Leptin as mediator of the effects of developmental programming

Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) 677–687

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Leptin as mediator of the effects of developmental programming M.H. Vickers, PhD, Senior Research Fellow, Dr. *, D.M. Sloboda, PhD, Senior Research Fellow Liggins Institute and The National Research Centre for Growth and Development, University of Auckland, 2-6 Park Avenue, Grafton, Auckland 1023, New Zealand

Keywords: developmental programming leptin leptin resistance obesity metabolic syndrome leptin antagonist

Considerable epidemiological, experimental and clinical data have amassed showing that the risk of developing disease in later life is dependent upon early life conditions. In particular, altered maternal nutrition, including undernutrition and overnutrition, can lead to metabolic disorders in offspring characterised by obesity and leptin resistance. The adipokine leptin has received significant interest as a potential programming factor; alterations in the profile of leptin in early life are associated with altered susceptibility to obesity and metabolic disorders in adulthood. Maintenance of a critical leptin level during early development facilitates the normal maturation of tissues and signalling pathways involved in metabolic homeostasis. A period of relative hypoor hyperleptinemia during this window of development will induce some of the metabolic adaptations which underlie developmental programming. However, it remains unclear whether leptin alone is a critical factor for the programming of obesity. At least in animal experimental studies, developmental programming is potentially reversible by manipulating the concentration of circulating leptin during a critical window of developmental plasticity and offers an exciting new approach for therapeutic intervention. Ó 2012 Elsevier Ltd. All rights reserved.

Introduction An adverse early life environment is associated with long term metabolic consequences, in particular obesity, insulin resistance and type 2 diabetes. Data from epidemiological and animal studies have given rise to the concept of developmental programming whereby an unfavourable prenatal * Corresponding author. Tel.: þ64 9 9236687; Fax: þ64 9 373 7497. E-mail address: [email protected] (M.H. Vickers). 1521-690X/$ – see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.beem.2012.03.005

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environment is believed to trigger adaptations that improve fetal survival or prepare the fetus in expectation of a particular range of environments postnatally.1,2 These adaptations (or predictive adaptive responses, PARs) may later prove to be disadvantageous when the pre- and postnatal environments are widely discrepant. In particular, both excess and reduced nutrient availability during early development can lead to an increased risk of obesity, although a possible commonality of mechanisms linking these processes is not yet understood. The emerging role of adipose tissue acting as a dynamic endocrine organ3 has led to a number of studies linking early life events with long term alterations in adipose tissue and structure.4 In particular, a large number of studies have identified the adipokine leptin as a potential mediator of programming-induced alterations in appetite and energy expenditure. Leptin, a 16-kDa nonglycosylated protein product of the obese (ob) gene, is a cytokine-like peptide hormone secreted primarily by white adipose tissue that is involved in the regulation of energy intake and expenditure, neuroendocrine function, immunity and lipid and glucose metabolism.3 In most humans with obesity, systemic leptin concentrations are elevated, consistent with a state of leptin resistance.5 Although the presence of hyperleptinemia with leptin resistance and obesity has long been recognized, a causal role of elevated leptin in these biological states remains unclear. In essence, the augmented leptin concentration accompanying obesity contributes to leptin resistance, and this leptin resistance promotes further obesity, leading to a vicious cycle of escalating metabolic disease. It has been shown in a range of animal models and a number of species that perturbations in the profile of leptin in early life are associated with altered susceptibility to obesity and metabolic disorders in adulthood. Manipulations of early life leptin levels in animal models utilising exogenous leptin and/ or leptin antagonists have clearly shown a role for leptin in the reprogramming of metabolic fate in later life.6,7 The source of leptin during this critical developmental window may be varied and likely includes maternal leptin transplacental transfer, endogenous fetal leptin but may also include milk leptin during lactation. Leptin in maternal milk is likely an important factor in the maturation of organ systems and feeding pathways in the neonate. Breast fed infants have higher serum leptin levels than formula fed infants; formula fed infants may be at an increased risk of developing obesity.8 Experimentally, oral intake of physiological doses of leptin during lactation in rats has been shown to prevent obesity in later life9 supporting the hypothesis that milk leptin plays a favourable role in developmental programming. However, it should be noted that, at least in the rat, leptin supplementation to neonates born to mothers with normal pregnancies, appears to result in adverse metabolic responses in these offspring as adults,10 which may be the result of an amplified and prolonged leptin surge; this has been shown in offspring of obese mothers.11 Whether leptin is the critical factor in the early life programming of obesity still remains unclear. However, it has been shown recently in the genetically obese ob/ob strain that leptin alone is not a critical factor for programming obesity and that factors other than leptin are crucial in the programming of energy homeostasis.12 Mechanisms of leptin action Under normal physiologic conditions leptin is an essential component in the regulation of energy balance. Leptin acts centrally, primarily at the level of the hypothalamus, to inhibit feeding and promote energy expenditure. Peripherally, it reduces the deposition of fat in non-adipose tissues, protecting against lipotoxicity and maintaining a level of glucose sensitivity.13 Leptin acts as a “lipostat” thereby maintaining a critical leptin level during development may allow the normal maturation of tissues and pathways involved in metabolic homeostasis and a period of relative hypo- or hyperleptinemia may induce some of the metabolic adaptations which underlie developmental programming.6 Leptin receptors are widely expressed in the developing brain from early developmental stages and leptin is known to have profound effects on the proliferation, maintenance, and differentiation of neuronal and glial cells. During the early postnatal period in rodents, there is a surge in circulating leptin concentrations.14 Despite this elevation in leptin concentrations, neonates maintain a high level of food intake and both feeding behaviour and metabolic responses to exogenous leptin administration are absent until near the time of weaning. These elevated leptin levels in early life are proposed to play a role in brain development15,16;direct neurotrophic actions of leptin have been demonstrated, with leptin promoting neurite outgrowth and the establishment of hypothalamic

