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The role of leptin in the regulation of neuroendocrine function and CNS development

Abstract

Leptin, a hormone produced by adipocytes in proportion to fat stores, signals the sufficiency of energy reserves to the brain to control feeding and metabolism. Leptin represents a vital link between metabolic and neuroendocrine pathways, and adequate circulating leptin levels are required to permit the expenditure of energy on reproduction, growth, and other energy-intensive endocrine outputs. Leptin mediates its effects by acting upon a distributed network of CNS neurons that express the signaling form of the leptin receptor (LRb). Nutritional status early in development influences a lifelong metabolic program that modulates risk for diabetes, obesity and other elements of the metabolic syndrome. Recent evidence has demonstrated a number of important roles for leptin in the regulation of neural development and metabolic programming. In this review, we discuss leptin action, the neural circuits on which leptin acts, and our nascent understanding of how early leptin exposure may influence neural development and the predisposition to metabolic diseases.

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References

  1. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998;395:763–70.

    PubMed  CAS  Google Scholar 

  2. Coleman DL. Obese and diabetes: two mutant genes causing diabetes–obesity syndromes in mice. Diabetologia 1978;14:141–8.

    PubMed  CAS  Google Scholar 

  3. Flier JS, Elmquist JK. Energetic pursuit of leptin function. Nat Biotechnol 1997;15:20–1.

    PubMed  CAS  Google Scholar 

  4. Coleman DL. Effects of parabiosis of obese with diabetic and normal mice. Diabetologia 1973;4:294–8.

    Google Scholar 

  5. Coleman DL, Hummel KP. Effects of parabiosis of normal with genetically diabetic mice. Am J Physiol 1969;217:1298–304

    PubMed  CAS  Google Scholar 

  6. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994;372:425–32.

    PubMed  CAS  Google Scholar 

  7. Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature 1996;379:632–5.

    PubMed  CAS  Google Scholar 

  8. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 1995;83:1263–71.

    PubMed  CAS  Google Scholar 

  9. Chua SC Jr, Chung WK, Wu-Peng XS, Zhang Y, Liu SM, Tartaglia LA, et al. Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (Leptin) receptor. Science 1996;271:994–6.

    PubMed  CAS  Google Scholar 

  10. Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, et al. Evidence that the diabetes gene encodes the leptin receptor: Identification of a mutatioan in the leptin receptor gene in db/db mice. Cell 1996;84:491–5.

    PubMed  CAS  Google Scholar 

  11. Flier JS. Leptin expression and action: New experimental paradigms. Proc Natl Acad Sci U S A 1997;94:4242–5.

    PubMed  CAS  Google Scholar 

  12. Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med 2002;346:570–8.

    PubMed  CAS  Google Scholar 

  13. Shimomura I, Hammer RE, Ikemoto S, Brown MS, Goldstein JL. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 1999;401:73–6.

    PubMed  CAS  Google Scholar 

  14. Coleman RA, Herrmann TS. Nutritional regulation of leptin in humans. Diabetologia 1999;42:639–46.

    PubMed  CAS  Google Scholar 

  15. Bradley RL, Cheatham B. Regulation of ob gene expression and leptin secretion by insulin and dexamethasone in rat adipocytes. Diabetes 1999;48:272–8.

    PubMed  CAS  Google Scholar 

  16. Lee MJ, Wang Y, Ricci MR, Sullivan S, Russell CD, Fried SK. Acute and chronic regulation of leptin synthesis, storage, and secretion by insulin and dexamethasone in human adipose tissue. Am J Physiol Endocrinol Metab 2007;292:E858–64.

    PubMed  CAS  Google Scholar 

  17. Ahima RS, Prabakaran D, Flier JS. Postnatal leptin surge and regulation of circadian rhythm of leptin by feeding. Implications for energy homeostasis and neuroendocrine function. J Clin Invest 1998;101:1020–7.

