Leptin and reproductive function

Biochimie 94 (2012) 2075e2081

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Review

Leptin and reproductive function Gary J. Hausman a, *, C. Richard Barb a, Clay A. Lents b a b

USDA, ARS, Richard B. Russell Research Center, RRC, 950 College Station Rd, Athens, GA 30605, USA USDA, ARS, U.S. Meat Animal Research Center, Clay Center, NE 68933, USA

a r t i c l e i n f o

a b s t r a c t

Article history: Received 19 October 2011 Accepted 17 February 2012 Available online 2 March 2012

Adipose tissue plays a dynamic role in whole-body energy homeostasis by acting as an endocrine organ. Collective evidence indicates a strong link between neural influences and adipocyte expression and secretion of leptin. Developmental changes in these relationships are considered important for pubertal transition in reproductive function. Leptin augments secretion of gonadotropin hormones, which are essential for initiation and maintenance of normal reproductive function, by acting centrally at the hypothalamus to regulate gonadotropin-releasing hormone (GnRH) neuronal activity and secretion. The effects of leptin on GnRH are mediated through interneuronal pathways involving neuropeptide-Y, proopiomelanocortin and kisspeptin. Increased infertility associated with diet induced obesity or central leptin resistance are likely mediated through the kisspeptin-GnRH pathway. Furthermore, Leptin regulates reproductive function by altering the sensitivity of the pituitary gland to GnRH and acting at the ovary to regulate follicular and luteal steroidogenesis. Thus leptin serves as a putative signal that links metabolic status with the reproductive axis. The intent of this review is to examine the biological role of leptin with energy metabolism, and reproduction. Published by Elsevier Masson SAS.

Keywords: Reproduction Adipose tissue Leptin Kisspeptin Luteinizing hormone Ovary

1. Adipose tissue as an endocrine organ Adipose tissue plays a dynamic role in physiological mechanisms and whole-body homeostasis. The role of adipose tissue includes responding to a variety of signals and subsequently secreting factors or “adipokines” that have important roles in physiology [1]. Current evidence indicates that many of the adipose tissue “adipokines, can be considered true endocrine factors [2]. Therefore, adiposity could impact physiological states, such as reproductive condition or status, through secretion of adipokines. Serum concentrations of many hormones and growth factors that regulate adipocyte function and leptin are influenced by body weight or nutritional status [3]. Proteomic analysis of conditioned media from adipocyte cultures identified several secreted proteins, including relaxin, interleukins (IL-1A, IL-1B, IL-8, IL-6, IL-15), and insulin-like growth factor binding protein (IGFBP-5 [4];). These studies demonstrate the expression of several major adipokines or cytokines (at the protein level) in pig adipose tissue which may influence metabolism and growth. Thus, the support continues to grow for the idea that adipose tissue functions as an endocrine organ.

* Corresponding author. Tel.: þ1 7065463124. E-mail addresses: [email protected], (G.J. Hausman).

[email protected]

0300-9084/$ e see front matter Published by Elsevier Masson SAS. doi:10.1016/j.biochi.2012.02.022

Recent studies in the field of adipocyte biology have demonstrated that adipose tissue is the largest endocrine and paracrine organ in the body producing, in addition to adipokines, a wider variety of factors than ever expected [5]. The discovery of leptin in 1994 clearly triggered the massive search for other adipose tissue derived factors. White adipose tissue consists of adipocytes and stromal vascular cells, some of which are stem cells capabable of differentiating into several lineages including neuronal cells [5]. Chaldakov [6] proposed the concept of neuroadipology, similar to links between neurobiology and other topics, such as neuroimmunology or neuroendocrinology. This is based on considerable evidence of adipose derived neuropeptides, neurotrophic factors, pituitary hormones, hypothalamic releasing factors, and neurotransmitters [5]. Furthermore, the brain can control adipose tissue functions in a bidirectional fashion since many neuropeptides and neurotrophic factors and their receptors are expressed by adipose tissue and brain [7,8]. Additionally, pituitary hormones and hypothalamic releasing factors are expressed in adipose tissue [9]. The influence of age on gene expression of neurotrophic, neuropeptides and associated receptors in adipose tissue was examined in studies of growing pigs [8]. Neuropeptide-Y (NPY) and NPY2 receptor (NPY2R) gene expression significantly decreased with age in pig adipose tissue. Immunocytochemical studies revealed NPYand NPY2R proteins in mouse and rat adipose tissue sympathetic nerves [10e12]. Release of NPY from sympathetic nerves and secretion from

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blood vessels could result in significant local levels of NPY in adipose tissue [12]. Decreased NPY and NPY2R gene expression and increased leptin gene expression in middle subcutaneous adipose tissue (MSQ) were correlated with age in these pigs [13]. The age decrease in NPY expression may reflect morphological changes in nerves and blood vessels driven by adipocyte hypertrophy. The expression of ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) genes has also been demonstrated in adipose tissue from growing pigs [8]. Recent studies indicate that CNTF could modulate adipocyte leptin gene expression and secretion at the local level [14]. Furthermore, CNTF directly affects adipocyte gene expression and preadipocytes express CNTF receptor components [15,16]. Other evidence relating local NPY to leptin expression and(or) secretion include in vivo studies in sheep [17] and in vitro studies of adipocytes and sympathetic neurons [18]. This collective evidence [5,8] indicates that the concept of neuroadipology involves a strong link between adipocyte leptin expression and secretion and neural influences that are expressed and possibly secreted by adipose tissue throughout growth. It is important to consider that leptin secretion and expression is adipose tissue depot dependent [19e22]. Furthermore, the extent of sympathetic innervation and blood flow and(or) blood vessels is also quite depot dependent [23]. Therefore, it is conceivable that amount of NPY and other neuropeptides in adipose tissue would reflect the levels of blood vessels and sympathetic innervation which, in turn, would be associated with variable levels of leptin expression and secretion. Possibly, the maturity of a particular depot in regards to innervation and blood flow may, in part, trigger the onset of puberty. 2. Leptin: a metabolic signal and puberty Metabolic signals are considered important in the initiation of puberty [24e26]. Identification of these signals has, however, remained elusive primarily due to the large number of substances originating peripherally that can act centrally to modify gonadotropin-releasing hormone (GnRH) neuronal activity. The discovery of leptin has improved our understanding of the relationship between adipose tissue, energy homeostasis and puberty [27]. Leptin treatment advanced sexual maturation in ad lib fed mice [28,29]. In addition, chronic leptin treatment not only reduced food intake and body weight in leptin deficient ob/ob mice, but also restored fertility [30]. Serum concentrations of leptin increase during puberty in the mouse [28,31], heifer [32] and pig [33] and, in the human female, age at first menarche was inversely related to serum concentrations of leptin [34]. Thus, leptin may serve as a circulating signal of nutritional state that activates the reproductive axis. Alternatively, several reports have demonstrated that circulating concentrations of leptin are relatively unchanged during pubertal development in the female mouse or rat [35e37], while leptin administration failed to advance puberty onset in well nourished female mice [36]. Together these data indicate that leptin does not serve as a triggering signal but acts mainly as a permissive signal that allows puberty to occur. Although serum leptin concentrations increased during puberty in the gilt, other factors in addition to leptin may regulate onset of puberty. It is hypothesized that estradiol modulates the hypothalamic-pituitary response to leptin. Moreover, estradiol may regulate the pubertal related changes in leptin gene expression. In the ovariectomized (OVX) prepubertal gilt, estrogen induced increased leptin mRNA expression in adipose tissue at the time of expected puberty but not in younger animals [33]. This was associated with greater LH secretion [38] and an age dependent increase in hypothalamic long form leptin receptor (OB-rb) gene expression [39].

