Leptin, an adipocyte-derived hormone, acts principally on the central nervous system to activate its cognate receptor. The absence of leptin or of its receptor in Lepob/ob or Leprdb/db mice, respectively, results in morbid obesity, hyperphagia, neuroendocrine dysfunction, and severe hyperglycemia and insulin resistance.1-6
Leptin receptors are expressed in a number of specific brain regions,7,8 and binding of leptin leads to regulation of a range of biological functions and processes, including energy intake and expenditure, body fat, neuroendocrine systems, autonomic function, and insulin-and-glucose balance.9-12 Although the specific function of each brain nucleus in leptin action is yet largely unknown, data suggest that distinct biological actions of leptin are mediated by different brain nuclei but that overlapping or redundant functional sites also exist. The arcuate nucleus of the hypothalamus (ARC) is a key area for mediating leptin actions on energy homeostasis. Consistent with this, leptin receptor messenger RNA is densely expressed in the ARC of mice and rats,13,14 and injection of leptin directly into the ARC is sufficient to acutely reduce food intake.15 Moreover, restoration of leptin receptor expression in the ARC of leptin receptor-deficient Leprdb/db mice leads to long-term reduction of body weight and food intake,16 and arcuate nucleus-specific Lepr gene therapy is sufficient to attenuate the obesity phenotype of leptin receptor-deficient Koletsky fak/fak rats.17
The ARC contains at least 2 subsets of leptin-responsive neurons, namely, the anorexigenic proopiomelanocortin (POMC) neurons and the orexigenic Agouti-related peptide (AgRP) neurons. Proopiomelanocortin neurons are depolarized by leptin, leading to release of α-melanocyte-stimulating hormone (α-MSH), a POMC-derived neuropeptide that mediates its anorexigenic effects through activation of melanocortin receptors.12,18,19 Agouti-related peptide is a melanocortin receptor antagonist that potently stimulates feeding.20 Consistent with this, AgRP neurons are inhibited by leptin, resulting in a reduction in AGRP neuropeptide release.21 Mice lacking leptin receptors only in POMC or AgRP neurons are mildly obese, demonstrating that both groups of cells are required for maintenance of body weight homeostasis by leptin.22,23 Furthermore, reexpression of leptin receptors exclusively in POMC neurons of the receptor-deficient Leprdb/db mice modestly reduces body weight and energy intake.24 The modest body weight changes observed in these studies compared with the morbid obesity in Leprdb/db mice that lack all functional leptin receptors demonstrates that neurons apart from POMC and AgRP neurons are also important for body weight regulation by leptin.
In addition to the ARC, neurons that express leptin receptors are found in a number of other hypothalamic and extrahypothalamic brain nuclei,7,8 and progress has been made in understanding their roles in leptin action. For example, leptin signaling of the ventromedial hypothalamic nucleus can, like the arcuate nucleus, mediate short-term energy intake suppression15 and long-term weight loss.25 Furthermore, the ventromedial hypothalamic nucleus may serve a role in regulation of the autonomic nervous system by leptin.26 In addition, leptin signaling in thyrotropin-releasing hormone neurons within the paraventricular hypothalamic nucleus of rats may account, at least in part, for leptin's effects on the thyroid axis.27,28 Furthermore, the ventral premammillary nucleus is likely critical for leptin's action on the neuroendocrine gonadal axis and reproduction.29 Leptin receptors are also expressed in the ventral tegmental area (VTA) of the mid brain. Specifically, leptin directly targets dopamine neurons of the VTA, suggesting that leptin can affect critical brain reward circuitries.30 Indeed, injection of leptin directly into the VTA reduces food intake and stimulates locomotor activity.31 The nucleus tractus solitarius (NTS) located in the caudal hindbrain is a major projection zone for sensory nerve input from the gastrointestinal system and contains leptin-regulated neurons.32 Interestingly, these latter neurons are also responsive to gastric distention in rats,24 and intraparenchymal NTS administration of leptin acutely reduces food intake and body weight.33 These latter data combined suggest that the effects of leptin on food intake in the hindbrain may result from modulation of gastrointestinal signal processing.34 The effect of leptin on food intake thus seems to be mediated by leptin receptors in several nuclei within the hypothalamus, in part via reward neurons located in the mid brain and in part by neurons in the NTS of the caudal brainstem. Future studies are needed to determine how different neurons mediate the same behavioral effects by leptin or whether those neurons in fact serve specific and separate functions under different circumstances.