    PubMed  CAS  Google Scholar 

  18. Ahima RS, Prabakaran D, Mantzoros CS, Qu D, Lowell BB, Maratos-Flier E, et al. Role of leptin in the neuroendocrine response to fasting. Nature 1996;382:250–2.

    PubMed  CAS  Google Scholar 

  19. Ahima RS, Saper CB, Flier JS, Elmquist JK. Leptin regulation of neuroendocrine systems. Front Neuroendocrinol 2000;21:263–307.

    PubMed  CAS  Google Scholar 

  20. Farooqi IS, O’Rahilly S. Monogenic human obesity syndromes. Recent Prog Horm Res 2004;59:409–24.

    PubMed  CAS  Google Scholar 

  21. Kennedy GC. The role of depot fat in the hypothalamic control of food intake in rats. Proc R Soc 1953;140:578–92.

    CAS  Article  Google Scholar 

  22. Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, Lechler RI. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 1998;394:897–901.

    PubMed  CAS  Google Scholar 

  23. Bates SH, Myers MG Jr. The role of leptin receptor signaling in feeding and neuroendocrine function. Trends Endocrinol Metab 2003;14:447–52.

    PubMed  CAS  Google Scholar 

  24. Chua SC Jr, Koutras IK, Han L, Liu SM, Kay J, Young SJ, et al. Fine structure of the murine leptin receptor gene: Splice site suppression is required to form two alternatively spliced transcripts. Genomics 1997;45:264–70.

    PubMed  CAS  Google Scholar 

  25. Yang G, Ge H, Boucher A, Yu X, Li C. Modulation of direct leptin signaling by soluble leptin receptor. Mol Endocrinol 2004;18:1354–62.

    PubMed  CAS  Google Scholar 

  26. Chua SC Jr, Liu SM, Li Q, Sun A, DeNino WF, Heymsfield SB, et al. Transgenic complementation of leptin receptor deficiency. II. Increased leptin receptor transgene dose effects on obesity/diabetes and fertility/lactation in lepr-db/db mice. Am J Physiol Endocrinol Metab 2004;286:E384–92.

    PubMed  CAS  Google Scholar 

  27. Kloek C, Haq AK, Dunn SL, Lavery HJ, Banks AS, Myers MG Jr. Regulation of Jak kinases by intracellular leptin receptor sequences. J Biol Chem 2002;277:41547–55.

    PubMed  CAS  Google Scholar 

  28. Baumann H, Morella KK, White DW, Dembski M, Bailon PS, Kim H, et al. The full-length leptin receptor has signaling capabilities of interleukin 6-type cytokine receptors. Proc Natl Acad Sci U S A 1996;93:8374–8.

    PubMed  CAS  Google Scholar 

  29. Taga T, Kishimoto T. gp130 and the interleukin-6 family of cytokines. Annu Rev Immunol 1997;15:797–819.

    PubMed  CAS  Google Scholar 

  30. Bjorbaek C, Uotani S, da Silva B, Flier JS. Divergent signaling capacities of the long and short isoforms of the leptin receptor. J Biol Chem 1997;272:32686–95.

    PubMed  CAS  Google Scholar 

  31. Myers MG Jr. Leptin receptor signaling and the regulation of mammalian physiology. Recent Prog Horm Res 2004;59:287–304.

    PubMed  CAS  Google Scholar 

  32. Hekerman P, Zeidler J, Bamberg-Lemper S, Knobelspies H, Lavens D, Tavernier J, et al. Pleiotropy of leptin receptor signalling is defined by distinct roles of the intracellular tyrosines. FEBS J 2005;272:109–19.

    PubMed  CAS  Google Scholar 

  33. Bjorbaek C, Lavery HJ, Bates SH, Olson RK, Davis SM, Flier JS, et al. SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985. J Biol Chem 2000;275:40649–57.