In the prepubertal ruminant, short-term feed restriction decreased adipose tissue leptin gene expression and leptin secretion, but increased hypothalamic OB-rb expression [40,41]. This was associated with decreased serum insulin, IGF-I and luteinizing hormone (LH) pulse frequency [41,42]. In addition, serum concentrations of leptin increased as did leptin gene expression in heifers during pubertal development. This coincided with increases in serum IGF-I concentrations and body weight [32]. In contrast to the prepubertal heifer [41], short-term fasting failed to reduce pulsatile LH secretion in the mature cow [43]. These reports suggest a heightened sensitivity of the hypothalamic-pituitary axis to variations in energy availability in the heifer. Several reports demonstrated that inhibition of LH secretion by restricted-feeding was reversed with leptin treatment, demonstrating a positive association between LH secretion and leptin [42e44]. Thus, leptin may act as a metabolic gate for puberty. In other words as circulating leptin concentrations increase during pubertal development, a threshold may be reached that permits activation of the reproductive axis. In this regard, leptin serves as a permissive signal for the onset of puberty, as opposed to a triggering signal for the initiation of puberty. 3. Leptin secretion and reproductive state Changes in body weight or nutritional status are characterized by alterations in serum levels of many hormones and growth factors that regulate adipocyte function and development, such as insulin, glucocorticoids, growth hormone (GH) and IGF-I [3,41,45]. In vivo studies demonstrated that increased leptin gene expression followed administration of glucocorticoids or insulin, suggesting that hormonal factors may mediate nutritionally induced changes in secretion of leptin [46,47]. Moreover, an acute 48 h fast or chronic feed restriction resulted in a marked reduction in leptin secretion coincident with a reduction in LH release in the cow [41] and ewe [42,44]. In contrast, an acute 28 h fast decreased leptin secretion but not LH secretion in the pig [3], while treatment with a competitive inhibitor of glycolysis suppressed LH secretion without affecting serum concentrations of leptin [3]. The ability of the pig to maintain euglycemia during an acute fast may account for the failure of acute feed deprivation to effect LH secretion [26]. In contrast, chronic feed restriction of mature OVX gilts for 7 days resulted in a concurrent reduction in serum leptin concentrations and LH secretion [48]. Although, leptin may serve as a metabolic signal which communicates energetic status to the brain, the neuroendocrine response to acute energy deprivation may be species specific and(or) dependent on metabolic mass. The effects of gonadal steroids on leptin secretion, and how this relates to LH release, are poorly understood. In general, circulating leptin concentrations are lower in males than females [49,50]. Leptin levels vary during the human menstrual cycle and peak during the luteal phase [51]. In mature heifers and cows, serum leptin concentrations decreased during the late luteal and early follicular phase of the estrous cycle and this was associated with a reduction in leptin gene expression in adipose tissue [32]. In the OVX prepubertal gilt, estrogen treatment induced leptin mRNA expression in adipose tissue, which occurred at the time of expected puberty in intact contemporaries [33], and was associated with greater LH secretion [38]. Release of LH in the ewe lambs was independent of pulsatile leptin secretion [52]. Therefore, the physiological relevance of varying levels of circulating leptin during the estrous cycle and pubertal development and its association with LH secretion suggests that leptin plays a pivotal role in metabolic control of neuroendocrine regulation of reproductive function as proposed by Tena-Sempere [53].

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4. Central effect of leptin on the hypothalamic-pituitary axis Acute intracerebroventricular (ICV) administration of leptin increased LH secretion in the estrogen primed OVX rat [54] and steroid implanted castrate male sheep [55]. Additionally, chronic ICV leptin treatment stimulated LH secretion in feed restricted OVX cows [43] and ewes [44]. In contrast, chronic ICV leptin treatment failed to stimulated LH secretion in well nourished OVX ewes with no steroid replacement [56], and in intact ewe lambs [42]. Leptin treatment stimulated basal and GnRH-induced LH secretion of pituitary explants from fasted, but not control fed cows, while having no effect on GnRH release from hypothalamic explants of either group of cows [57]. These results support the idea that metabolic state is a primary determinant of the hypothalamicpituitary response to leptin in ruminants. The localization of OB-rb expression in the ventromedial and arcuate nuclei (ARC) of the hypothalamus and the anterior pituitary gland of the pig [39], ewe [40], rat [58], and mouse [59], suggest that leptin could act at the brain and(or) pituitary to regulate gonadotropin secretion. Although it has been proposed that leptin acts directly on GnRH neurons [60], recent evidence indicates that GnRH cell bodies are not affected by leptin directly [61]. It is more likely that other neuropeptides, such as NPY [62], proopiomelanocortin (POMC [63];), gama-aminobutyric acid (GABA [60];) and kisspeptin [64] mediate the action of leptin. Colocalization of leptin receptor mRNA with NPY gene expression is compelling evidence that hypothalamic NPY is a potential target for leptin [62,65]. In addition, NPY has been implicated in regulation of GnRH and LH secretion in the rodent [66], primate [67], ewe [68], cow [69] and pig [70]. Central administration of NPY stimulated appetite in the ewe [71] and pig [72] and this was reversed by ICV injection of leptin in the pig [70]. However, it is also likely that other neuronal systems mediate the action of leptin, since fertility was only partially restored by leptin treatment in the ob/ob mouse with a homozygous null mutation for NPY [73]. In addition, in vivo perfusion of the median eminence-arcuate nucleus complex with leptin failed to affect NPY secretion, but did increase GH-releasing factor (GRF)/GH secretion [74]. Furthermore, leptin treatment failed to affect acute release of NPY from mouse [75], rat [76] or pig [77] hypothalamic tissue in vitro. Due to the action of kisspeptin directly on GnRH neurons [78e80], it has emerged as being a key factor that mediates the effects of leptin on LH secretion [53]. Caloric restriction and fasting reduces hypothalamic expression of kisspeptin mRNA in many species including rodents [64,81], sheep [82], and nonhuman primates [83], and its expression is also suppressed during lactation [84,85]. Normal secretion of LH under each of these conditions is restored by treatment with kisspeptin [84,86,87], which also rescues LH secretion in leptin deficient ob/ob mice [88]. A complex organization between neural networks that regulate appetite and kisspeptin neurons is beginning to be revealed, and appears to involve NPY and POMC, which as explained above are both regulated by leptin. Expression of kisspeptin mRNA was increased in murine hypothalamic N6 cells treated with NPY in vitro [64], and 13e30% of kisspeptin neurons in the ovine ARC are in close apposition to NPY fibers [82]. Similarly, 32e44% of kisspeptin cell bodies were contacted by POMC fibers [82]. Moreover, blockade of the mammalian target of rapamycin (mTOR), a cellular sensor for energy homeostasis and potential downstream mediator of leptin’s action, suppressed LH secretion and expression of kisspeptin mRNA in the anteroventral periventricular (AVPV) and ARC of the rat hypothalamus [89]. The effect of Leptin on gonadotropin secretion could, therefore, be mediated through kisspeptin neurons indirectly via its action at NPY and(or) POMC cell bodies. Interestingly, there appears to be a mechanism for feedback from kisspeptin cells to NPY