Leptin is structurally similar to cytokines consistent with its receptor belonging to the cytokine receptor class 1 superfamily.35 Several isoforms of ObR exists, including a long signaling form (ObRb).36 The murine ObRb receptor contains 3 conserved intracellular tyrosine residues, located at amino acid positions7 985, 1077, and 1138. Tyrosine phosphorylation sites provide binding motifs for src homology 2 domain-containing proteins, such as signal transducers and activators of transcription (STATs). Leptin binding to its receptor activates Janus tyrosine kinase (JAK) enzymes that are constitutively associated with membrane-proximal regions of the receptor. Janus tyrosine kinase mediates leptin-dependent tyrosine phosphorylation of the leptin receptor itself.37 Phosphorylated Tyr1138 recruits the latent cytoplasmic transcription factor STAT3, facilitating its phosphorylation by JAK followed by STAT3 dimerization and nuclear translocation.38 Signal transducer and activator of transcription 3 plays a role in regulation of POMC and AgRP gene expressions by leptin.39,40 In addition, we reported that leptin signaling via the STAT3 pathway rapidly induces hypothalamic expression of suppressor-of-cytokine-signaling-3 (SOCS-3), a potent inhibitor of leptin receptor signaling,41 by binding to Tyr985 and inhibits JAK2 kinase activity, thereby acting in a negative feedback loop.42,43 Another key negative leptin receptor regulator is protein-tyrosine-phosphotase-1B, which acts by directly inhibiting JAK2 kinase activity.44-46 Tyr1077 has been reported to play a role in binding and activation of STAT5,47,48 but the downstream signaling events of this pathway are yet unknown. Phosphorylated Tyr985 of ObRb also binds SHP2, a protein that participates in activation of extracellular signal-regulated kinase (mitogen-activated protein kinase) signaling and is important for c-fos transcriptional activation,43,49 and likely other events. The specific intracellular mechanisms whereby ObRb regulates intracellular signaling via other effector proteins such as insulin-receptor-substrate 2,50-52 phosphoinositol-3-kinase (PI3K),50,53-55 mammalian target of rapamycin,56,57 Fox01,40,58 and adenosine monophosphate-activated protein kinase,59-62 are currently less well understood. Further genetic and immunohistochemical studies are also required to determine whether these proteins are regulated only in first-order leptin-responsive neurons or in downstream neurocircuitries, or in both.
Genetic studies in mice demonstrate that signaling through Tyr1138 of the leptin receptor is required for normal regulation of energy balance. Specifically, mice with Tyr1138 mutated into a serine residue exhibit severe hyperphagia and obesity similar to that of Leprdb/db mice.63 However, in contrast to Leprdb/db mice, Ser1138 mice are fertile, longer, and less hyperglycemic, altogether indicating that STAT3 signaling is critical for leptin's regulation of energy intake and whole body energy balance but that signals other than STAT3 are likely important for other leptin actions such as reproduction. In more recent studies also using homologous recombination in mice leading to mutation of Tyr985 into a leucine residue, it was reported that female, but not male, animals had modestly reduced body weight and energy intake and were protected from high-fat diet-induced obesity.64 The mice also showed increased leptin sensitivity and preservation of reproductive function. Thus, these data suggest that Tyr985 of the leptin receptor may serve to convey inhibition of leptin signaling thereby attenuating the antiadiposity effects of leptin, especially in females. These data are consistent with those from in vitro signaling studies that strongly point to an inhibitory role of SOCS-3 acting via Tyr985. However, because Tyr985 recruits both SHP2 and SOCS3, either of these proteins could theoretically underlie the lean, leptin-sensitive phenotype. Alternatively, it may be speculated that because the lean phenotype is quiet modest and is only present in 1 sex, SOCS-3 and SHP2 may have opposite functions with regard to regulation of whole body energy balance by leptin. Further studies are needed to investigate this possibility and to determine the specific cellular functions of individual receptor tyrosine residues, including those of Tyr1077, within each anatomically and chemically separate population of leptin-responsive neurons.
