, Resistance to the satiety action of leptin following chronic central leptin infusion is associated with the development of leptin resistance in neuropeptide Y neurones, J. Neuroendocrinol. 14 (2002) 796–804. A. Sahu, Interactions of neuropeptide Y, hypocretin-I (orexin A) and melanin-concentrating hormone on feeding in rats, Brain Res. 944 (2002) 232–238. A. Sahu, S.P. Kalra, Neuropeptidergic regulation of feeding behavior: neuropeptide Y, Trends Endocrinol. Metab. 4 (1993) 217–224. A. Sahu, L. Nguyen, R.M. OÕDoherty, Nutritional regulation of hypothalamic leptin receptor gene expression is defective in dietinduced obesity, J. Neuroendocrinol. 14 (2002) 887–893. A. Sahu, T.M. Plant, Leptin, neuropeptide Y and puberty in non-human primates, in: J.P. Bourguignon, T.M. Plant (Eds.), Control of the onset of puberty V, Elsevier Science B.V, Amsterdam, 2000, pp. 351–361. A. Sahu, R. Pal, Phosphodiesterase 3B-cyclic AMP pathway of leptin signaling in the hypothalamus is altered during chronic central leptin infusion: implication in leptin resistance, in: Proceedings of the 33rd Annual Meeting of the Society for Neuroscience, New Orleans, LA, November 8–12, 2003. T. Sakurai, A. Amemiya, M. Ishii, I. Matsuzaki, R.M. Chemelli, H. Tanaka, S.C. Williams, J.A. Richardson, G.P. Kozlowski, S. Wilson, J.R. Arch, R.E. Buckingham, A.C. Haynes, S.A. Carr, R.S. Annan, D.E. Mcnulty, W.S. Liu, J.A. Terrett, N.A. Elshourbagy, D.J. Bergsma, M. Yanagisawa, Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior, Cell 92 (1998) 573–585. R. Saladin, P. De Vos, M. Guerre-Millo, A. Leturque, J. Girard, B. Staels, J. Auwerx, Transient increase in obese gene expression after food intake or insulin administration, Nature 377 (1995) 527–529. G. Sanacora, M. Kershaw, J.A. Finkelstein, J.D. White, Increased hypothalamic content of preproneuropeptide Y messenger ribonucleic acid in genetically obese Zucker rats and its regulation by food deprivation, Endocrinology 127 (1990) 730– 737. N. Satoh, Y. Ogawa, T. Katsuura, M. Hayase, T. Tsuji, K. Imagawa, Y. Yoshimasa, S. Nighi, K. Hosoda, K. Nakao, The arcuate nucleus s a primary site of satiety effect of leptin in rats, Neurosci. Lett. 224 (1997) 149–152. N. Satoh, Y. Ogawa, G. Katsuura, T. Tsuji, H. Masuzaki, J. Hiraoka, T. Okazaki, M. Tamaki, M. Hayase, Y. Yoshimasa, S. Nishi, K. Hosoda, K. Nakao, Pathophysiological significance of the obese gene product, leptin, in ventromedial hypothalamus (VMH)-lesioned rats: evidence for loss of its satiety effect in VMH-lesioned rats, Endocrinology 138 (1997) 947–954. P.J. Scarpace, M. Matheny, R.L. Moore, N. Tumer, Impaired leptin responsiveness in aged rats, Diabetes 49 (2000) 431–435. P.J. Scarpace, N. Tumer, Peripheral and hypothalamic leptin resistance with age-related obesity, Physiol. Behav. 74 (2001) 721–727. P.J. Scarpace, M. Matheny, N. Tumer, Hypothalamic leptin resistance is associated with impaired leptin signal transduction in aged obese rats, Neuroscience 104 (2001) 1111–1117. P.J. Scarpace, M. Matheny, Y. Zhang, N. Tumer, C.D. Frase, E.W. Shek, B. Hong, V. Prima, S. Zolotukhin, Central leptin

A. Sahu / Frontiers in Neuroendocrinology 24 (2004) 225–253

[285]

[286]

[287]