    CAS  Google Scholar 

  34. Dunn SL, Bjornholm M, Bates SH, Chen Z, Seifert M, Myers MG Jr. Feedback inhibition of leptin receptor/Jak2 signaling via Tyr1138 of the leptin receptor and suppressor of cytokine signaling 3. Mol Endocrinol 2005;19:925–38.

    PubMed  CAS  Google Scholar 

  35. Banks AS, Davis SM, Bates SH, Myers MG Jr. Activation of downstream signals by the long form of the leptin receptor. J Biol Chem 2000;275:14563–72.

    PubMed  CAS  Google Scholar 

  36. Li C, Friedman JM. Leptin receptor activation of SH2 domain containing protein tyrosine phosphatase 2 modulates Ob receptor signal transduction. Proc Natl Acad Sci U S A 1999;96:9677–82.

    PubMed  CAS  Google Scholar 

  37. Carpenter LR, Farruggella TJ, Symes A, Karow ML, Yancopoulos G. Enhancing leptin response by preventing SH2-containing phosphatase 2 interaction with Ob receptor. Proc Natl Acad Sci U S A 1998;95:6061–6.

    PubMed  CAS  Google Scholar 

  38. Bates SH, Stearns WH, Schubert M, Tso AWK, Wang Y, Banks AS, et al. STAT3 signaling is required for leptin regulation of energy balance but not reproduction. Nature 2003;421:856–9.

    PubMed  CAS  Google Scholar 

  39. Bjornholm M, Munzberg H, Leshan RL, Villanueva E, Bates SH, Louis GW, et al. Mice lacking inhibitory leptin receptor signals are lean with normal endocrine function. J Clin Invest 2007;117:1354–60.

    PubMed  CAS  Google Scholar 

  40. Bates SH, Dundon TA, Seifert M, Carlson M, Maratos-Flier E, Myers MG Jr. LRb-STAT3 signaling is required for the neuroendocrine regulation of energy expenditure by leptin. Diabetes 2004;53:3067–73.

    PubMed  CAS  Google Scholar 

  41. Bates SH, Kulkarni RN, Seifert M, Myers MG Jr. Roles for leptin receptor/STAT3-dependent and -independent signals in the regulation of glucose homeostasis. Cell Metab 2005;1:169–78.

    PubMed  CAS  Google Scholar 

  42. Bodary PF, Shen Y, Ohman M, Bahrou KL, Vargas FB, Cudney SS, et al. Leptin regulates neointima formation after arterial injury through mechanisms independent of blood pressure and the leptin receptor/STAT3 signaling pathways involved in energy balance. Arterioscler Thromb Vasc Biol 2007;27:70–6.

    PubMed  CAS  Google Scholar 

  43. de Luca C, Kowalski TJ, Zhang Y, Elmquist JK, Lee C, Kilimann MW, et al. Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes. J Clin Invest 2005;115:3484–93.

    PubMed  Google Scholar 

  44. Cohen P, Zhao C, Cai X, Montez JM, Rohani SC, Feinstein P, et al. Selective deletion of leptin receptor in neurons leads to obesity. J Clin Invest 2001;108:1113–21.

    PubMed  CAS  Google Scholar 

  45. McMinn JE, Liu SM, Liu H, Dragatsis I, Dietrich P, Ludwig T, et al. Neuronal deletion of Lepr elicits diabesity in mice without affecting cold tolerance or fertility. Am J Physiol Endocrinol Metab 2005;289:E403–11.

    PubMed  CAS  Google Scholar 

  46. Farooqi IS, Matarese G, Lord GM, Keogh JM, Lawrence E, Agwu C, et al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest 2002;110:1093–103.

    PubMed  CAS  Google Scholar 

  47. Elmquist JK, Bjorbaek C, Ahima RS, Flier JS, Saper CB. Distributions of leptin receptor mRNA isoforms in the rat brain. J Comp Neurol 1998;395:535–47.