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circuitry.17 Work by Bouret and Simerly showed a marked decrease in hypothalamic neuronal fibre density in leptin deficient ob/ob mice; a deficit that could be restored with neonatal leptin treatment.17 The period of intervention was limited to the early neonatal period of developmental plasticity with post-weaning leptin treatment having no effect. A recent study has shown that basal concentrations of endogenous leptin elicit metabolic responses in newborn rat pups.18 Treatment with leptin, but not a leptin antagonist, produced a significant increase in hypothalamic phosphorylated signal transducer and activator of transcription 3 (pSTAT3) relative to saline treatment. Systemically administered leptin antagonist effectively blocked leptin signal induction of hypothalamic JAK-STAT signalling. Co-treatment with leptin and leptin antagonist attenuated the leptin-induced increase in pSTAT3. Leptin signalling is subject to negative feedback regulation, which appears to be more pronounced in obesity and associated hyperleptinemia.3 Leptin is a key element of the adipoinsular axis.19 Insulin is adipogenic; it increases body fat mass and stimulates the production and secretion of leptin. Leptin in turn suppresses insulin secretion by both central and peripheral actions on b-cells. Reduced substrate supply during fetal development can trigger permanent dysregulation of the adipoinsular feedback system leading to hyperleptinemia, hyperinsulinemia and compensatory leptin production by pancreatic d-cells in a further attempt to reduce insulin hypersecretion in the progression to adipogenic diabetes.20 The arcuate nucleus (ARC) is a major target for leptin in the hypothalamus.21 In this nucleus the long form of the leptin receptor (ObRb) is present on two different populations of neurons; one of which preferentially expresses orexigenic neuropeptide Y (NPY) and agouti-related protein (Agrp) and a second population that express anorexigenic proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART).30 The orexigenic NPY/Agrp neurons are inhibited by leptin, whereas the anorexigenic POMC/CART neurons are activated.21 Differences in the pattern of ObRb gene expression between the fetus and the adult may reflect an immaturity of the central neural network in the fetus compared to the adult.22 This is supported by data demonstrating remodelling of the neuronal circuitry of the appetite regulatory system within the hypothalamus after birth in the nonhuman primate.23 Whereas the principal function of this neuronal circuitry in the adult is to maintain energy homeostasis, the fetus and newborn must remain in positive energy balance to promote growth and fat deposition. Relative resistance to the anorexigenic actions of leptin may therefore be important for neonatal survival. Appetite-mediated ingestive behaviours develop and are likely programmed in utero, thus preparing for newborn and adult appetite behaviour.24 Of note, the role of leptin in regulating fetal ingestive behaviour is interesting as, contrary to actions in adults, leptin does not suppress fetal ingestive behaviour.24 This may be of value during the newborn period, as unopposed appetite stimulatory mechanisms may facilitate rapid fetal and newborn weight gain. An adverse intrauterine environment, with altered fetal orexic factors during the critical developmental period of fetal life, may therefore alter the normal setpoints of appetitive behaviour and potentially lead to programming of adulthood hyperphagia and obesity.24 There is clear evidence for sexual dimorphism in the early life programming of circulating leptin levels in the human25 and in animal models26 and responsiveness to neonatal leptin treatment has been shown to be different between males and females.10,27 Moreover the sexual dimorphism in the rodent is reversed from that seen in the human; this dichotomy may relate to differences in the distribution and extent of fat stores.26 Leptin dysregulation in developmental programming Prenatal events are compounded by the postnatal environment including overnutrition or lifestyle choices which are in conflict with the programming of the fetus. The relative importance of the interactions between the pre- and postnatal environment is not easily discernable from human studies due to the lack of controls for dietary content and quantity or the severity of obesity or undernutrition in the mothers and offspring.28 Thus, animal studies have become the mainstay for investigation of interactions between pre- and postnatal influences on leptin sensitivity. Developmental alterations in leptin regulation in the early life period have been widely studied across a range of animal models. A primary focus has been on altered early life nutrition with relative