In addition to these global manipulations of leptin receptor signaling, several intracellular proteins downstream of the leptin receptor have also been investigated with regard to their role in leptin action within specific neurons. For example, the STAT3 transcriptional factor has specifically been deleted from POMC and AgRP neurons in mice. In mice lacking STAT3 in POMC neurons, females exhibited reduced pomc gene expression and a modest increase in fat mass and total body weight.65 The animals remained responsive to leptin-induced hypophagia and were not hypersensitive to development of increased weight given a high-fat diet. However, mutant mice failed to mount a normal compensatory refeeding response. These results suggest a role for STAT3 in transcriptional regulation of the pomc gene, consistent with those of previous in vitro studies of the pomc promoter,39 and indicate that STAT3 expression in POMC neurons plays only a modest role in leptin's antiobesity actions. Removal of STAT3 or expression of a constitutive active form of STAT3 in AgRP neurons also demonstrates a requirement of STAT3 in those cells for normal energy balance.47,66 For example, deletion of STAT3 from AgRP neurons leads to a slight weight gain of the mice.47 These AgRP STAT3-deficient mice were also hyperleptinemic and exhibited high-fat diet-induced hyperinsulinemia. Agouti-related peptide messenger RNA levels were unaffected. Behaviorally, mice without STAT3 in AgRP neurons were mildly hyperphagic and hyporesponsive to leptin's intake inhibitory actions. Combined, STAT3 in AgRP and POMC neurons is therefore required for normal energy homeostasis, but it is suggested that STAT3 signaling in other leptin-responsive neurons also plays important roles in promoting leptin's antiobesity effect. As might be predicted from earlier studies,22,41 deletion of SOCS-3 selectively from POMC neurons enhances leptin sensitivity, although weight gain with age was normal on a chow diet.67 However, on a high-fat diet, the rate of weight gain was reduced. Interestingly, on the chow diet where the body weights were normal, baseline glucose levels were reduced. This altogether supports a role of POMC neurons in leptin's control of glucose balance5,24 and suggests a role of SOCS-3 in those cells in the increased weight response to a high-energy diet.68,69 In addition to those studies, the PI3K pathway has been examined in significant detail in POMC neurons. Mice with genetically disrupted PI3K signaling lack the normal response of leptin-induced POMC neuronal depolarization and increased firing frequency.70 In addition, the suppression of feeding elicited by leptin was blunted. Interestingly, however, despite these alterations in POMC neuronal function, the mice had normal body weight. However, in apparent contrast to these studies, inactivation of PTEN, a phosphatidylinositol-3,4,5-trisphosphate phosphatase, specifically in POMC cells resulted in hyperphagia and a sexually dimorphic diet-sensitive obesity. Interestingly, and in contrast to the study by Hill et al., leptin failed to stimulate POMC electrical activity.71 Similar however to the study by Hill et al., leptin was not able to acutely inhibit energy intake. Finally, younger mice with selective inactivation of 3-phosphoinositide-dependent protein kinase 1, an upstream activator of PI3K, in POMC-expressing cells display hyperphagia and increased body weight.72 The reasons for the electrical discrepancies between these studies of PI3K signaling in POMC neurons are yet unclear. The observed metabolic differences between the studies may relate to variable impacts on the activity of the hypothalamic-pituitary-adrenal axis because the genetic strategies used also lead to gene alteration in pituitary corticotrophs owing to the activity of the POMC promoter driving CRE expression in those cells. Importantly, and in contrast to the studies of mice with leptin receptor mutations or cell-specific leptin receptor deletions or overexpression, the interpretation of metabolic data from mice with alterations of intracellular proteins (such as PI3K, PTEN, 3-phosphoinositide-dependent protein kinase 1, and adenosine monophosphate-activated protein kinase) suffers significantly from the fact that these proteins are regulated by many stimuli in addition to leptin. Furthermore, these enzymes affect a number of different signaling pathways that vary depending on the stimuli. It is therefore unclear whether the observed metabolic phenotypes are specifically due to alteration in leptin action or to changes in other signaling systems, or both.