[288]

[289]

[290]

[291]

[292]

[293]

[294]

[295]

[296]

[297]

[298]

[299]

[300]

[301]

gene delivery evokes persistent leptin signal transduction in young and aged-obese rats but physiological responses become attenuated over time in aged-obese rats, Neuropharmacology 42 (2002) 548–561. P.J. Scarpace, M. Matheny, Y. Zhang, E.W. Shek, V. Prima, S. Zolotukhin, N. Tumer, Leptin-induced leptin resistance reveals separate roles for the anorexic and thermogenic responses in weight maintenance, Endocrinology 143 (2002) 3026–3035. U. Scherrer, D. Randin, L. Tappy, P. Vollenweider, E. Jequier, P. Nicod, Body fat and sympathetic nerve activity in healthy subjects, Circulation 89 (1994) 2634–2640. R.R. Schick, S. Samsami, J.P. Zimmermann, T. Eberl, C. Endres, V. Schusdziarra, M. Classen, Effect of galanin on food intake in rats: involvement of lateral and ventromedial hypothalamic sites, Am. J. Physiol. 264 (1993) R355–R361. D.A. Schoeller, L.K. Cella, M.K. Sinha, J.F. Caro, Entrainment of the diurnal rhythm of plasma leptin to meal timing, J. Clin. Invest. 100 (1997) 1882–1887. M.W. Schwartz, J.L. Marks, A.J. Sipols, D.G. Baskin, S.C. Woods, S.E. Kahn, D. Porte Jr., Central insulin administration reduces neuropeptide Y mRNA expression in the arcuate nucleus of food-deprived lean (Fa/Fa) but not obese (fa/fa) Zucker rats, Endocrinology 128 (1991) 2645–2647. M.W. Schwartz, A.J. Sipols, J.L. Marks, G. Sanacora, J.D. White, A. Scheurink, S.E. Kahn, D.G. Baskin, S.C. Woods, D.P. Figlewicz, et al., Inhibition of hypothalamic neuropeptide Y gene expression by insulin, Endocrinology 130 (1992) 3608–3616. M.W. Schwartz, R.J. Seeley, L.A. Campfield, P. Burn, D.G. Baskin, Identification of targets of leptin action in rat hypothalamus, J. Clin. Invest. 98 (1996) 1101–1106. M.W. Schwartz, E. Peskind, M. Raskind, E.J. Boyko, D. Porte Jr., Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans, Nat. Med. 2 (1996) 589–593. M.W. Schwartz, R.J. Seeley, S.C. Woods, D.S. Weigle, L.A. Campfield, P. Burn, D.G. Baskin, Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus, Diabetes 46 (1997) 2119–2123. M.W. Schwartz, S.C. Woods, D. Porte Jr., R.J. Seeley, D.G. Baskin, Central nervous system control of food intake, Nature 404 (2000) 661–671. R.S. Schwartz, Obesity in the elderly, in: G.A. Bray, C. Bouchard, W.P.T. James (Eds.), Hand book of obesity, Marcel Dekker, New York, 1998, pp. 103–114. R.M. Seeber, J.T. Smith, B.J. Waddell, Plasma leptin-binding activity and hypothalamic leptin receptor expression during pregnancy and lactation in the rat, Biol. Reprod. 66 (2002) 1762– 1767. R.J. Seeley, K.A. Yagaloff, S.L. Fisher, P. Burn, T.E. Thiele, G. Van Dijk, D.G. Baskin, M.W. Schwartz, Melanocortin receptors in leptin effects, Nature 390 (1997) 349. G. Segal-Lieberman, R.H. Bradley, E. Kokkotou, M. Carlson, D. Trombly, X. Wang, S.H. Bates, M.G. Myers Jr., J.S. Flier, E. Maratos-Flier, Melanin-concentrating hormone is a critical mediator of the leptin-deficient phenotype, Proc. Natl. Acad. Sci. USA. 100 (2003) 10085–10090. R. Senaris, T. Garcia-Caballero, X. Casabiell, R. Gallego, R. Castro, R.V. Considine, C. Dieguez, F.F. Casanueva, Synthesis of leptin in human placenta, Endocrinology 138 (1997) 4501– 4504. L.M. Seoane, M. Lopez, S. Tovar, F.F. Casanueva, R. Senaris, C. Dieguez, Agouti-related peptide, neuropeptide Y, and somatostatin-producing neurons are targets for ghrelin actions in the rat hypothalamus, Endocrinology 144 (2003) 544–551. V. Sergeyev, C. Broberger, T. Hokfelt, Effect of LPS administration on the expression of POMC, NPY, galanin, CART and MCH mRNAs in the rat hypothalamus, Brain Res. Mol. Brain Res. 90 (2001) 93–100.