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under- and overnutrition both resulting in marked alterations in the timing and magnitude of the leptin surge and wiring of the hypothalamic circuitry regulating food intake. It is however important to differentiate maternal diabetes from maternal obesity per se. Low concentrations of circulating leptin have been reported in fetuses from intrauterine growth restriction (IUGR) and obese pregnancies29,30 whereas macrosomic offspring of diabetic mothers have elevated leptin concentrations.31 In neonates of diabetic mothers, hyperleptinemia may result in neonatal hypoglycaemia due to impairment of gluconeogenic pathways.32 Paradoxically, both fetal growth restriction and macrosomia associated with maternal obesity lead to programming of the metabolic syndrome and its long term consequences.33 The role of leptin as a regulator of fetal growth is still unclear.29 The initial and recurrent assumption that leptin acts as a fetal growth factor was based on the association between neonatal anthropometrics and umbilical leptin concentration. This view was challenged by data showing that placental- and fetal-derived leptin function independently of each other. In addition, the marked discrepancies between placental and fetal leptin suggest that placental leptin is not a direct determinant of fetal growth. Thus, increased umbilical leptin in macrosomic babies and low umbilical leptin in growth restricted infants appear as a consequence rather than a stimulus to fetal growth. The independence of leptin in the fetal compartment is further supported by an absence of a correlation between maternal and neonatal leptin levels.34 A further issue to address before considering leptin as a prenatal growth factor is that neonates born with total congenital leptin deficiency have a normal birth weight.35 Maternal undernutrition Maternal undernutrition is known to have significant effects on the neonatal leptin surge. In the rodent, a maternal low protein diet delays the leptin surge36 and global food restriction reduces the amplification of the surge.37 Furthermore, this delay and inhibition of the leptin surge following IUGR leads to hypothalamic disorganisation.38 Maternal perinatal undernutrition affects the development of arcuate POMC neurons in neonatal male rat pups.37 Early postnatal nutritional programming is associated with increased sensitivity to leptin and a melanocortin receptor (MC3R) agonist and decreased sensitivity to NPY.39 Following postnatal protein malnutrition, food intake in adult rats was shown to be more sensitive to reduction by leptin and melanocortins, and less sensitive to stimulation by NPY. It was proposed that this altered sensitivity contributes to increased leptin sensitivity and resistance to obesity and may occur via increased expression of ObRb and MC3R although other downstream mechanisms must also be involved. At birth, IUGR pups have increased hypothalamic ObRb mRNA and total STAT3 protein expression though reduced leptin activated pSTAT3. By 3 weeks of age, IUGR offspring exhibit decreased hypothalamic ObRb mRNA expression, although with continued elevated STAT3 protein levels. These IUGR offspring demonstrated resistance to anorexigenic agents (leptin and sibutramine) in later life as evidenced by less reduction in food intake and less body weight loss than controls.40 Hypothalamic organisation has been shown to be altered following IUGR with ObRb expression in control offspring showing preferential localisation to the ARC whereas in IUGR offspring, ObRb expression has been shown to be equally distributed between the ARC and the paraventricular nucleus (PVN)41 representative of a more immature stage of hypothalamic development.22 Some studies suggest maintenance of peripheral leptin sensitivity in the presence of central and blood brain barrier (BBB) leptin resistance.42 Female offspring exposed to prenatal undernutrition during pregnancy develop leptin resistance in adulthood independently of postnatal diet-induced obesity.42 Thus the programmed leptin resistance in undernourished offspring provides a mechanism for increased susceptibility to diet-induced obesity. It has been reported in the sheep that there is no significant impact of maternal undernutrition, imposed either during the periconceptional period or throughout gestation on fetal plasma leptin concentrations in late gestation.43 Similarly, in the rat, maternal low protein intake has no effect on circulating fetal leptin levels in late gestation despite a significant decrease in maternal leptin levels.44 In the mouse, fetal leptin levels are reduced in the first half of pregnancy as a result of maternal food restriction.45 It has also been observed that the source of leptin differs during pregnancy with greater