Most mouse and rat strains develop obesity when given free access to a high-fat/high-carbohydrate-containing diet. Such diet-induced obese (DIO) rodents are principal models of common-type human obesity. Rodent and human obesity is characterized by hyperleptinemia and by leptin resistance that has yet to be understood.73,74 Leptin likely enters the brain via the blood-brain barrier,41,75,76 and decreased transport of leptin into the brain of DIO animals has been reported.77 However, impaired blood-brain barrier leptin transport may be acquired during development of obesity,77,78 suggesting that downstream intracellular signaling defects may be primary causes of leptin resistance. Interestingly, phospho-STAT3 immunohistochemistry on brain sections from leptin-treated DIO mice and rats has demonstrated regional differences in leptin sensitivity. Specifically, leptin signaling within the ARC is dramatically decreased whereas other hypothalamic and extrahypothalamic nuclei seem to remain relatively leptin sensitive.68 The decreased leptin signaling of the arcuate nucleus includes POMC and AgRP neurons and is associated with altered release of these neuropeptides and with increased expression of SOCS-3.68,69 This suggests that the ARC is selectively leptin resistant in DIO mice and may therefore play a direct role in the development of diet-induced obesity in rodents. Suppressor-of-cytokine-signaling-3 deficiency in the brain68 and specifically in POMC neurons67 enhances leptin-induced weight loss and protects mice from development of diet-induced obesity. Similarly, neuronal deletion of protein-tyrosine-phosphotase-1B increases leptin sensitivity and attenuates weight gain of high-fat-fed mice.46 Altogether, these data suggest that defects in leptin action specifically within the arcuate play a critical role in the pathogenesis of leptin-resistant obesity and that drugs aimed at ameliorating arcuate leptin-resistance might prevent the development of diet-induced obesity. The mechanism by which the arcuate becomes resistant to leptin and the process leading to increased SOCS-3 expression of DIO mice, and the causal-relationship between these events and the appearance of obesity, are critical issues that have yet to be resolved.
In addition to its role in energy homeostasis, leptin can regulate peripheral glucose and insulin balance via the central nervous system. For example, leptin-deficient Lepob/ob mice exhibit profound diabetes that can be fully prevented after 3 weeks of low doses of leptin that do not affect body weight and food intake.5 In addition, intracerebroventricular leptin can acutely stimulate glucose uptake in skeletal muscle59,79-81 and inhibit hepatic glucose production.82,83 Moreover, leptin dramatically improves insulin sensitivity in human lipodystrophy and in lipodystrophic mouse models, which are characterized by low serum leptin levels and by severe insulin resistance.84-86 This altogether suggests that leptin has an independent specific capacity to regulate glucose balance, but the neurons mediating this action have remained elusive.
Lack of central melanocortin receptor action in mice results in marked obesity, hyperinsulinemia, and late-onset hyperglycemia,87 and insulin resistance is detectable before the onset of obesity in these melanocortin-4-receptor-deficient mice.88 In addition, ventricular infusion of α-MSH enhances short-term insulin-stimulated muscle glucose uptake and reduces hepatic glucose production, whereas a melanocortin receptor antagonist exerts opposite effects.89 Furthermore, loss of glucose sensing by POMC neurons and subsequent glucose-dependent α-MSH release lead to impaired whole body glucose tolerance.90 Moreover, genetic studies in diabetic mice suggest that the arcuate nucleus plays a major role in mediating effects of leptin on glucose balance16; however, the specific arcuate neurons responsible remain unspecified.