    PubMed  CAS  Google Scholar 

  48. Horsch D, Goke R, Eissele R, Michel B, Goke B. Reciprocal cellular distribution of glucagon-like peptide 1 (GLP-1) immunoreactivity and GLP-1 receptor mRNA in pancreatic islets of rat. Pancreas 1997;14:290–4.

    PubMed  CAS  Article  Google Scholar 

  49. Leshan RL, Bjornholm M, Munzberg H, Myers MG Jr. Leptin receptor signaling and action in the central nervous system. Obesity (Silver Spring) 2006;14 Suppl 5:208S–12S.

    CAS  Google Scholar 

  50. Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature 2000;404:661–71.

    PubMed  CAS  Google Scholar 

  51. Elmquist JK, Elias CF, Saper CB. From lesions to leptin: hypothalamic control of food intake and body weight. Neuron 1999;22:221–32.

    PubMed  CAS  Google Scholar 

  52. Elias CF, Aschkenasi C, Lee C, Kelly J, Ahima RS, Bjorbaek C, et al. Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 1999;23:775–86.

    PubMed  CAS  Google Scholar 

  53. Appleyard SM, Hayward M, Young JI, Butler AA, Cone RD, Rubinstein M, et al. A role for the endogenous opioid beta-endorphin in energy homeostasis. Endocrinology 2003;144:1753–60.

    PubMed  CAS  Google Scholar 

  54. Cowley MA, Smart JL, Rubinstein M, Cerdan MG, Diano S, Horvath TL, et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 2001;411:480–4.

    PubMed  CAS  Google Scholar 

  55. Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone RD. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 1997;385:165–8.

    PubMed  CAS  Google Scholar 

  56. Seeley RJ, Yagaloff KA, Fisher SL, Burn P, Thiele TE, van Dijk G, et al. Melanocortin receptors in leptin effects. Nature 1997;390:349.

    PubMed  CAS  Google Scholar 

  57. Erickson JC, Hollopeter G, Palmiter RD. Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y. Science 1996;274:1704–7.

    PubMed  CAS  Google Scholar 

  58. Breen TL, Conwell IM, Wardlaw SL. Effects of fasting, leptin, and insulin on AGRP and POMC peptide release in the hypothalamus. Brain Res 2005;1032:141–8.

    PubMed  CAS  Google Scholar 

  59. Korner J, Savontaus E, Chua SC Jr, Leibel RL, Wardlaw SL. Leptin regulation of Agrp and Npy mRNA in the rat hypothalamus. J Neuroendocrinol 2001;13:959–66.

    PubMed  CAS  Google Scholar 

  60. Elmquist JK, Coppari R, Balthasar N, Ichinose M, Lowell BB. Identifying hypothalamic pathways controlling food intake, body weight, and glucose homeostasis. J Comp Neurol 2005;493:63–71.

    PubMed  CAS  Google Scholar 

  61. Schwartz MW. Central nervous system regulation of food intake. Obesity (Silver Spring) 2006;14 Suppl 1:1S–8S.

    CAS  Article  Google Scholar 

  62. Mountjoy KG, Mortrud MT, Low MJ, Simerly RB, Cone RD. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol Endocrinol 1994;8:1298–308.

    PubMed  CAS  Google Scholar 

  63. Butler AA, Cone RD. The melanocortin receptors: lessons from knockout models. Neuropeptides 2002;36:77–84.

    PubMed  CAS  Google Scholar 

  64. Dhillon H, Zigman JM, Ye C, Lee CE, McGovern RA, Tang V, 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.

    PubMed  CAS  Google Scholar 

  65. Hommel JD, Trinko R, Sears RM, Georgescu D, Liu ZW, Gao XB, et al. Leptin receptor signaling in midbrain dopamine neurons regulates feeding. Neuron 2006;51:801–10.

    PubMed  CAS  Google Scholar 

  66. Fulton S, Pissios P, Manchon RP, Stiles L, Frank L, Pothos EN, et al. Leptin regulation of the mesoaccumbens dopamine pathway. Neuron 2006;51:811–22.