251

[302] A. Seth, S. Stanley, W. Dhillo, K. Murphy, M. Ghatei, S. Bloom, Effects of galanin-like peptide on food intake and the hypothalamo–pituitary–thyroid axis, Neuroendocrinology 77 (2003) 125– 131. [303] E.W. Shek, P.J. Scarpace, Resistance to the anorexic and thermogenic effects of centrally administrated leptin in obese aged rats, Regul. Pept. 92 (2000) 65–71. [304] M. Shimada, N.A. Tritos, B.B. Lowell, J.S. Flier, E. MaratosFlier, Mice lacking melanin-concentrating hormone are hypophagic and lean, Nature 396 (1998) 670–674. [305] M. Shimizu-Albergine, D.L. Ippolito, J.A. Beavo, Downregulation of fasting-induced cAMP response element-mediated gene induction by leptin in neuropeptide Y neurons of the arcuate nucleus, J. Neurosci. 21 (2001) 1238–1246. [306] M. Shintani, Y. Ogawa, K. Ebihara, M. Aizawa-Abe, F. Miyanaga, K. Takaya, T. Hayashi, G. Inoue, K. Hosoda, M. Kojima, K. Kangawa, K. Nakao, Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway, Diabetes 50 (2001) 227– 232. [307] B. Shirley, The food intake of rats during pregnancy and lactation, Lab. Anim. Sci. 34 (1984) 169–172. [308] J.R. Shutter, M. Graham, A.C. Kinsey, S. Scully, R. Luthy, K.L. Stark, Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice, Genes Dev. 11 (1997) 593–602. [309] M.R. Sierra-Honigmann, A.K. Nath, C. Murakami, G. GarciaCardena, A. Papapetropoulos, W.C. Sessa, L.A. Madge, J.S. Schechner, M.B. Schwabb, P.J. Polverini, J.R. Flores-Riveros, Biological action of leptin as an angiogenic factor, Science 281 (1998) 1683–1686. [310] F.J. Smith, L.A. Campfield, J.A. Moschera, P.S. Bailon, P. Burn, Feeding inhibition by neuropeptide Y, Nature 382 (1996) 307. [311] S.H. Soderling, J.A. Beavo, Regulation of cAMP and cGMP signaling: new phosphodiesterases and new functions, Curr. Opin. Cell Biol. 12 (2000) 174–179. [312] D. Spanswick, M.A. Smith, V.E. Groppi, S.D. Logan, M.L. Ashford, Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels, Nature 390 (1997) 521– 525. [313] N. Stahl, T.J. Farruggella, T.G. Boulton, Z. Zhong, J.E. Darnell Jr., G.D. Yancopoulos, Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors, Science 267 (1995) 1349–1353. [314] B.G. Stanley, S.F. Leibowitz, N. Eppel, S. St. Pierre, B.G. Hoebel, Suppression of norepinephrine-elicited feeding by neurotensin: evidence for behavioral, anatomical and pharmacological specificity, Brain Res. 343 (1985) 297–304. [315] B.G. Stanley, S.E. Kyrkouli, S. Lampert, S.F. Leibowitz, Neuropeptide Y chronically injected into the hypothalamus: a powerful neurochemical inducer of hyperphagia and obesity, Peptides 7 (1986) 1189–1192. [316] R. Starr, T.A. Willson, E.M. Viney, L.J. Murray, J.R. Rayner, B.J. Jenkins, T.J. Gonda, W.S. Alexander, D. Metcalf, N.A. Nicola, D.J. Hilton, A family of cytokine-inducible inhibitors of signalling, Nature 387 (1997) 917–921. [317] T.W. Stephens, M. Basinski, P.K. Bristow, J.M. Bue-Valleskey, S.G. Burgett, L. Craft, J. Hale, J. Hoffmann, H.M. Hsiung, A. Kriauciunas, W. MacKeller, P.R. Rosteck Jr., B. Schoner, D. Smith, F.C. tinsley, X.-Y. Zhang, M. Heiman, The role of neuropeptide Y in the antiobesity action of the obese gene product, Nature 377 (1995) 530–532. [318] H. Stromberg, S.P. Svensson, O. Hermanson, Distribution of CREB-binding protein immunoreactivity in the adult rat brain, Brain Res. 818 (1999) 510–514.