Given that arcuate POMC neurons express leptin receptors and that both leptin and the melanocortin system can influence glucose homeostasis, we hypothesized that specifically, POMC neurons mediate this leptin action and recently reported that CRE-mediated expression of ObRb only in POMC neurons in the morbidly obese and severely diabetic leptin receptor-deficient Leprdb/db mice remarkably leads to a complete normalization of blood glucose levels.24 This occurred entirely independently of changes in energy intake and body weight. In addition, insulin sensitivity was enhanced, and hypothalamic α-MSH neuropeptide levels were greatly elevated in the transgenic mice. Based on these data, we conclude that leptin signaling in POMC neurons is sufficient to prevent diabetes in Leprdb/db mice and that this action might be mediated by the central melanocortin pathway. Future studies are needed to explain how deletion of leptin receptors in POMC of normal mice does not lead to significant impairments in glucose balance22 but that reexpression of receptors in POMC neurons of diabetic Leprdb/db mice leads to this dramatic correction of blood glucose levels.24 Regardless, POMC neurons and their downstream neurocircuitries hold promise for identifying novel pathways, which may eventually help develop antidiabetes drugs for humans experiencing severe insulin-resistant diabetes and morbid obesity.
Important questions and future areas of research include (a) determination of the role of individual brain nuclei and specific neuronal groups in each of leptin's actions; (b) identification of the mechanism underlying the redundancy of different brain regions each capable of mediating leptin's effects on intake inhibition; (c) studies aimed at explaining how different groups of neurons have additive effects on body weight regulation; (d) experiments directed toward increasing our understanding of how leptin receptor reexpression in POMC neurons of diabetic Leprdb/db mice appears to play a major role in glucose control, whereas deletion of the receptor from POMC neurons in normoglycemic lean mice does not lead to impairment of glucose homeostasis; (e) elucidation of the specific neurocircuitries downstream of POMC neurons and the peripheral processes responsible for the control of blood glucose by leptin in Leprdb/db mice; (f) identification of specific roles and relative importance of individual intracellular leptin receptor signaling pathways in neuronal functions, including regulation of electrical activity, neuromodulation, and gene expression; and (g) determination of the primary causes of diet-induced obesity and the role of leptin resistance in its development.
1. Coleman DL. Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia. 1978;14:141-148.
2. Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372:425-432.
3. Ahima RS, Prabakaran D, Mantzoros C, et al. Role of leptin in the neuroendocrine response to fasting. Nature. 1996;382:250-252.
4. Chen H, Charlat O, Tartaglia LA, et al. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell. 1996;84:491-495.
5. Pelleymounter MA, Cullen MJ, Baker MB, et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science. 1995;269:540-543.
6. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature. 1998;395:763-770.
7. Bjørbaek C, Kahn BB. Leptin signaling in the central nervous system and the periphery. Recent Prog Horm Res. 2004;59:305-331.
8. Scott MM, Lachey JL, Sternson SM, et al. Leptin targets in the mouse brain. J Comp Neurol. 2009;514:518-532.
9. Ahima RS, Saper CB, Flier JS, et al. Leptin regulation of neuroendocrine systems. Front Neuroendocrinol. 2000;21:263-307.
10. Barsh GS, Farooqi IS, O'Rahilly S. Genetics of body-weight regulation. Nature. 2000;404:644-651.
11. Friedman JM. Obesity in the new millennium. Nature. 2000;404:632-634.
12. Schwartz MW, Woods SC, Porte D Jr, et al. Central nervous system control of food intake. Nature. 2000;404:661-671.
13. Elmquist JK, Bjorbaek C, Ahima RS, et al. Distributions of leptin receptor mRNA isoforms in the rat brain. J Comp Neurol. 1998;395:535-547.
14. Mercer JG, Hoggard N, Williams LM, et al. Coexpression of leptin receptor and preproneuropeptide Y mRNA in arcuate nucleus of mouse hypothalamus. J Neuroendocrinol. 1996;8:733-735.
15. Satoh N, Ogawa Y, Katsuura G, et al. The arcuate nucleus as a primary site of satiety effect of leptin in rats. Neurosci Lett. 1997;224:149-152.
16. Coppari R, Ichinose M, Lee CE, et al. The hypothalamic arcuate nucleus: a key site for mediating leptin's effects on glucose homeostasis and locomotor activity. Cell Metab. 2005;1:63-72.
17. Morton GJ, Niswender KD, Rhodes CJ, et al. Arcuate nucleus-specific leptin receptor gene therapy attenuates the obesity phenotype of Koletsky (fa(k)/fa(k)) rats. Endocrinology. 2003;144:2016-2024.