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and POMC neurons. Kisspeptin fibers are found in close apposition to approximately 7% of NPY neurons and 20% of POMC cell bodies in the ovine hypothalamus, and infusion of kisspeptin into the third ventricle increased NPY mRNA but reduced POMC mRNA in the ARC [82]. The functional consequence of this is not presently known. Luque et al. [64] found that expression of kisspeptin mRNA in the whole hypothalamus of ob/ob mice was unchanged compared with wild-type control animals; however, evaluation of discrete regions of the hypothalamus revealed that expression of kisspeptin mRNA was unchanged in the AVPV but significantly reduced in the ARC of ob/ob mice [88,90]. Therefore, as is the case with gonadal steroids [91e94], leptin appears to act on a subpopulation of kisspeptin neurons within the hypothalamus to control gonadotropin release. Leptin stimulated firing of kisspeptin neurons in hypothalamic slices of the ARC from guinea pigs [95]. The effect of leptin on kisspeptin cells in the ARC is probably direct because kisspeptin cells in the ARC of guinea pigs [95] and mice [88,96] express leptin receptor mRNA. Furthermore, treating murine and human hypothalamic cell lines with leptin increased the expression of kisspeptin mRNA [64,97], and treating ob/ob or Kiss1-Cre mice with leptin increased mRNA for kisspeptin in cells in the ARC [88,90] but not the AVPV [88,90,98]. Quennell et al. [90] found that kisspeptin cell bodies in the ARC contained leptin-activated second messengers (i.e. STAT-3) whereas kisspeptin cells in the AVPV did not. Secretion of LH was reduced and kisspeptin mRNA in the ARC and the dorsolateral region of the preoptic area was decreased in lean ovariectomized ewes when compared with ewes that had greater body fat [82]. Administering leptin into the third ventricle of these lean sheep for 72 h restored LH pulses [99]; however, hypothalamic expression of kisspeptin mRNA was only partially rescued [82]. Similarly, leptin did not fully reverse the lactationinduced reduction in expression of kisspeptin mRNA in rats [100]. This reinforces the expectation that the kisspeptin system, and consequently reproductive function, can be controlled by other metabolic factors beyond leptin alone. Conversely, Donato et al. [96] used the Cre/loxP system to selectively delete leptin receptor from kisspeptin neurons of mice and found this did not impair the animal’s ability to reach puberty nor their subsequent fertility. A series of studies led them to conclude that leptin’s stimulatory effect on puberty in mice can be relayed through the ventral premammillary nucleus and signaling through kisspeptin cells of the ARC is not involved in this pathway. Leptin-modulated activity of the kisspeptin neurons could contribute to increased infertility that arises in various metabolically diseased states such as obesity or diabetes. Gene expression of kisspeptin was reduced in the hypothalamus of streptozotocininduced diabetic male rats [101], and treating them with exogenous kisspeptin rescued LH release [101]. Moreover, concentrations of LH and testosterone and expression of kisspeptin mRNA was fully restored by treating the diabetic rats with exogenous leptin [101]. Secretion of LH was also restored when obese fa/fa Zucker rats (a model for leptin resistance and hypogonadotropism) were treated with kisspeptin [86], and diet induced leptin resistance was also associated with reduced LH and kisspeptin mRNA in the preoptic periventricular region of ovariectomized female BDA/2J mice [90]. Further support for the importance of leptin sensitivity is provided by Iwasa et al. [102] who found that female rats that underwent intrauterine growth retardation during their development as fetuses demonstrated leptin resistance after birth, and had reduced amounts of mRNA for kisspeptin in the hypothalamus during postnatal development resulting in delayed onset of puberty. Thus it appears that reduced fertility caused by hypothalamic hypogonadotropism arising from central leptin resistance could be mediated by kisspeptin neurons, at least in individuals that are predisposed to the condition.

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5. Leptin and ovarian function Leptin receptors have also been identified in both granulosa and theca cells of the human [103,104] bovine [105,106] and porcine [107] ovarian follicles. Several in vitro studies demonstrated that treatment with supraphysiological concentrations of leptin inhibited steroidogenesis in bovine granulosa [105,108] and theca cells [106]. Similar results were reported for the human [109,110], rat [111], sheep [112] and pig [113]. In contrast, physiological doses of leptin stimulated steroidogenesis in porcine granulosa cells in vitro [113] in the presence or absence of IGF-I. Thus circulating concentrations of leptin may influence reproduction by directly modulating follicular development or function. Passive immunization against leptin during the follicular phase of the estrous cycle increased ovarian estradiol secretion but had no effect on gonadotropin secretion, ovulation or subsequent luteal function in the ewe [114]. In contrast, direct ovarian arterial infusion of a high dose (20 mg/h) or a low dose (2 mg/h) of leptin had no effect on estradiol production but increased the progesterone production from the subsequent corpus luteum. This paradox may in part be explained by activation of alternate pathways which stimulate ovarian function, such as the GnRH-LH axis [77,115], GHIGF axis [116,117] and(or) altered ovarian blood flow [118,119]. The exposure of somatic cells of the porcine preovulatory follicle to leptin increased steroidogenic capacity of the luteal cells suggests a role for leptin in corpus luteum development. In support of this hypothesis, increased progesterone production from porcine granulosa cells treated with leptin was associated with increased expression of steroidogenic acute regulatory protein (StAR). The authors suggested that this may be a key regulatory event in the action of leptin on steroidogenesis [113]. In addition, leptin receptor expression increased during in vitro luteinization and was greater