252

A. Sahu / Frontiers in Neuroendocrinology 24 (2004) 225–253

[319] J.G. Sutcliffe, L. De Lecea, The hypocretins: excitatory neuromodulatory peptides for multiple homeostatic systems, including sleep and feeding, J. Neurosci. Res. 62 (2000) 161–168. [320] D.C. Sweet, A.S. Levine, C.J. Billington, C.M. Kotz, Feeding response to central orexins, Brain Res. 821 (1999) 535–538. [321] I. Szanto, C.R. Kahn, Selective interaction between leptin and insulin signaling pathways in a hepatic cell line, Proc. Natl. Acad. Sci. USA 97 (2000) 2355–2360. [322] M. Taira, S.C. Hockman, J.C. Calvo, P. Belfrage, V.C. Manganiello, Molecular cloning of the rat adipocyte hormonesensitive cyclic GMP-inhibited cyclic nucleotide phosphodiesterase, J. Biol. Chem. 268 (1993) 18573–18579. [323] Y. Takatsu, H. Matsumoto, T. Ohtaki, S. Kumano, C. Kitada, H. Onda, O. Nishimura, M. Fujino, Distribution of galanin-like peptide in the rat brain, Endocrinology 142 (2001) 1626–1634. [324] F. Takenoya, H. Funahashi, H. Matsumoto, T. Ohtaki, S. Katoh, H. Kageyama, R. Suzuki, M. Takeuchi, S. Shioda, Galanin-like peptide is co-localized with alpha-melanocyte stimulating hormone but not with neuropeptide Y in the rat brain, Neurosci. Lett. 331 (2002) 119–122. [325] F. Takenoya, K. Aihara, H. Funahashi, H. Matsumoto, T. Ohtaki, S. Tsurugano, S. Yamada, S. Katoh, H. Kageyama, M. Takeuchi, S. Shioda, Galanin-like peptide is target for regulation by orexin in the rat hypothalamus, Neurosci. Lett. 340 (2003) 209–212. [326] M. Tang-Christensen, P.J. Havel, R.R. Jacobs, P.J. Larsen, J.L. Cameron, Central administration of leptin inhibits food intake and activates the sympathetic nervous system in rhesus macaques, J. Clin. Endocrinol. Metab. 84 (1999) 711–717. [327] L.A. Tartaglia, M. Dembski, X. Weng, N. Deng, J. Culpepper, R. Devos, G.J. Richards, L.A. Campfield, F.T. Clark, J. Deeds, C. Muir, S. Sanker, A. Moriarty, K.J. Moore, J.S. Smutko, G.G. Mays, E.A. Woolf, C.A. Monroe, R.I. Tepper, Identification and expression cloning of a leptin receptor, OB-R, Cell 83 (1995) 1263–1271. [328] L.A. Tartaglia, The leptin receptor, J. Biol. Chem. 272 (1997) 6093–6096. [329] J.E. Thornton, C.C. Cheung, D.K. Clifton, R.A. Steiner, Regulation of hypothalamic proopiomelanocortin mRNA by leptin in ob/ob mice, Endocrinology 138 (1997) 5063–5066. [330] C. Torri, P. Pedrazzi, G. Leo, E.E. Muller, D. Cocchi, L.F. Agnati, M. Zoli, Diet-induced changes in hypothalamic proopiomelanocortin mRNA in the rat hypothalamus, Peptides 23 (2002) 1063–1068. [331] K. Toshinai, Y. Date, N. Murakami, M. Shimada, M.S. Mondal, T. Shimbara, J.L. Guan, Q.P. Wang, H. Funahashi, T. Sakurai, S. Shioda, S. Matsukura, K. Kangawa, M. Nakazato, Ghrelin-induced food intake is mediated via the orexin pathway, Endocrinology 144 (2003) 1506–1512. [332] N.A. Tritos, D. Vicent, J. Gillette, D.S. Ludwig, E.S. Flier, E. Maratos-Flier, Functional interactions between melanin-concentrating hormone, neuropeptide Y, and anorectic neuropeptides in the rat hypothalamus, Diabetes 47 (1998) 1687–1692. [333] M. Tschop, D.L. Smiley, M.L. Heiman, Ghrelin induces adiposity in rodents, Nature 407 (2000) 908–913. [334] Y. Uehara, H. Shimizu, K. Ohtani, N. Sato, M. Mori, Hypothalamic corticotropin-releasing hormone is a mediator of the anorexigenic effect of leptin, Diabetes 47 (1998) 890–893. [335] C. Vaisse, J.L. Halaas, C.M. Horvath, J.E. Darnell Jr., M. Stoffel, J.M. Friedman, Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice, Nat. Genet. 14 (1996) 95–97. [336] C. Vaisse, K. Clement, B. Guy-Grand, P. Froguel, A frameshift mutation in human MC4R is associated with a dominant form of obesity, Nat. Genet. 20 (1998) 113–114. [337] C. Vaisse, K. Clement, E. Durand, S. Hercberg, B. Guy-Grand, P. Froguel, Melanocortin-4 receptor mutations are a frequent