18. Cone RD. Anatomy and regulation of the central melanocortin system. Nat Neurosci. 2005;8:571-578.
19. Cowley MA, Smart JL, Rubinstein M, et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature. 2001;411:480-484.
20. Ollmann MM, Wilson BD, Yang YK, et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science. 1997;278:135-138.
21. van den Top M, Lee K, Whyment AD, et al. Orexigen-sensitive NPY/AgRP pacemaker neurons in the hypothalamic arcuate nucleus. Nat Neurosci. 2004;7:493-494.
22. Balthasar N, Coppari R, McMinn J, et al. Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron. 2004;42:983-991.
23. van de Wall E, Leshan R, Xu AW, et al. Collective and individual functions of leptin receptor modulated neurons controlling metabolism and ingestion. Endocrinology. 2008;149:1773-1785.
24. Huo L, Gamber K, Greeley S, et al. Leptin-dependent control of glucose balance and locomotor activity by POMC neurons. Cell Metab. 2009;9:537-547.
25. Dhillon H, Zigman JM, Ye C, et al. Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis. Neuron. 2006;49:191-203.
26. Satoh N, Ogawa Y, Katsuura G, et al. Sympathetic activation of leptin via the ventromedial hypothalamus: leptin-induced increase in catecholamine secretion. Diabetes. 1999;48:1787-1793.
27. Lechan RM, Fekete C. The TRH neuron: a hypothalamic integrator of energy metabolism. Prog Brain Res. 2006;153:209-235.
28. Hollenberg AN. The role of the thyrotropin-releasing hormone (TRH) neuron as a metabolic sensor. Thyroid. 2008;18:131-139.
29. Donato J Jr, Silva RJ, Sita LV, et al. The ventral premammillary nucleus links fasting-induced changes in leptin levels and coordinated luteinizing hormone secretion. J Neurosci. 2009;29:5240-5250.
30. Fulton S, Pissios P, Manchon RP, et al. Leptin regulation of the mesoaccumbens dopamine pathway. Neuron. 2006;51:811-822.
31. Hommel JD, Trinko R, Sears RM, et al. Leptin receptor signaling in midbrain dopamine neurons regulates feeding. Neuron. 2006;51:801-810.
32. Huo L, Grill HJ, Bjorbaek C. Divergent regulation of proopiomelanocortin neurons by leptin in the nucleus of the solitary tract and in the arcuate hypothalamic nucleus. Diabetes. 2006;55:567-573.
33. Grill HJ, Schwartz MW, Kaplan JM, et al. Evidence that the caudal brainstem is a target for the inhibitory effect of leptin on food intake. Endocrinology. 2002;143:239-246.
34. Grill HJ, Hayes MR. The nucleus tractus solitarius: a portal for visceral afferent signal processing, energy status assessment and integration of their combined effects on food intake. Int J Obes (Lond). 2009;(suppl 1):S11-S15.
35. Tartaglia LA, Dembski M, Weng X, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell. 1995;83:1263-1271.
36. Lee GH, Proenca R, Montez JM, et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature. 1996;379:632-635.
37. Bjørbaek C, Uotani S, da Silva B, et al. Divergent signaling capacities of the long and short isoforms of the leptin receptor. J Biol Chem. 1997;272:32686-32695.
38. Leinninger GM, Myers MG Jr. LRb signals act within a distributed network of leptin-responsive neurones to mediate leptin action. ActaPhysiol (Oxf). 2008;192:49-59.
39. Munzberg H, Huo L, Nillni EA, et al. Role of signal transducer and activator of transcription 3 in regulation of hypothalamic proopiomelanocortin gene expression by leptin. Endocrinology. 2003;144:2121-2131.
40. Kitamura T, Feng Y, Kitamura YI, et al. Forkhead protein FoxO1 mediates Agrp-dependent effects of leptin on food intake. Nat Med. 2006;12:534-540.
41. Bjorbaek C, Elmquist JK, Frantz JD, et al. Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol Cell. 1998;1:619-625.
42. Bjørbaek C, El-Haschimi K, Frantz JD, et al. The role of SOCS-3 in leptin signaling and leptin resistance. J Biol Chem. 1999;274:30059-30065.