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production in visceral fat in pregnant mice, and greater production in subcutaneous fat in nonpregnant mice.45 Bispham et al. have shown that, irrespective of maternal nutrition in late gestation, term fetuses sampled from nutrient restricted ewes in early gestation possess more adipose tissue, whereas when ewes were fed to appetite throughout gestation, fetal adipose tissue deposition and leptin mRNA abundance were both reduced. These changes suggested that offspring of nutrient restricted mothers were at increased risk of developing obesity in later life.46 These observations suggest that the increased incidence of obesity in adults born to mothers exposed to the Dutch Famine during early pregnancy may be a direct consequence of adaptations in the endocrine sensitivity of fetal adipose tissue. One area receiving increased attention is that of leptin and skeletal mass. Adverse early life events are known to lead to altered bone development47 and an increased risk of osteoporosis in later life.47,48 Leptin has complex effects on trabecular and cortical bone, both directly and via the hypothalamus.49 There are at least two possible mechanisms by which developmental programming could affect bone development via altered leptin action: 1) via direct effects on osteoblast progenitors and mature osteoblasts and 2) via leptin-induced alterations in hypothalamic-mediated b–adrenergic signalling.49 In addition, there are likely indirect effects of leptin on bone homeostasis via modulation of other hormones including osteocalcin and adiponectin.50 Maternal obesity/overnutrition There is a similarity in offspring phenotypes derived from both ends of the maternal nutritional spectrum; offspring of both under- and over-nourished mothers display common metabolic derangements including obesity and insulin resistance. The components of the maternal diabetic and/or obesogenic environment that mediate the detrimental effects on hypothalamic function and consequently offspring health are not clearly established. A common phenotypic outcome across a range of programming models is resistance to leptin in adulthood in relation to inhibition of food intake.51 There has been less focus however on whether leptin resistance during the very early stages of life, at a time when leptin has no effect on food intake, plays a mechanistic role in metabolic programming.52,53 Established maternal obesity in the rat has been shown to reprogram hypothalamic appetite regulators and leptin signalling at birth.54 Maternal obesity, together with lower leptin levels in offspring may contribute to the lower expression of key appetite regulators at birth, suggesting altered fetal neuronal development in response to intrauterine overnutrition, which may contribute to eating disorders later in life. It has been shown that offspring of high fat fed (HF) dams exhibit an alteration in hypothalamic leptin-dependent STAT3 phosphorylation, independent of the level of post-weaning nutrition.55 The result of early overnutrition is early-onset ARC leptin resistance and increased sensitivity to a high fat (HF) diet.53 In a model of litter reduction to induce neonatal overfeeding, offspring exhibited early and persistent leptin resistance in the ARC nucleus and, in response to an HF diet, rapid development of obesity and insulin resistance. These studies suggest that early overnutrition can permanently alter energy homeostasis and significantly increase susceptibility to obesity and insulin resistance.53 Further, the ability of leptin to activate intracellular signalling in ARC neurons is significantly reduced in neonates born to diabetic dams.56 The mechanisms proposed to underlie the development of leptin resistance in models of dietinduced obesity focus on defects influencing leptin transport across the BBB and downstream signalling of the leptin receptor.57,58,59 Work by Banks et al. demonstrated that elevations in plasma triglycerides can have a direct effect on the BBB, rapidly impairing leptin transport into the brain.60 Leptin resistance is commonly observed in conjunction with elevations in fasting plasma triglycerides and hyperinsulinemia in programmed offspring.42 Hyperinsulinemia may also influence leptin sensitivity through cross-talk between the insulin and leptin receptors.61 Leptin and epigenetic regulation Epigenetics is the study of heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence.62 This process is emerging as an