Fig. 1. Leptin is synthesized in adipose tissues and secreted into the peripheral circulation. It acts centrally in the hypothalamus to suppress activity of NPY (neuropeptide-Y) neurons, which reduces the stimulatory drive on food intake and lessens NPY inhibition of kisspeptin cell bodies. Acting directly on POMC (proopiomelanocortin) neurons, leptin stimulates a-MSH (melanocyte stimulating hormone) release which functions to suppress food intake and alter growth. Activation of POMC cells stimulates kisspeptin neurons, which have axons that terminate near NPY and POMC expressing cell bodies where kisspeptin stimulates and inhibits each, respectively. Leptin can also act directly on subpopulations of kisspeptin neurons to further increase the stimulatory drive on GnRH (gonadotropin-releasing hormone) release and gonadotropin secretion from the pituitary gland. Leptin may further enhance LH (luteinizing hormone) secretion and support reproduction by acting to increase the sensitivity of gonadotrope cells in the pituitary gland to GnRH. A fluctuation in energy balance changes leptin secretion and alters these pathways. Solid lines represent established pathways. Dashed arrows represent recently proposed mechanisms.

in luteal tissue collected during the mid luteal phase in the pig [107]. Collectively, these data demonstrate that leptin plays a role in both follicular development and subsequent luteal function. 6. Conclusion Leptin is a key metabolic signal synthesized and secreted by fat cells that communicates information about body energy reserves, nutritional state, and metabolic shifts to the reproductive axis. Leptin can act peripherally at the ovary or centrally at the hypothalamus (Fig. 1) to augment reproductive function of females. Kisspeptin neurons are a key part of the central pathway by which leptin affects gonadotropin secretion. Hypogonadotropism and infertility observed in animal models with severe perturbations to circulating concentrations of leptin or hypothalamic sensitivity to leptin can partially be explained by suppression of the hypothalamic kisspeptin system. Whether this is a direct or indirect effect of leptin’s action on kisspeptin neurons is yet to be fully resolved. Acknowledgments We thank Linda Parnell for assisting in preparation of the manuscript. References [1] R.S. Ahima, Adipose tissue as an endocrine organ, Obesity 14 (2006) 242Se249S. [2] H. Hauner, Secretory factors from human adipose tissue and their functional role, Proc. Nutr. Soc. 64 (2005) 163e169. [3] C.R. Barb, J.B. Barrett, R.R. Kraeling, G.B. Rampacek, Serum leptin concentrations, luteinizing hormone and growth hormone secretion during feed and metabolic fuel restriction in the prepuberal gilt, Domest. Anim. Endocrinol. 20 (2001) 47e63. [4] G.J. Hausman, S.P. Poulos, R.L. Richardson, C.R. Barb, T. Andacht, H.C. Kirk, R.L. Mynatt, Secreted proteins and genes in fetal and neonatal pig adipose tissue and stromal-vascular cells, J. Anim. Sci. 84 (2006) 1666e1681. [5] G.N. Chaldakov, M. Fiore, G. Rancic, A.B. Tonchev, M.G. Hristova, N. Tuncel, D.D. Kostov, V. Bojanic, P. Atanassova, P.I. Ghenev, L. Aloe, The adipose tissue: a new member of the diffuse neuroendocrine system? Adipobiology 1 (2009) 87e93. [6] G.N. Chaldakov, M. Fiore, A.B. Tonchev, L. Aloe, Neuroadipology: a novel component of neuroendocrinology, Cell Biol. Int. 34 (2010) 1051e1053. [7] F. Sornelli, M. Fiore, G.N. Chaldakov, L. Aloe, Adipose tissue-derived nerve growth factor and brain-derived neurotrophic factor: results from experimental stress and diabetes, Gen. Physiol. Biophys. 28 (2009) 179e183. [8] G.J. Hausman, C.R. Barb, R.G. Dean, Patterns of gene expression in pig adipose tissue: insulin-like growth factor system proteins, neuropeptide Y (NPY), NPY receptors, neurotrophic factors and other secreted factors, Domest. Anim. Endocrinol. 35 (2008) 24e34. [9] A. Schäffler, J. Schölmerich, C. Buechler, The role of ’adipotropins’ and the clinical importance of a potential hypothalamic-pituitary-adipose axis, Nat. Rev. Endocrinol. 2 (2006) 374e383. [10] R. De Matteis, D. Ricquier, S. Cinti, TH-, NPY-, SP-, and CGRP-immunoreactive nerves in interscapular brown adipose tissue of adult rats acclimated at different temperatures: an immunohistochemical study, J. Neurocytol. 27 (1998) 877e886. [11] A. Giordano, M. Morroni, G. Santone, G.F. Marchesi, S. Cinti, Tyrosine hydroxylase, neuropeptide Y, substance P, calcitonin gene-related peptide and vasoactive intestinal peptide in nerves of rat periovarian adipose tissue: an immunohistochemical and ultrastructural investigation, J. Neurocytol. 25 (1996) 125e136. [12] L.E. Kuo, J.B. Kitlinska, J.U. Tilan, L. Li, S.B. Baker, M.D. Johnson, E.W. Lee, M.S. Burnett, S.T. Fricke, R. Kvetnansky, H. Herzog, Z. Zukowska, Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome, Nat. Med. 13 (2007) 803e811. [13] G.J. Hausman, C.R. Barb, R.G. Dean, Patterns of gene expression in pig adipose tissue: transforming growth factors, interferons, interleukins, and apolipoproteins, J. Anim. Sci. 85 (2007) 2445e2456. [14] Z. Zukowska-Grojec, E. Karwatowska-Prokopczuk, W. Rose, J. Rone, S. Movafagh, H. Ji, Y. Yeh, W.-T. Chen, H.K. Kleinman, E. Grouzmann, D.S. Grant, Neuropeptide Y: a novel angiogenic factor from the sympathetic nerves and endothelium, Circ. Res. 83 (1998) 187e195. [15] V. Ott, M. Fasshauer, B. Meier, A. Dalski, D. Kraus, T.W. Gettys, N. Perwitz, J. Klein, Ciliary neurotrophic factor influences endocrine adipocyte function: inhibition of leptin via PI 3-kinase, Mol. Cell. Endocrinol. 224 (2004) 21e27.