    PubMed  CAS  Google Scholar 

  67. Coppari R, Ichinose M, Lee CE, Pullen AE, Kenny CD, McGovern RA, 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.

    PubMed  CAS  Google Scholar 

  68. Xu AW, Ste-Marie L, Kaelin CB, Barsh GS. Inactivation of Stat3 in Pomc neurons causes decreased Pomc expression, mild obesity and defects in compensatory refeeding. Endocrinology 2006;148:72–80.

    PubMed  Google Scholar 

  69. Kaelin CB, Gong L, Xu AW, Yao F, Hockman K, Morton GJ, et al. Signal transducer and activator of transcription (stat) binding sites but not stat3 are required for fasting-induced transcription of agouti-related protein messenger ribonucleic acid. Mol Endocrinol 2006;20:2591–602.

    PubMed  CAS  Google Scholar 

  70. Balthasar N, Coppari R, McMinn J, Liu SM, Lee CE, Tang V, et al. Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 2004;42:983–91.

    PubMed  CAS  Google Scholar 

  71. Kelley AE, Berridge KC. The neuroscience of natural rewards: relevance to addictive drugs. J Neurosci 2002;22:3306–11.

    PubMed  CAS  Google Scholar 

  72. Georgescu D, Zachariou V, Barrot M, Mieda M, Willie JT, Eisch AJ, et al. Involvement of the lateral hypothalamic peptide orexin in morphine dependence and withdrawal. J Neurosci 2003;23:3106–11.

    PubMed  CAS  Google Scholar 

  73. Georgescu D, Sears RM, Hommel JD, Barrot M, Bolanos CA, Marsh DJ, et al. The hypothalamic neuropeptide melanin-concentrating hormone acts in the nucleus accumbens to modulate feeding behavior and forced-swim performance. J Neurosci 2005;25:2933–40.

    PubMed  CAS  Google Scholar 

  74. DiLeone RJ, Georgescu D, Nestler EJ. Lateral hypothalamic neuropeptides in reward and drug addiction. Life Sci 2003;73:759–68.

    PubMed  CAS  Google Scholar 

  75. Figlewicz DP, Evans SB, Murphy J, Hoen M, Baskin DG. Expression of receptors for insulin and leptin in the ventral tegmental area/substantia nigra (VTA/SN) of the rat. Brain Res 2003;964:107–15.

    PubMed  CAS  Google Scholar 

  76. Figlewicz DP, Higgins MS, Ng-Evans SB, Havel PJ. Leptin reverses sucrose-conditioned place preference in food-restricted rats. Physiol Behav 2001;73:229–34.

    PubMed  CAS  Google Scholar 

  77. Figlewicz DP, Bennett J, Evans SB, Kaiyala K, Sipols AJ, Benoit SC. Intraventricular insulin and leptin reverse place preference conditioned with high-fat diet in rats. Behav Neurosci 2004;118:479–87.

    PubMed  CAS  Google Scholar 

  78. Harris GC, Wimmer M. Aston-Jones G. A role for lateral hypothalamic orexin neurons in reward seeking. Nature 2005;437:556–9.

    PubMed  CAS  Google Scholar 

  79. Ahmed SH, Lutjens R, van der Stap LD, Lekic D, Romano-Spica V, Morales M, et al. Gene expression evidence for remodeling of lateral hypothalamic circuitry in cocaine addiction. Proc Natl Acad Sci U S A 2005;102:11533–38.

    PubMed  CAS  Google Scholar 

  80. Boutrel B, Kenny PJ, Specio SE, Martin-Fardon R, Markou A, Koob GF, et al. Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior. Proc Natl Acad Sci U S A 2005;102:19168–73.