[338]

[339]

[340]

[341]

[342]

[343]

[344]

[345]

[346]

[347]

[348]

[349]

[350]

[351]

[352]

[353]

and heterogeneous cause of morbid obesity, J. Clin. Invest. 106 (2000) 253–262. G. Van Dijk, T.E. Thiele, J.C. Donahey, L.A. Campfield, F.J. Smith, P. Burn, I.L. Bernstein, S.C. Woods, R.J. Seeley, Central infusions of leptin and GLP-1-(7-36) amide differentially stimulate c-FLI in the rat brain, Am. J. Physiol. 271 (1996) R1096– R1100. G. Van Dijk, R.J. Seeley, T.E. Thiele, M.I. Friedman, H. Ji, C.W. Wilkinson, P. Burn, L.A. Campfield, R. Tenenbaum, D.G. Baskin, S.C. Woods, M.W. Schwartz, Metabolic, gastrointestinal, and CNS neuropeptide effects of brain leptin administration in the rat, Am. J. Physiol. 276 (1999) R1425– R1433. M. Van Heek, D.S. Compton, C.F. France, R.P. Tedesco, A.B. Fawzi, M.P. Graziano, E.J. Sybertz, C.D. Strader, H.R. Davis Jr., Diet-induced obese mice develop peripheral, but not central, resistance to leptin, J. Clin. Invest. 99 (1997) 385–390. N. Vrang, P.J. Larsen, J.T. Clausen, P. Kristensen, Neurochemical characterization of hypothalamic cocaine- amphetamineregulated transcript neurons, J. Neurosci. 19 (1999) RC5. J. Wang, K.L. Leibowitz, Central insulin inhibits hypothalamic galanin and neuropeptide Y gene expression and peptide release in intact rats, Brain Res. 777 (1997) 231–236. Z.W. Wang, Y.T. Zhou, T. Kakuma, Y. Lee, M. Higa, S.P. Kalra, M.G. Dube, P.S. Kalra, R.H. Unger, Comparing the hypothalamic and extrahypothalamic actions of endogenous hyperleptinemia, Proc. Natl. Acad. Sci. USA 96 (1999) 10373– 10378. Z.W. Wang, W.T. Pan, Y. Lee, T. Kakuma, Y.T. Zhou, R.H. Unger, The role of leptin resistance in the lipid abnormalities of aging, FASEB J. 15 (2001) 108–114. L. Wang, D.H. Saint-Pierre, Y. Tache, Peripheral ghrelin selectively increases Fos expression in neuropeptide Y—synthesizing neurons in mouse hypothalamic arcuate nucleus, Neurosci. Lett. 325 (2002) 47–51. H. Watanobe, Leptin directly acts within the hypothalamus to stimulate gonadotropin-releasing hormone secretion in vivo in rats, J. Physiol. 545 (2002) 255–268. D.S. Weigle, T.R. Bukowski, D.C. Foster, S. Holderman, J.M. Kramer, G. Lasser, C.E. Lofton-Day, D.E. Prunkard, C. Raymond, J.L. Kuijper, Recombinant ob protein reduces feeding and body weight in the ob/ob mouse, J. Clin. Invest. 96 (1995) 2065–2070. J.D. White, D. Olchovsky, M. Kershaw, M. Berelowitz, Increased hypothalamic content of preproneuropeptide-Y messenger ribonucleic acid in streptozotocin-diabetic rats, Endocrinology 126 (1990) 765–772. J.D. White, M. Kershaw, Increased hypothalamic neuropeptide Y expression following food deprivation, Mol. Cell Neurosci. 