G.J. Hausman et al. / Biochimie 94 (2012) 2075e2081 [16] S. Zvonic, P. Cornelius, W.C. Stewart, R.L. Mynatt, J.M. Stephens, The regulation and activation of ciliary neurotrophic factor signaling proteins in adipocytes, J. Biol. Chem. 278 (2003) 2228e2235. [17] C.J. Dyer, J.M. Simmons, R.L. Matteri, D.H. Keisler, Effects of an intravenous injection of NPY on leptin and NPY-Y1 receptor mRNA expression in ovine adipose tissue, Domest. Anim. Endocrinol. 14 (1997) 325e333. [18] L.C. Turtzo, R. Marx, M.D. Lane, Cross-talk between sympathetic neurons and adipocytes in coculture, Proc. Natl. Acad. Sci. USA 98 (2001) 12385e12390. [19] F. Hube, U. Lietz, M. Igel, P.B. Jensen, H. Tornqvist, H.-G. Joost, H. Hauner, Difference in leptin mRNA levels between omental and subcutaneous abdominal adipose tissue from obese humans, Horm. Metab. Res. 28 (1996) 690e693. [20] B.C. Villafuerte, J.B. Fine, Y. Bai, W. Zhao, S. Fleming, M. DiGirolamo, Expressions of leptin and insulin-like growth factor-I are highly correlated and region-specific in adipose tissue of growing rats, Obes. Res. 8 (2000) 646e655. [21] T. Yamada, S. Kawakami, N. Nakanishi, Fat depot-specific differences in angiogenic growth factor gene expression and its relation to adipocyte size in cattle, J. Vet. Med. Sci. 72 (2010) 991e997. [22] C.T. Montague, J.B. Prins, L. Sanders, J. Zhang, C.P. Sewter, J. Digby, C.D. Byrne, S. O’Rahilly, Depot-related gene expression in human subcutaneous and omental adipocytes, Diabetes 47 (1998) 1384e1391. [23] D.B. Hausman, M. DiGirolamo, T.J. Bartness, G.J. Hausman, R.J. Martin, The biology of white adipocyte proliferation, Obes. Rev. 2 (2001) 239e254. [24] R.E. Frisch, Body fat, puberty and fertility, Biol. Rev. Camb. Philos. Soc. 59 (1984) 161e188. [25] J.L. Cameron, D.J. Koerker, R.A. Steiner, Metabolic changes during maturation of male monkeys: possible signals for onset of puberty, Am. J. Physiol. Endocrinol. Metab. 249 (1985) E385eE391. [26] C.R. Barb, R.R. Kraeling, G.B. Rampacek, C.R. Dove, Metabolic changes during the transition from the fed to the acute feed-deprived state in prepuberal and mature gilts, J. Anim. Sci. 75 (1997) 781e789. [27] 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) 546e549. [28] 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) 3144e3147. [29] 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) 391e395. [30] 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) 318e320. [31] 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) 88e90. [32] M.R. Garcia, M. Amstalden, S.W. Williams, R.L. Stanko, C.D. Morrison, D.H. Keisler, S.E. Nizielski, G.L. Williams, Serum leptin and its adipose gene expression during pubertal development, the estrous cycle, and different seasons in cattle, J. Anim. Sci. 80 (2002) 2158e2167. [33] H. Qian, C.R. Barb, M.M. Compton, G.J. Hausman, M.J. Azain, R.R. Kraeling, C.A. Baile, Leptin mRNA expression and serum leptin concentrations as influenced by age, weight, and estradiol in pigs, Domest. Anim. Endocrinol. 16 (1999) 135e143. [34] V. Matkovic, J.Z. Ilich, M. Skugor, N.E. Badenhop, P. Goel, A. Clairmont, D. Klisovic, R.W. Nahhas, J.D. Landoll, Leptin is inversely related to age at menarche in human females, J. Clin. Endocrinol. Metab. 82 (1997) 3239e3245. [35] R.S. Ahima, D. Prabakaran, J.S. Flier, Postnatal leptin surge and regulation of circadian rhythm of leptin by feeding. Implications for energy homeostasis and neuroendocrine function, J. Clin. Invest. 101 (1998) 1020e1027. [36] C.C. Cheung, J.E. Thornton, S.D. Nurani, D.K. Clifton, R.A. Steiner, A reassessment of leptin’s role in triggering the onset of puberty in the rat and mouse, Neuroendocrinology 74 (2001) 12e21. [37] F.H. Bronson, Puberty in female mice is not associated with increases in either body fat or leptin, Endocrinology 142 (2001) 4758e4761. [38] C.R. Barb, G.J. Hausman, R.R. Kraeling, Luteinizing hormone secretion as influenced by age and estradiol in the prepubertal gilt, Anim. Reprod. Sci. 122 (2010) 324e327. [39] J. Lin, C.R. Barb, R.R. Kraeling, G.B. Rampacek, Developmental changes in the long form leptin receptor and related neuropeptide gene expression in the pig brain, Biol. Reprod. 64 (2001) 1614e1618. [40] C.J. Dyer, J.M. Simmons, R.L. Matteri, D.H. Keisler, Leptin receptor mRNA is expressed in ewe anterior pituitary and adipose tissues and is differentially expressed in hypothalamic regions of well-fed and feed-restricted ewes, Domest. Anim. Endocrinol. 14 (1997) 119e128. [41] M. Amstalden, M.R. Garcia, S.W. Williams, R.L. Stanko, S.E. Nizielski, C.D. Morrison, D.H. Keisler, G.L. Williams, Leptin gene expression, circulating leptin, and luteinizing hormone pulsatility are acutely responsive to short-term fasting in prepubertal heifers: relationships to circulating insulin and insulin-like growth factor I, Biol. Reprod. 63 (2000) 127e133. [42] C.D. Morrison, J.A. Daniel, B.J. Holmberg, J. Djiane, N. Raver, A. Gertler, D.H. Keisler, Central infusion of leptin into well-fed and undernourished ewe

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50] [51]

[52]

[53] [54]

[55]

[56]

[57]

[58]

[59] [60]

[61]

[62]

[63]

[64]

[65]

[66]