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important contributor to the changes in gene expression undergone by adipose tissue during obesity. Importantly, epigenetic marks may be reprogrammed in response to both stochastic and environmental stimuli, such as changes in diet and the in utero environment.63 Within tissues and organs that control metabolic homeostasis, a range of phenotypes can be induced by sustained changes in maternal diet via modulation of genes that control DNA methylation and by histone acetylation, which suggests epigenetic programming.64 Leptin’s 3-kb promoter region is embedded within a CpG island and contains many putative binding sites for known transcription factors, such as Sp-1, cAMP response element, glucocorticoid response element and a functional CCAAT/enhancer binding protein (C/EBP-a) site which contains a CG dinucleotide and is sufficient for tissue-specific gene expression.65,66 It has been shown that leptin’s promoter is subject to epigenetic programming and leptin’s expression can be modulated by DNA methylation. Such potential mechanisms underlying epigenetic modification of tissue function resulting in a predisposition to altered leptin and insulin signalling are discussed by Holness et al.67 For example, activation of the leptin receptor induces expression of suppressor of cytokine signalling-3 (SOCS-3). This protein inhibits further leptin signal transduction and also potently inhibits signalling by the insulin receptor. Altered SOCS-3 methylation may therefore have lasting effects on the leptin-insulin feedback loop (the adipoinsular axis19) and adversely impact on developmental programming. Impaired glucose tolerance during pregnancy is associated with leptin gene DNA methylation adaptations with potential functional impacts.68 The application of epigenomic approaches and the determination of targets (e.g. imprinted or non-imprinted genes and methylation sites) for early nutritional effects on epigenetic gene regulation are exciting and important new areas of investigation.69 In patients analyzed before and after bariatric surgery-induced weight loss, a decrease in white adipose tissue leptin expression (about 50%) did not correspond to changes in promoter methylation density. Thus, methylation density in the leptin promoter may constitute one control level for cell-type specific leptin expression, whereas weight loss induced changes in leptin expression does not appear to be methylation-dependent.70 Fixed genomic variation explains only a small proportion of the risk of adiposity. In animal models, maternal diet alters offspring body composition, accompanied by epigenetic changes in metabolic control genes. Little is known about whether such processes operate in humans.2 Recent work has shown the utility for perinatal epigenetic analysis in identifying individual vulnerability to later obesity and metabolic disease.2 In this study, epigenetic gene promoter methylation at birth was associated with adiposity in children. Identification of in vivo methylation of the leptin promoter provides a molecular entry point to study the timing, factors and conditions that lead to tissue-specific methylation patterns of gene promoters.65 Leptin and reversibility of developmental programming As noted above and in contrast to obese subjects with a congenital leptin deficiency, common obesity is characterised by elevated leptin concentrations and resistance to the effects of leptin.3 Initial trials with leptin as a monotherapy for obesity using supraphysiological doses yielded modest, if any, weight loss and large variability amongst participants.71,72 Work in the rodent and piglet has shown that neonatal leptin treatment can reverse or ameliorate the adverse metabolic effects associated with developmental programming.6,27,41 Leptin treatment to neonatal female rats born to undernourished mothers prevented the development of the programmed phenotype in adulthood.27 The complete normalisation of the “programmed” phenotype by neonatal leptin treatment implied that leptin has effects that can reverse the prenatal adaptations resulting from relative fetal undernutrition. In agreement with the observations in rodents, neonatal leptin treatment to piglets with IUGR can partially reverse the IUGR phenotype by correcting growth rate, body composition, and development of several organs involved in metabolic regulation.41 It has recently been reported that intranasal leptin reduces appetite and induces weight loss in rats with diet-induced obesity73 but this approach has yet to be utilised in the context of developmental programming. Use of a leptin antagonist in early life mimics the effects of maternal caloric restriction. Attig et al. have shown that blockade of leptin action in the neonatal rat via administration of a specific