    PubMed  CAS  Google Scholar 

  81. Narita M, Nagumo Y, Hashimoto S, Narita M, Khotib J, Miyatake M, et al. Direct involvement of orexinergic systems in the activation of the mesolimbic dopamine pathway and related behaviors induced by morphine. J Neurosci 2006;26:398–405.

    PubMed  CAS  Google Scholar 

  82. Nagatani S, Guthikonda P, Thompson RC, Tsukamura H, Maeda KI, Foster DL. Evidence for GnRH regulation by leptin: leptin administration prevents reduced pulsatile LH secretion during fasting. Neuroendocrinology 1998;67:370–6.

    PubMed  CAS  Google Scholar 

  83. Duhl DM, Vrieling H, Miller KA, Wolff GL, Barsh GS. Neomorphic agouti mutations in obese yellow mice. Nature Genet 1994;8:59–65.

    PubMed  CAS  Google Scholar 

  84. Balthasar N, Dalgaard LT, Lee CE, Yu J, Funahashi H, Williams T, et al. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell 2005;123:493–505.

    PubMed  CAS  Google Scholar 

  85. Barsh GS, Farooqi IS, O’Rahilly S. Genetics of body-weight regulation. Nature 2000;404:644–51.

    PubMed  CAS  Google Scholar 

  86. Smith MS, Grove KL. Integration of the regulation of reproductive function and energy balance: lactation as a model. Front Neuroendocrinol 2002;23:225–56.

    PubMed  CAS  Google Scholar 

  87. Clark JT, Kalra PS, Kalra SP. Neuropeptide Y stimulates feeding but inhibits sexual behavior in rats. Endocrinology 1985;117:2435–42.

    PubMed  CAS  Article  Google Scholar 

  88. Elias CF, Kelly JF, Lee CE, Ahima RS, Drucker DJ, Saper CB, et al. Chemical characterization of leptin-activated neurons in the rat brain. J Comp Neurol 2000;423:261–81.

    PubMed  CAS  Google Scholar 

  89. Simerly RB. Organization and regulation of sexually dimorphic neuroendocrine pathways. Behav Brain Res 1998;92:195–203.

    PubMed  CAS  Google Scholar 

  90. Sliwowska JH, Billings HJ, Goodman RL, Coolen LM, Lehman MN. The premammillary hypothalamic area of the ewe: anatomical characterization of a melatonin target area mediating seasonal reproduction. Biol Reprod 2004;70:1768–75.

    PubMed  CAS  Google Scholar 

  91. Yahr P, Jacobsen CH. Hypothalamic knife cuts that disrupt mating in male gerbils sever efferents and forebrain afferents of the sexually dimorphic area. Behav Neurosci 1994;108:735–42.

    PubMed  CAS  Google Scholar 

  92. Veening JG, Coolen LM, de Jong TR, Joosten HW, de Boer SF, Koolhaas JM, et al. Do similar neural systems subserve aggressive and sexual behaviour in male rats? Insights from c-Fos and pharmacological studies. Eur J Pharmacol 2005;526:226–39.

    PubMed  CAS  Google Scholar 

  93. Rondini TA, Baddini SP, Sousa LF, Bittencourt JC, Elias CF Hypothalamic cocaine- and amphetamine-regulated transcript neurons project to areas expressing gonadotropin releasing hormone immunoreactivity and to the anteroventral periventricular nucleus in male and female rats. Neuroscience 2004;125:735–48.

    PubMed  CAS  Google Scholar 

  94. Hahn JD, Coen CW. Comparative study of the sources of neuronal projections to the site of gonadotrophin-releasing hormone perikarya and to the anteroventral periventricular nucleus in female rats. J Comp Neurol 2006;494:190–214.

    PubMed  Google Scholar 

  95. Canteras NS, Simerly RB, Swanson LW. Projections of the ventral premammillary nucleus. J Comp Neurol 1992;324:195–212.