2079

lambs: effects on feed intake and serum concentrations of growth hormone and luteinizing hormone, J. Endocrinol. 168 (2001) 317e324. M. Amstalden, M.R. Garcia, R.L. Stanko, S.E. Nizielski, C.D. Morrison, D.H. Keisler, G.L. Williams, Central infusion of recombinant ovine leptin normalizes plasma insulin and stimulates a novel hypersecretion of luteinizing hormone after short-term fasting in mature beef cows, Biol. Reprod. 66 (2002) 1555e1561. B.A. Henry, J.W. Goding, A.J. Tilbrook, F.R. Dunshea, I.J. Clarke, Intracerebroventricular infusion of leptin elevates the secretion of luteinising hormone without affecting food intake in long-term food-restricted sheep, but increases growth hormone irrespective of bodyweight, J. Endocrinol. 168 (2001) 67e77. Y. Chilliard, M. Bonnet, C. Delavaud, Y. Faulconnier, C. Leroux, J. Djiane, F. Bocquier, Leptin in ruminants. Gene expression in adipose tissue and mammary gland, and regulation of plasma concentration, Domest. Anim. Endocrinol. 21 (2001) 271e295. P. De Vos, R. Saladin, J. Auwerx, B. Staels, Induction of ob gene expression by corticosteroids is accompanied by body weight loss and reduced food intake, J. Biol. Chem. 270 (1995) 15958e15961. 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) 527e529. C.S. Whisnant, R.J. Harrell, Effect of short-term feed restriction and refeeding on serum concentrations of leptin, luteinizing hormone and insulin in ovariectomized gilts, Domest. Anim. Endocrinol. 22 (2002) 73e80. H. Shimizu, Y. Shimomura, Y. Nakanishi, T. Futawatari, K. Ohtani, N. Sato, M. Mori, Estrogen increases in vivo leptin production in rats and human subjects, J. Endocrinol. 154 (1997) 285e292. W.F. Blum, Leptin: the voice of the adipose tissue, Horm. Res. 48 (Suppl 4) (1997) 2e8. M. Ludwig, H.H. Klein, K. Diedrich, O. Ortmann, Serum leptin concentrations throughout the menstrual cycle, Arch. Gynecol. Obstet. 263 (2000) 99e101. S.E. Recabarren, A. Lobos, C. Vilches, P. Munoz, T. Sir-Petermann, Pulsatile leptin secretion is independent of luteinizing hormone secretion in prepubertal sheep, Endocrine 17 (2002) 175e184. M. Tena-Sempere, KiSS-1 and reproduction: focus on its role in the metabolic regulation of fertility, Neuroendocrinology 83 (2006) 275e281. W.H. Yu, M. Kimura, A. Walczewska, S. Karanth, S.M. McCann, Role of leptin in hypothalamic-pituitary function, Proc. Natl. Acad. Sci. USA 94 (1997) 1023e1028. D.W. Miller, P.A. Findlay, M.A. Morrison, N. Raver, C.L. Adam, Seasonal and dose-dependent effects of intracerebroventricular leptin on LH secretion and appetite in sheep, J. Endocrinol. 175 (2002) 395e404. B.A. Henry, J.W. Goding, W.S. Alexander, A.J. Tilbrook, B.J. Canny, F. Dunshea, A. Rao, A. Mansell, I.J. Clarke, Central administration of leptin to ovariectomized ewes inhibits food intake without affecting the secretion of hormones from the pituitary gland: evidence for a dissociation of effects on appetite and neuroendocrine function, Endocrinology 140 (1999) 1175e1182. M. Amstalden, D.A. Zieba, J.F. Edwards, P.G. Harms, T.H. Welsh Jr., R.L. Stanko, G.L. Williams, Leptin acts at the bovine adenohypophysis to enhance basal and gonadotropin-releasing hormone-mediated release of luteinizing hormone: differential effects are dependent upon nutritional history, Biol. Reprod. 69 (2003) 1539e1544. P.L. Zamorano, V.B. Mahesh, L.M. De Sevilla, L.P. Chorich, G.K. Bhat, D.W. Brann, Expression and localization of the leptin receptor in endocrine and neuroendocrine tissues of the rat, Neuroendocrinology 65 (1997) 223e228. L.A. Tartaglia, The leptin receptor, J. Biol. Chem. 272 (1997) 6093e6096. S.D. Sullivan, S.M. Moenter, g-aminobutyric acid neurons integrate and rapidly transmit permissive and inhibitory metabolic cues to gonadotropinreleasing hormone neurons, Endocrinology 145 (2004) 1194e1202. J.H. Quennell, A.C. Mulligan, A. Tups, X. Liu, S.J. Phipps, C.J. Kemp, A.E. Herbison, D.R. Grattan, G.M. Anderson, Leptin indirectly regulates gonadotropin-releasing hormone neuronal function, Endocrinology 150 (2009) 2805e2812. J. Iqbal, S. Pompolo, T. Murakami, E. Grouzmann, T. Sakurai, B. Meister, I.J. Clarke, Immunohistochemical characterization of localization of longform leptin receptor (OB-Rb) in neurochemically defined cells in the ovine hypothalamus, Brain Res. 920 (2001) 55e64. A. Sahu, Evidence suggesting that galanin (GAL), melanin-concentrating hormone (MCH), neurotensin (NT), proopiomelanocortin (POMC) and neuropeptide Y (NPY) are targets of leptin signaling in the hypothalamus, Endocrinology 139 (1998) 795e798. R.M. Luque, R.D. Kineman, M. Tena-Sempere, Regulation of hypothalamic expression of KiSS-1 and GPR54 genes by metabolic factors: analyses using mouse models and a cell line, Endocrinology 148 (2007) 4601e4611. K. Czaja, M. Lakomy, W. Sienkiewicz, J. Kaleczyc, Z. Pidsudko, C.R. Barb, G.B. Rampacek, R.R. Kraeling, Distribution of neurons containing leptin receptors in the hypothalamus of the pig, Biochem. Biophys. Res. Commun. 298 (2002) 333e337. S.P. Kalra, Mandatory neuropeptide-steroid signaling for the preovulatory luteinizing hormone-releasing hormone discharge, Endocr. Rev. 14 (1993) 507e538.