43. Bjorbak C, Lavery HJ, Bates SH, et al. SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985. J Biol Chem. 2000;275:40649-40657.
44. Zabolotny JM, Bence-Hanulec KK, Stricker-Krongrad A, et al. PTP1B regulates leptin signal transduction in vivo. Dev Cell. 2002;2:489-495.
45. Lund IK, Hansen JA, Andersen HS, et al. Mechanism of protein tyrosine phosphatase 1B-mediated inhibition of leptin signalling. J Mol Endocrinol. 2005;34:339-351.
46. Bence KK, Delibegovic M, Xue B, et al. Neuronal PTP1B regulates body weight, adiposity and leptin action. Nat Med. 2006;12:917-924.
47. Gong L, Yao F, Hockman K, et al. Signal transducer and activator of transcription-3 is required in hypothalamic agouti-related protein/neuropeptide Y neurons for normal energy homeostasis. Endocrinology. 2008;149:3346-3354.
48. Mütze J, Roth J, Gerstberger R, et al. Nuclear translocation of the transcription factor STAT5 in the rat brain after systemic leptin administration. Neurosci Lett. 2007;417:286-291.
49. Banks AS, Davis SM, Bates SH, et al. Activation of downstream signals by the long form of the leptin receptor. J Biol Chem. 2000;275:14563-14572.
50. Niswender KD, Morton GJ, Stearns WH, et al. Intracellular signalling. Key enzyme in leptin-induced anorexia. Nature. 2001;413:794-795.
51. Niswender KD, Gallis B, Blevins JE, et al. Immunocytochemical detection of phosphatidylinositol 3-kinase activation by insulin and leptin. J Histochem Cytochem. 2003;51:275-283.
52. Pardini AW, Nguyen HT, Figlewicz DP, et al. Distribution of insulin receptor substrate-2 in brain areas involved in energy homeostasis. Brain Res. 2006;1112:169-178.
53. Rahmouni K, Haynes WG, Morgan DA, et al. Role of melanocortin-4 receptors in mediating renal sympathoactivation to leptin and insulin. J Neurosci. 2003;23:5998-6004.
54. Xu AW, Kaelin CB, Takeda K, et al. PI3K integrates the action of insulin and leptin on hypothalamic neurons. J Clin Invest. 2005;115:951-958.
55. Fukuda M, Jones JE, Olson D, et al. Monitoring FoxO1 localization in chemically identified neurons. J Neurosci. 2008;28:13640-13648.
56. Cota D, Proulx K, Smith KA, et al. Hypothalamic mTOR signaling regulates food intake. Science. 2006;312:927-930.
57. Blouet C, Ono H, Schwartz GJ. Mediobasal hypothalamic p70 S6 kinase 1 modulates the control of energy homeostasis. Cell Metab. 2008;8:459-467.
58. Kim MS, Pak YK, Jang PG, et al. Role of hypothalamic Foxo1 in the regulation of food intake and energy homeostasis. Nat Neurosci. 2006;9:901-906.
59. Minokoshi Y, Haque MS, Shimazu T. Microinjection of leptin into the ventromedial hypothalamus increases glucose uptake in peripheral tissues in rats. Diabetes. 1999;48:287-291.
60. Carling D. The role of the AMP-activated protein kinase in the regulation of energy homeostasis. Novartis Found Symp. 2007;286:72-81.
61. Hayes MR, Skibicka KP, Bence KK, et al. Dorsal hindbrain 5′-adenosine monophosphate-activated protein kinase as an intracellular mediator of energy balance. Endocrinology. 2009;150:2175-2182.
62. Claret M, Smith MA, Batterham RL, et al. AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. J Clin Invest. 2007;117:2325-2336.
63. Bates SH, Stearns WH, Dundon TA, et al. STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature. 2003;421:856-859.
64. Björnholm M, Münzberg H, Leshan RL, et al. Mice lacking inhibitory leptin receptor signals are lean with normal endocrine function. J Clin Invest. 2007;117:1354-1360.
65. Xu AW, Ste-Marie L, Kaelin CB, et al. Inactivation of signal transducer and activator of transcription 3 in proopiomelanocortin (Pomc) neurons causes decreased pomc expression, mild obesity, and defects in compensatory refeeding. Endocrinology. 2007;148:72-80.