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ObRb antagonist predisposed offspring to later leptin resistance and increased body weight gain when fed a high energy diet postnatally.7 Further work using leptin antagonists has shown that postnatal leptin is necessary for maturation of numerous organs in the newborn rat74 with leptin antagonism resulting in aberrant pancreas, kidney and ovarian development. Pregnancy is characterised by a state of leptin resistance comprising an adaptive response that facilitates energy storage in preparation for the high metabolic demands of pregnancy and subsequent lactation.75 However, despite resistance to the central anorectic effects of leptin, it has also been reported that maternal leptin treatment to dams fed a low protein diet can prevent the adverse metabolic programming-induced as a consequence of protein malnutrition.76 A potential mechanism for leptin action in the pregnancies compromised by low protein intake may be due to normalisation of placental 11b-hydroxysteroid dehydrogenase-2 (11b-HSD2) levels76 Of note, maternal leptin administration to normally nourished dams in a subsequent study also conferred protection against dietinduced obesity in offspring77 suggestive of effects independent of level of maternal diet. Maternal folic acid supplementation in the rat following protein restriction prevents epigenetic modification of hepatic gene expression in the offspring including PPAR-a and -g.78 However, a recent study using a similar model reported that maternal protein and folic acid intake during gestation does not program leptin transcription or serum concentration in rat progeny.79 The role of catch-up growth on development of the adult obese phenotype is still under debate. Work by Plagemann et al. argued that it may not be fetal undernutrition and low birth weight per se that predisposes to adult onset obesity; rather it is the overfeeding of underweight newborns that may substantially contribute to their long term risk.80 When IUGR offspring are permitted rapid catch-up growth by nutrient availability, these offspring will demonstrate evidence of increased body weight and body fat, and leptin resistance as adults. Conversely, if catch-up growth is delayed by postnatal nutrient restriction, these offspring exhibit normal body weight, body fat and plasma leptin levels as adults.81 However, in contrast to the observations by Plagemann, Lopez et al. have reported that perinatal overfeeding (using small litters, SL) does not induce alterations in either the anorectic response to central leptin administration or expression of leptin receptors and neuropeptides in adult rats.82 The leptin resistance to peripheral leptin in adult SL rats may be related to impaired leptin transport across the BBB. This transport mechanism could be triglyceride-mediated as reported by Banks et al.60 Triglycerides inhibit the transport of leptin across the BBB and so could be key in the onset of the peripheral leptin resistance, which is a hallmark of obesity. Although leptin treatment has beneficial effects in ameliorating metabolic disorders resultant from developmental programming, leptin treatment to offspring of normal pregnancies may have adverse long term metabolic effects which may relate to alterations in the amplification and timing of the neonatal leptin surge.83 Itoh et al. have shown that neonatal leptin treatment to control mice leads to impaired glucose tolerance in adult offspring83 and in the rat the effects of exogenous leptin in male rat offspring are directionally dependent upon maternal nutritional status.10 A study by Yura et al. showed that treatment of male control offspring with leptin in the neonatal period resulted in a modest increase in the risk for obesity as compared to saline treated controls.84 This concurs with a previous study of neonatal leptin to normal rats which showed programmed hyperleptinemia and hyperinsulinemia in adulthood, which lead to leptin resistance by reducing the expression of the hypothalamic leptin receptor.85 Results from interventional studies in humans demonstrate that leptin administration in subjects with congenital complete leptin deficiency or subjects with partial leptin deficiency (subjects with lipoatrophy, congenital or related to HIV infection, and women with hypothalamic amenorrhoea) reverses the energy homeostasis and neuroendocrine and metabolic abnormalities associated with these conditions.3,86 In contrast, leptin’s effects are largely absent in the obese hyperleptinemic state, primarily as a result of leptin resistance or tolerance.3 However, failure of leptin in the clinic as an intervention in obesity, and withdrawal of numerous anti-obesity drugs from clinical use e.g. sibutramine, has stimulated new approaches in the development of anti-obesity drugs. These efforts are focused on utilizing leptin-related synthetic peptides as leptin receptor antagonists or leptin-related synthetic peptide analogues or mimetics.87 The current animal data fit with the PAR hypothesis proposed by Gluckman and Hanson. Following the PAR hypothesis, in response to a given in utero or early postnatal nutritional plane (either high or