2080

G.J. Hausman et al. / Biochimie 94 (2012) 2075e2081

[67] A.H. Kaynard, K.-H.F. Pau, D.L. Hess, H.G. Spies, Third-ventricular infusion of neuropeptide Y suppresses luteinizing hormone secretion in ovariectomized Rhesus Macaques, Endocrinology 127 (1990) 2437e2444. [68] C.D. Morrison, J.A. Daniel, J.H. Hampton, P.R. Buff, T.M. McShane, M.G. Thomas, D.H. Keisler, Luteinizing hormone and growth hormone secretion in ewes infused intracerebroventricularly with neuropeptide Y, Domest. Anim. Endocrinol. 24 (2003) 69e80. [69] M.G. Thomas, O.S. Gazal, G.L. Williams, R.L. Stanko, D.H. Keisler, Injection of neuropeptide Y into the third cerebroventricle differentially influences pituitary secretion of luteinizing hormone and growth hormone in ovariectomized cows, Domest. Anim. Endocrinol. 16 (1999) 159e169. [70] C.R. Barb, R.R. Kraeling, G.B. Rampacek, G.J. Hausman, The role of neuropeptide Y and interaction with leptin in regulating feed intake and luteinizing hormone and growth hormone secretion in the pig, Reproduction 131 (2006) 1127e1135. [71] J.L. Miner, Recent advances in the central control of intake in ruminants, J. Anim. Sci. 70 (1992) 1283e1289. [72] C.R. Barb, G.J. Hausman, K.L. Houseknecht, Biology of leptin in the pig, Domest. Anim. Endocrinol. 21 (2001) 297e317. [73] 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) 1704e1707. [74] H. Watanobe, S. Habu, Leptin regulates growth hormone-releasing factor, somatostatin, and a-melanocyte-stimulating hormone but not neuropeptide Y release in rat hypothalamus in vivo: relation with growth hormone secretion, J. Neurosci. 22 (2002) 6265e6271. [75] M. Jang, A. Mistry, A.G. Swick, D.R. Romsos, Leptin rapidly inhibits hypothalamic neuropeptide Y secretion and stimulates corticotropin-releasing hormone secretion in adrenalectomized mice, J. Nutr. 130 (2000) 2813e2820. [76] P.J. King, P.S. Widdowson, H. Doods, G. Williams, Regulation of neuropeptide Y release from hypothalamic slices by melanocortin-4 agonists and leptin, Peptides 21 (2000) 45e48. [77] C.R. Barb, J.B. Barrett, R.R. Kraeling, Role of leptin in modulating the hypothalamic-pituitary axis and luteinizing hormone secretion in the prepuberal gilt, Domest. Anim. Endocrinol. 26 (2004) 201e214. [78] M.S. Irwig, G.S. Fraley, J.T. Smith, B.V. Acohido, S.M. Popa, M.J. Cunningham, M.L. Gottsch, D.K. Clifton, R.A. Steiner, Kisspeptin activation of gonadotropin releasing hormone neurons and regulation of KiSS-1 mRNA in the male rat, Neuroendocrinology 80 (2004) 264e272. [79] A.E. Herbison, X. d’Anglemont de Tassigny, J. Doran, W.H. Colledge, Distribution and postnatal development of Gpr54 gene expression in mouse brain and gonadotropin-releasing hormone neurons, Endocrinology 151 (2010) 312e321. [80] S. Constantin, C.S. Caligioni, S. Stojilkovic, S. Wray, Kisspeptin-10 facilitates a plasma membrane-driven calcium oscillator in gonadotropin-releasing hormone-1 neurons, Endocrinology 150 (2009) 1400e1412. [81] J.M. Castellano, V.M. Navarro, R. Fernández-Fernández, R. Nogueiras, S. Tovar, J. Roa, M.J. Vazquez, E. Vigo, F.F. Casanueva, E. Aguilar, L. Pinilla, C. Dieguez, M. Tena-Sempere, Changes in hypothalamic KiSS-1 system and restoration of pubertal activation of the reproductive axis by kisspeptin in undernutrition, Endocrinology 146 (2005) 3917e3925. [82] K. Backholer, J.T. Smith, A. Rao, A. Pereira, J. Iqbal, S. Ogawa, Q. Li, I.J. Clarke, Kisspeptin cells in the ewe brain respond to leptin and communicate with neuropeptide Y and proopiomelanocortin cells, Endocrinology 151 (2010) 2233e2243. [83] F. Wahab, F. Ullah, Y.-M. Chan, S.B. Seminara, M. Shahab, Decrease in hypothalamic Kiss1 and Kiss1r expression: a potential mechanism for fasting-induced suppression of the HPG axis in the adult male rhesus monkey (Macaca mulatta), Horm. Metab. Res. 43 (2011) 81e85. [84] S. Yamada, Y. Uenoyama, M. Kinoshita, K. Iwata, K. Takase, H. Matsui, S. Adachi, K. Inoue, K.-I. Maeda, H. Tsukamura, Inhibition of metastin (Kisspeptin-54)-GPR54 signaling in the arcuate nucleus-median eminence region during lactation in rats, Endocrinology 148 (2007) 2226e2232. [85] C. True, M. Kirigiti, P. Ciofi, K.L. Grove, M.S. Smith, Characterisation of arcuate nucleus kisspeptin/neurokinin B neuronal projections and regulation during lactation in the rat, J. Neuroendocrinol. 23 (2011) 52e64. [86] V.M. Navarro, R. Fernández-Fernández, J.M. Castellano, J. Roa, A. Mayen, M.L. Barreiro, F. Gaytan, E. Aguilar, L. Pinilla, C. Dieguez, M. Tena-Sempere, Advanced vaginal opening and precocious activation of the reproductive axis by KiSS-1 peptide, the endogenous ligand of GPR54, J. Physiol. 561 (2004) 379e386. [87] J. Roa, E. Vigo, D. García-Galiano, J.M. Castellano, V.M. Navarro, R. Pineda, C. Diéguez, E. Aguilar, L. Pinilla, M. Tena-Sempere, Desensitization of gonadotropin responses to kisspeptin in the female rat: analyses of LH and FSH secretion at different developmental and metabolic states, Am. J. Physiol. Endocrinol. Metab. 294 (2008) E1088eE1096. [88] J.T. Smith, B.V. Acohido, D.K. Clifton, R.A. Steiner, KiSS-1 neurones are direct targets for leptin in the ob/ob mouse, J. Neuroendocrinol. 18 (2006) 298e303. [89] J. Roa, D. Garcia-Galiano, L. Varela, M.A. Sánchez-Garrido, R. Pineda, J.M. Castellano, F. Ruiz-Pino, M. Romero, E. Aguilar, M. López, F. Gaytan, C. Diéguez, L. Pinilla, M. Tena-Sempere, The mammalian target of rapamycin as novel central regulator of puberty onset via modulation of hypothalamic Kiss1 system, Endocrinology 150 (2009) 5016e5026.