66. Mesaros A, Koralov SB, Rother E, et al. Activation of Stat3 signaling in AgRP neurons promotes locomotor activity. Cell Metab. 2008;7:236-248.
67. Kievit P, Howard JK, Badman MK, et al. Enhanced leptin sensitivity and improved glucose homeostasis in mice lacking suppressor of cytokine signaling-3 in POMC-expressing cells. Cell Metab. 2006;4:123-132.
68. Munzberg H, Flier JS, Bjorbaek C. Region-specific leptin resistance within the hypothalamus of diet-induced obese mice. Endocrinology. 2004;145:4880-4889.
69. Enriori PJ, Evans AE, Sinnayah P, et al. Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons. Cell Metab. 2007;5:181-194.
70. Hill JW, Williams KW, Ye C, et al. Acute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mice. J Clin Invest. 2008;118:1796-1805.
71. Plum L, Ma X, Hampel B, et al. Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity. J Clin Invest. 2006;116:1886-1901.
72. Belgardt BF, Husch A, Rother E, et al. PDK1 deficiency in POMC-expressing cells reveals FOXO1-dependent and -independent pathways in control of energy homeostasis and stress response. Cell Metab. 2008;7:291-301.
73. Frederich RC, Hamann A, Anderson S, et al. Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat Med. 1995;1:1311-1314.
74. Maffei M, Halaas J, Ravussin E, et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med. 1995;1:1155-1161.
75. Hileman SM, Tornøe J, Flier JS, et al. Transcellular transport of leptin by the short leptin receptor isoform ObRa in Madin-Darby canine kidney cells. Endocrinology. 2000;141:1955-1961.
76. Banks WA. The blood-brain barrier as a cause of obesity. Curr Pharm Des. 2008;14:1606-1614.
77. Banks WA, Farrell CL. Impaired transport of leptin across the blood-brain barrier in obesity is acquired and reversible. Am J Physiol Endocrinol Metab. 2003;285:E10-E15.
78. Levin BE, Dunn-Meynell AA, Banks WA. Obesity-prone rats have normal blood-brain barrier transport but defective central leptin signaling before obesity onset. Am J Physiol Regul Integr Comp Physiol. 2004;286:R143-R150.
79. Cusin I, Zakrzewska KE, Boss O, et al. Chronic central leptin infusion enhances insulin-stimulated glucose metabolism and favors the expression of uncoupling proteins. Diabetes. 1998;47:1014-1019.
80. Haque MS, Minokoshi Y, Hamai M, et al. Role of the sympathetic nervous system and insulin in enhancing glucose uptake in peripheral tissues after intrahypothalamic injection of leptin in rats. Diabetes. 1999;48:1706-1712.
81. Kamohara S, Burcelin R, Halaas JL, et al. Acute stimulation of glucose metabolism in mice by leptin treatment. Nature. 1997;389:374-377.
82. Pocai A, Morgan K, Buettner C, et al. Central leptin acutely reverses diet-induced hepatic insulin resistance. Diabetes. 2005;54:3182-3189.
83. van den Hoek AM, Teusink B, Voshol PJ, et al. Leptin deficiency per se dictates body composition and insulin action in ob/ob mice. J Neuroendocrinol. 2008;20:120-127.
84. Oral EA, Simha V, Ruiz E, et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med. 2002;346:570-578.
85. Petersen KF, Oral EA, Dufour S, et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest. 2002;109:1345-1350.
86. Shimomura I, Hammer RE, Ikemoto S, et al. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature. 1999;401:73-76.
87. Huszar D, Lynch CA, Fairchild-Huntress V, et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell. 1997;88:131-141.
88. Fan W, Dinulescu DM, Butler AA, et al. The central melanocortin system can directly regulate serum insulin levels. Endocrinology. 2000;141:3072-3079.
89. Obici S, Feng Z, Tan J, et al. Central melanocortin receptors regulate insulin action. J Clin Invest. 2001;108:1079-1085.
90. Parton LE, Ye CP, Coppari R, et al. Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature. 2007;449:228-232.