1 (1990) 41–48. D.W. White, K.K. Kuropatwinski, R. Devos, H. Baumann, L.A. Tartaglia, Leptin receptor (OB-R) signaling. Cytoplasmic domain mutational analysis and evidence for receptor homooligomerization, J. Biol. Chem. 272 (1997) 4065–4071. P.S. Widdowson, R. Upton, R. Buckingham, J. Arch, G. Williams, Inhibition of food response to intracerebroventricular injection of leptin is attenuated in rats with diet-induced obesity, Diabetes 46 (1997) 1782–1785. J.P. Wilding, S.G. Gilbey, C.J. Bailey, R.A. Batt, G. Williams, M.A. Ghatei, S.R. Bloom, Increased neuropeptide-Y messenger ribonucleic acid (mRNA) and decreased neurotensin mRNA in the hypothalamus of the obese (ob/ob) mouse, Endocrinology 132 (1993) 1939–1944. M.G. Willesen, P. Kristensen, J. Romer, Co-localization of growth hormone secretagogue receptor and nPY mRNA in the arcuate nucleus of the rat, Neuroendocrinology 70 (1999) 306–316.

A. Sahu / Frontiers in Neuroendocrinology 24 (2004) 225–253 [354] G. Williams, H. Cardoso, Y.C. Lee, M.A. Ghatei, P.R. Flatt, C.J. Bailey, S.R. Bloom, Reduced hypothalamic neurotensin concentrations in the genetically obese diabetic (ob/ob) mouse: possible relationship to obesity, Metabolism 40 (1991) 1112– 1116. [355] B.D. Wilson, D. Bagnol, C.B. Kaelin, M.M. Ollmann, I. Gantz, S.J. Watson, G.S. Barsh, Physiological and anatomical circuitry between Agouti-related protein and leptin signaling, Endocrinology 140 (1999) 2387–2397. [356] A.J. Woods, M.J. Stock, Leptin activation in hypothalamus, Nature 381 (1996) 745. [357] S.C. Woods, R.J. Seeley, D. Porte Jr., M.W. Schwartz, Signals that regulate food intake and energy homeostasis, Science 280 (1998) 1378–1383. [358] A.M. Wren, C.J. Small, H.L. Ward, K.G. Murphy, C.L. Dakin, S. Taheri, A.R. Kennedy, G.H. Roberts, D.G. Morgan, M.A. Ghatei, S.R. Bloom, The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion, Endocrinology 141 (2000) 4325–4328. [359] B. Xu, P.S. Kalra, W.G. Farmerie, S.P. Kalra, Daily changes in hypothalamic gene expression of neuropeptide Y, galanin, proopiomelanocortin, and adipocyte leptin gene expression and secretion: effects of food restriction, Endocrinology 140 (1999) 2868–2875. [360] B. Xu, E.H. Goulding, K. Zang, D. Cepoi, R.D. Cone, K.R. Jones, L.H. Tecott, L.F. Reichardt, Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor, Nat. Neurosci. 6 (2003) 736–742. [361] A. Yamanaka, K. Kunii, T. Nambu, N. Tsujino, A. Sakai, I. Matsuzaki, Y. Miwa, K. Goto, T. Sakurai, Orexin-induced food intake involves neuropeptide Y pathway, Brain Res. 859 (2000) 404–409. [362] G.S. Yeo, I.S. Farooqi, S. Aminian, D.J. Halsall, R.G. Stanhope, S. OÕrahilly, A frameshift mutation in MC4R associated with dominantly inherited human obesity, Nat. Genet. 20 (1998) 111–112. [363] M. Yokosuka, B. Xu, S. Pu, P.S. Kalra, S.P. Kalra, Neural substrates for leptin and neuropeptide Y (NPY) interaction:

[364]

[365]

[366]

[367]

[368]

[369]

[370]

[371]

[372]

253

hypothalamic sites associated with inhibition of NPY-induced food intake, Physiol. Behav. 64 (1998) 331–338. S. Yura, Y. Ogawa, N. Sagawa, H. Masuzaki, H. Itoh, K. Ebihara, M. Aizawa-Abe, S. Fujii, K. Nakao, Accelerated puberty and late-onset hypothalamic hypogonadism in female transgenic skinny mice overexpressing leptin, J. Clin. Invest. 105 (2000) 749–755. J.M. Zabolotny, K.K. Bence-Hanulec, A. Stricker-Krongrad, F. Haj, Y. Wang, Y. Minokoshi, Y.B. Kim, J.K. Elmquist, L.A. Tartaglia, B.B. Kahn, B.G. Neel, PTP1B regulates leptin signal transduction in vivo, Dev. Cell 2 (2002) 489–495. N. Zarjevski, I. Cusin, R. Vettor, F. Rohner-Jeanrenaud, B. Jeanrenaud, Chronic intracerebroventricular neuropeptide-Y administration to normal rats mimics hormonal and metabolic changes of obesity, Endocrinology 133 (1993) 1753–1758. Y. Zhang, R. Proenca, M. Maffei, M. Barone, L. Leopold, J.M. Friedman, Positional cloning of the mouse obese gene and its human homologue, Nature 372 (1994) 425–432. A.Z. Zhao, H. Zhao, J. Teague, W. Fujimoto, J.A. Beavo, Attenuation of insulin secretion by insulin-like growth factor 1 is mediated through activation of phosphodiesterase 3B, Proc. Natl. Acad. Sci. USA 94 (1997) 3223–3228. A.Z. Zhao, K.E. Bornfeldt, J.A. Beavo, Leptin inhibits insulin secretion by activation of phosphodiesterase 3B, J. Clin. Invest. 102 (1998) 869–873. A.Z. Zhao, M.M. Shinohara, D. Huang, M. Shimizu, H. EldarFinkelman, E.G. Krebs, J.A. Beavo, K.E. Bornfeldt, Leptin induces insulin-like signaling that antagonizes cAMP elevation by glucagon in hepatocytes, J. Biol. Chem. 275 (2000) 11348– 11354. A.Z. Zhao, J.N. Huan, S. Gupta, R. Pal, A. Sahu, A phosphatidylinositol 3-kinase phosphodiesterase 3B-cyclic AMP pathway in hypothalamic action of leptin on feeding, Nat. Neurosci. 5 (2002) 727–728. M. Ziotopoulou, C.S. Mantzoros, S.M. Hileman, J.S. Flier, Differential expression of hypothalamic neuropeptides in the early phase of diet-induced obesity in mice, Am. J. Physiol. Endocrinol. Metab. 279 (2000) E838–E845.