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low), cellular processes are invoked to cope with the predicted environment. This hypothesis suggests that disease only manifests when the actual nutritional environment diverges from that which was predicted. Since the development of critical pathways involved in energy homeostasis in rodents continue well into the postnatal period, it can be modified by both pre- and postnatal environmental manipulation (e.g. prevention of catch-up growth) and thus obesity can be potentiated, reversed or attenuated postnatally. It is likely that similar principles hold true for humans although the timing of pathway development occurs earlier than in rodents. Summary Epidemiological studies in humans and animal studies have demonstrated that maternal undernutrition, obesity and diabetes during gestation and lactation can all produce obesity and leptin resistance in offspring, the effects of which are amplified with rapid catch-up growth and exposure to an obesogenic postnatal dietary environment. Observational and interventional studies in animals and humans have highlighted a role for leptin in regulation of energy homeostasis, neuroendocrine function, metabolism, immune function, reproduction and bone metabolism.3 It is notable that the variety of different insults in early life (calorie restriction, protein deprived, HF) produce similar effects on leptin regulation in adult life, suggestive of a common mechanism that may underlie the developmental programming of adult disease. These manipulations appear to promote obesity in offspring by malprogramming the development of central neural pathways involved in the regulation of food intake, energy expenditure and storage. Given its strong neurotrophic properties, it is likely that leptin is a likely major effector of these developmental changes during the perinatal period. Experimental data also suggest that this activity is restricted to a neonatal critical period that precedes leptin’s acute regulation of food intake in adults.21 However, it is important to note that the developmental events that occur postnatally in the rodent hypothalamus occur in utero in primates, including humans.88,89 Taken together, recent work highlight the importance of leptin in disorders manifest as a consequence of developmental programming and offer exciting new strategies for therapeutic intervention, whether it be maternal or neonatal intervention or targeted nutritional manipulation in postnatal life. There is also now increasing evidence, both in animals and humans, that such developmental plasticity is mediated in part by epigenetic mechanisms.2 To fully understand the mechanism by which leptin modifies the desired developmental target, it is necessary to understand the mechanisms underlying the timing and amplitude of the leptin surge, optimising the developmental response to exogenous leptin and a detailed understanding of the role of leptin in the development of the neural circuits controlling appetite regulation and energy homeostasis.

Research agenda  Evidence from animal models suggests that maintenance of a critical leptin level in early life allows the normal maturation of tissues and pathways involved in metabolic homeostasis.  A period of relative hypo- or hyperleptinemia may induce some of the metabolic adaptations which underlie developmental programming.  Studies in animal models have highlighted a critical postnatal period whereby leptin treatment can modify the development of neural circuitry.  Evidence suggests that exogenous leptin treatment to neonates of normal pregnancies may potentiate an adverse metabolic phenotype due to amplification of the leptin surge.  It is important to recognise that developmental events that occur postnatally in the rodent hypothalamus occur in utero in primates, including humans.  While leptin itself failed as an obesity drug, renewed efforts now focus on utilizing leptin receptor antagonists or leptin-related synthetic peptide analogues or mimetics as drug targets.

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