    PubMed  CAS  Google Scholar 

  96. Cavalcante JC, Bittencourt JC, Elias CF. Female odors stimulate CART neurons in the ventral premammillary nucleus of male rats. Physiol Behav 2006;88:160–6.

    PubMed  CAS  Google Scholar 

  97. Yokosuka M, Matsuoka M, Ohtani-Kaneko R, Iigo M, Hara M, Hirata K, et al. Female-soiled bedding induced fos immunoreactivity in the ventral part of the premammillary nucleus (PMv) of the male mouse. Physiol Behav 1999;68:257–61.

    PubMed  CAS  Google Scholar 

  98. Heeb MM, Yahr P. c-Fos immunoreactivity in the sexually dimorphic area of the hypothalamus and related brain regions of male gerbils after exposure to sex-related stimuli or performance of specific sexual behaviors. Neuroscience 1996;72:1049–71.

    PubMed  CAS  Google Scholar 

  99. Malpaux B, Daveau A, Maurice-Mandon F, Duarte G, Chemineau P. Evidence that melatonin acts in the premammillary hypothalamic area to control reproduction in the ewe: Presence of binding sites and stimulation of luteinizing hormone secretion by in situ microimplant delivery. Endocrinology 2007;139:1508–16.

    Google Scholar 

  100. Perello M, Stuart RC, Nillni EA. The role of intra-cerebro ventricular administration of leptin in the stimulation of prothyrotropin releasing hormone (proTRH) neurons in the hypothalamic paraventricular nucleus. Endocrinology 2006;147:3296–306.

    PubMed  CAS  Google Scholar 

  101. Cripps RL, Martin-Gronert MS, Ozanne SE. Fetal and perinatal programming of appetite. Clin Sci (Lond) 2005;109:1–11.

    CAS  Article  Google Scholar 

  102. Rogers I. The influence of birthweight and intrauterine environment on adiposity and fat distribution in later life. Int J Obes Relat Metab Disord 2003;27:755–77.

    PubMed  CAS  Google Scholar 

  103. Gluckman PD, Hanson MA. Maternal constraint of fetal growth and its consequences. Semin Fetal Neonatal Med 2004;9:419–25.

    PubMed  Google Scholar 

  104. Sartor BM, Dickey RP. Polycystic ovarian syndrome and the metabolic syndrome. Am J Med Sci 2005;330:336–42.

    PubMed  Google Scholar 

  105. Pasquali R, Gambineri A, Pagotto U. The impact of obesity on reproduction in women with polycystic ovary syndrome. BJOG 2006;113:1148–59.

    PubMed  CAS  Google Scholar 

  106. Dumesic DA, Schramm RD, Abbott DH. Early origins of polycystic ovary syndrome. Reprod Fertil Dev 2005;17:349–60.

    PubMed  CAS  Google Scholar 

  107. Davies MJ. Evidence for effects of weight on reproduction in women. Reprod Biomed Online 2006;12:552–61.

    PubMed  Article  Google Scholar 

  108. Davies MJ, Norman RJ. Programming and reproductive functioning. Trends Endocrinol Metab 2002;13:386–92.

    PubMed  CAS  Google Scholar 

  109. Marshall JC, Eagleson CA, McCartney CR. Hypothalamic dysfunction. Mol Cell Endocrinol 2001;183:29–32.

    PubMed  CAS  Google Scholar 

  110. Marshall JC, Eagleson CA. Neuroendocrine aspects of polycystic ovary syndrome. Endocrinol Metab Clin North Am 1999;28:295–324.

    PubMed  CAS  Google Scholar 

  111. Schaefer-Graf UM, Pawliczak J, Passow D, Hartmann R, Rossi R, Buhrer C, et al. Birth weight and parental BMI predict overweight in children from mothers with gestational diabetes. Diabetes Care 2005;28:1745–50.

    PubMed  Google Scholar 

  112. Ravelli GP, Stein ZA, Susser MW. Obesity in young men after famine exposure in utero and early infancy. N Engl J Med 1976;295:349–53.