[90] J.H. Quennell, C.S. Howell, J. Roa, R.A. Augustine, D.R. Grattan, G.M. Anderson, Leptin deficiency and diet-induced obesity reduce hypothalamic kisspeptin expression in mice, Endocrinology 152 (2011) 1541e1550. [91] J. Tomikawa, T. Homma, S. Tajima, T. Shibata, Y. Inamoto, K. Takase, N. Inoue, S. Ohkura, Y. Uenoyama, K.-I. Maeda, H. Tsukamura, Molecular characterization and estrogen regulation of hypothalamic KISS1 gene in the pig, Biol. Reprod. 82 (2010) 313e319. [92] K.M. Estrada, C.M. Clay, S. Pompolo, J.T. Smith, I.J. Clarke, Elevated KiSS-1 expression in the arcuate nucleus prior to the cyclic preovulatory gonadotrophin-releasing hormone/lutenising hormone surge in the ewe suggests a stimulatory role for kisspeptin in oestrogen-positive feedback, J. Neuroendocrinol. 18 (2006) 806e809. [93] J.T. Smith, C.M. Clay, A. Caraty, I.J. Clarke, KiSS-1 messenger ribonucleic acid expression in the hypothalamus of the ewe is regulated by sex steroids and season, Endocrinology 148 (2007) 1150e1157. [94] J.T. Smith, H.M. Dungan, E.A. Stoll, M.L. Gottsch, R.E. Braun, S.M. Eacker, D.K. Clifton, R.A. Steiner, Differential regulation of KiSS-1 mRNA expression by sex steroids in the brain of the male mouse, Endocrinology 146 (2005) 2976e2984. [95] J. Qiu, Y. Fang, M.A. Bosch, O.K. Rønnekleiv, M.J. Kelly, Guinea pig kisspeptin neurons are depolarized by leptin via activation of TRPC channels, Endocrinology 152 (2011) 1503e1514. [96] J. Donato Jr., R.M. Cravo, R. Frazao, L. Gautron, M.M. Scott, J. Lachey, I.A. Castro, L.O. Margatho, S. Lee, C. Lee, J.A. Richardson, J. Friedman, S. Chua Jr., R. Coppari, J.M. Zigman, J.K. Elmquist, C.F. Elias, Leptin’s effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons, J. Clin. Invest. 121 (2011) 355e368. [97] A. Morelli, M. Marini, R. Mancina, M. Luconi, L. Vignozzi, B. Fibbi, S. Filippi, A. Pezzatini, G. Forti, G.B. Vannelli, M. Maggi, Sex steroids and leptin regulate the "first Kiss" (KiSS 1/G-protein-coupled receptor 54 system) in human gonadotropin-releasing-hormone-secreting neuroblasts, J. Sex. Med. 5 (2008) 1097e1113. [98] R.M. Cravo, L.O. Margatho, S. Osborne-Lawrence, J. Donato Jr., S. Atkin, A.L. Bookout, S. Rovinsky, R. Frazao, C.E. Lee, L. Gautron, J.M. Zigman, C.F. Elias, Characterization of Kiss1 neurons using transgenic mouse models, Neuroscience 173 (2011) 37e56. [99] K. Backholer, M. Bowden, K. Gamber, C. Bjørbaek, J. Iqbal, I.J. Clarke, Melanocortins mimic the effects of leptin to restore reproductive function in lean hypogonadotropic ewes, Neuroendocrinology 91 (2010) 27e40. [100] J. Xu, M.A. Kirigiti, K.L. Grove, M.S. Smith, Regulation of food intake and gonadotropin-releasing hormone/luteinizing hormone during lactation: role of insulin and leptin, Endocrinology 150 (2009) 4231e4240. [101] J.M. Castellano, V.M. Navarro, R. Fernández-Fernández, J. Roa, E. Vigo, R. Pineda, C. Dieguez, E. Aguilar, L. Pinilla, M. Tena-Sempere, Expression of hypothalamic KiSS-1 system and rescue of defective gonadotropic responses by kisspeptin in streptozotocin-induced diabetic male rats, Diabetes 55 (2006) 2602e2610. [102] T.Iwasa, T. Matsuzaki, M. Murakami, S. Fujisawa, R. Kinouchi, G. Gereltsetseg, A. Kuwahara, T. Yasui, M. Irahara, Effects of intrauterine undernutrition on hypothalamic Kiss1 expression and the timing of puberty in female rats, J. Physiol. 588 (2010) 821e829. [103] J.A. Cioffi, J. Van Blerkom, M. Antczak, A. Shafer, S. Wittmer, H.R. Snodgrass, The expression of leptin and its receptors in pre-ovulatory human follicles, Mol. Hum. Reprod. 3 (1997) 467e472. [104] C. Karlsson, K. Lindell, E. Svensson, C. Bergh, P. Lind, H. Billig, L.M.S. Carlsson, B. Carlsson, Expression of functional leptin receptors in the human ovary, J. Clin. Endocrinol. Metab. 82 (1997) 4144e4148. [105] L.J. Spicer, C.C. Francisco, The adipose obese gene product, leptin: evidence of a direct inhibitory role in ovarian function, Endocrinology 138 (1997) 3374e3379. [106] L.J. Spicer, C.C. Francisco, Adipose obese gene product, leptin, inhibits bovine ovarian thecal cell steroidogenesis, Biol. Reprod. 58 (1998) 207e212. [107] Z.T. Ruiz-Cortés, T. Men, M.-F. Palin, B.R. Downey, D.A. Lacroix, B.D. Murphy, Porcine leptin receptor: molecular structure and expression in the ovary, Mol. Reprod. Dev. 56 (2000) 465e474. [108] L.J. Spicer, C.S. Chamberlain, C.C. Francisco, Ovarian action of leptin: effects on insulin-like growth factor-I-stimulated function of granulosa and thecal cells, Endocrine 12 (2000) 53e59. [109] S.K. Agarwal, K. Vogel, S.R. Weitsman, D.A. Magoffin, Leptin antagonizes the insulin-like growth factor-I augmentation of steroidogenesis in granulosa and theca cells of the human ovary, J. Clin. Endocrinol. Metab. 84 (1999) 1072e1076. [110] J.D. Brannian, Y. Zhao, M. McElroy, Leptin inhibits gonadotrophin-stimulated granulosa cell progesterone production by antagonizing insulin action, Hum. Reprod. 14 (1999) 1445e1448. [111] R.J. Zachow, D.A. Magoffin, Direct intraovarian effects of leptin: impairment of the synergistic action of insulin-like growth factor-I on follicle-stimulating hormone-dependent estradiol-17b production by rat ovarian granulosa cells, Endocrinology 138 (1997) 847e850. [112] B.K. Campbell, et al., Leptin: in-vitro and in-vivo evidence for direct effects on the ovary in monovulatory ruminants. Hum. Reprod. 14 (1999) 15e16 (Abstract). [113] Z.T. Ruiz-Cortés, Y. Martel-Kennes, N.Y. Gévry, B.R. Downey, M.-F. Palin, B.D. Murphy, Biphasic effects of leptin in porcine granulosa cells, Biol. Reprod. 68 (2003) 789e796.

G.J. Hausman et al. / Biochimie 94 (2012) 2075e2081 [114] N.R. Kendall, C.G. Gutierrez, R.J. Scaramuzzi, D.T. Baird, R. Webb, B.K. Campbell, Direct in vivo effects of leptin on ovarian steroidogenesis in sheep, Reproduction 128 (2004) 757e765. [115] M. Kimura, M. Irahara, T. Yasui, S. Saito, M. Tezuka, S. Yamano, M. Kamada, T. Aono, The obesity in bilateral ovariectomized rats is related to a decrease in the expression of leptin receptors in the brain, Biochem. Biophys. Res. Commun. 290 (2002) 1349e1353. [116] K.L. Houseknecht, M.K. McGuire, C.P. Portocarrero, M.A. McGuire, K. Beerman, Leptin is present in human milk and is related to maternal plasma leptin concentration and adiposity, Biochem. Biophys. Res. Commun. 240 (1997) 742e747.

2081

[117] G.L. Williams, M. Amstalden, M.R. Garcia, R.L. Stanko, S.E. Nizielski, C.D. Morrison, D.H. Keisler, Leptin and its role in the central regulation of reproduction in cattle, Domest. Anim. Endocrinol. 23 (2002) 339e349. [118] B. Berisha, D. Schams, A. Miyamoto, The expression of angiotensin and endothelin system members in bovine corpus luteum during estrous cycle and pregnancy, Endocrine 19 (2002) 305e312. [119] D. Schams, B. Berisha, T. Neuvians, W. Amselgruber, W.-D. Kraetzl, Real-time changes of the local vasoactive peptide systems (angiotensin, endothelin) in the bovine corpus luteum after induced luteal regression, Mol. Reprod. Dev. 65 (2003) 57e66.