    PubMed  CAS  Article  Google Scholar 

  113. Painter RC, Roseboom TJ, Bleker OP. Prenatal exposure to the Dutch famine and disease in later life: An overview. Reprod Toxicol 2005;20:345–52.

    PubMed  CAS  Google Scholar 

  114. Yamashita H, Shao J, Qiao L, Pagliassotti M, Friedman JE. Effect of spontaneous gestational diabetes on fetal and postnatal hepatic insulin resistance in Lepr(db/+) mice. Pediatr Res 2003;53:411–8.

    PubMed  CAS  Google Scholar 

  115. Yura S, Itoh H, Sagawa N, Yamamoto H, Masuzaki H, Nakao K, et al. Role of premature leptin surge in obesity resulting from intrauterine undernutrition. Cell Metab 2005;1:371–8.

    PubMed  CAS  Google Scholar 

  116. Vickers MH, Gluckman PD, Coveny AH, Hofman PL, Cutfield WS, Gertler A, et al. Neonatal leptin treatment reverses developmental programming. Endocrinology 2005;146:4211–6.

    PubMed  CAS  Google Scholar 

  117. Bouret SG, Draper SJ, Simerly RB. Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 2004;304:108–10.

    PubMed  CAS  Google Scholar 

  118. Ahima RS, Bjorbaek C, Osei S, Flier JS. Regulation of neuronal and glial proteins by leptin: implications for brain development. Endocrinology 1999;140:2755–62.

    PubMed  CAS  Google Scholar 

  119. Mistry AM, Swick A, Romsos DR. Leptin alters metabolic rates before acquisition of its anorectic effect in developing neonatal mice. Am J Physiol 1999;277:R742–7.

    PubMed  CAS  Google Scholar 

  120. Pinto S, Roseberry AG, Liu H, Diano S, Shanabrough M, Cai X, et al. Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 2004;304:110–5.

    PubMed  CAS  Google Scholar 

  121. Steppan CM, Swick AG. A role for leptin in brain development. Biochem Biophys Res Commun 1999;256:600–2.

    PubMed  CAS  Google Scholar 

  122. Bouret SG, Draper SJ, Simerly RB. Formation of projection pathways from the arcuate nucleus of the hypothalamus to hypothalamic regions implicated in the neural control of feeding behavior in mice. J Neurosci 2004;24:2797–805.

    PubMed  CAS  Google Scholar 

  123. Barrett T, Ehtisham S, Maher E, Plagemann A, Harder T, Cheng TO, et al. The changing face and implications of childhood obesity. N Engl J Med 2004;350:2414–6.

    PubMed  CAS  Google Scholar 

  124. Sarandakou A, Protonotariou E, Rizos D, Malamitsi-Puchner A, Giannaki G, Phocas I, et al. Serum leptin concentrations during the perinatal period. Am J Perinatol 2000;17:325–8.

    PubMed  CAS  Google Scholar 

  125. Jaquet D, Leger J, Levy-Marchal C, Oury JF, Czernichow P. Ontogeny of leptin in human fetuses and newborns: effect of intrauterine growth retardation on serum leptin concentrations. J Clin Endocrinol Metab 1998;83:1243–6.

    PubMed  CAS  Google Scholar 

  126. Stowe ZN, Nemeroff CB. The electrophysiological actions of neurotensin in the central nervous system. Life Sci 1991;49:987–1002.

    PubMed  CAS  Google Scholar 

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Correspondence to Martin G. Myers Jr.

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Louis, G.W., Myers, M.G. The role of leptin in the regulation of neuroendocrine function and CNS development. Rev Endocr Metab Disord 8, 85–94 (2007). https://doi.org/10.1007/s11154-007-9043-3

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  • DOI: https://doi.org/10.1007/s11154-007-9043-3

Keywords

  • Leptin
  • Development
  • Metabolic syndrome
  • Brain