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Leptin Signaling In the Brain

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Energy Metabolism and Obesity

Part of the book series: Contemporary Endocrinology ((COE))

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Abstract

This chapter reviews current literature on hormonal and neural signals critical for the regulation of individual meals and body fat. Body weight is regulated via an ongoing process called energy homeostasis, or the long-term matching of food intake to energy expenditure. Reductions from an individual’s “normal” weight due to lack of sufficient food lowers levels of adiposity signals (leptin and insulin) reaching the brain from the blood, activates anabolic hormones that stimulate food intake, and decreases the efficacy of meal-generated signals (such as cholecystokinin, or CCK) that normally reduce meal size. A converse sequence of events happens when individuals gain weight: adiposity signals are increased, catabolic hormones are stimulated, and the consequence is a reduction in food intake and a normalization of body weight. The brain also functions as a “fuel sensor” and thereby senses nutrients and generates signals and activation of neuronal systems and circuits that regulate energy homeostasis. This chapter focuses on how these signals are received and integrated by the central nervous system.

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Abstract

  1. Stellar E. The physiology of motivation. Psychol Rev 1954;61:5–22.

    Article  PubMed  CAS  Google Scholar 

  2. Powley TL. The ventromedial hypothalamic syndrome, satiety, and a cephalic phase hypothesis. Psychol Rev 1977;84:89–126.

    Article  PubMed  CAS  Google Scholar 

  3. Sclafani A. The role of hyperinsulinema and the vagus nerve in hypothalamic hyperphagia reexamined. Diabetologia 1981;20(Suppl):402–410.

    Article  PubMed  CAS  Google Scholar 

  4. Bray GA, Sclafani A, Novin D. Obesity-inducing hypothalamic knife cuts: effects on lipolysis and blood insulin levels. Am J Physiol 1982;243:R445–R449.

    PubMed  CAS  Google Scholar 

  5. Aravich PF, Sclafani A. Paraventricular hypothalamic lesions and medial hypothalamic knife cuts produce similar hyperphagia syndromes. Behav Neurosci 1983;97:970–983.

    Article  PubMed  CAS  Google Scholar 

  6. Grill HJ, Norgren R. Chronically decerebrate rats demonstrate satiation but not bait shyness. Science 1978;201:267–269.

    Article  PubMed  CAS  Google Scholar 

  7. Grill HJ, Norgren R. The taste reactivity test. II. Mimetic responses to gustatory stimuli in chronic thalamic and chronic decerebrate rats. Brain Res 1978;143: 281–297.

    Article  PubMed  CAS  Google Scholar 

  8. Grill HJ, Smith GP. Cholecystokinin decreases sucrose intake in chronic decerebrate rats. Am J Physiol 1988;254:R853–R856.

    Google Scholar 

  9. Flynn FW, Grill HJ. Intraoral intake and taste reactivity responses elicited by sucrose and sodium chloride in chronic decerebrate rats. Behav Neurosci 1988;102:934–941.

    Article  PubMed  CAS  Google Scholar 

  10. Kennedy GC. The role of depot fat in the hypothalamic control of food intake in the rat. Proc R Soc Lond (Biol) 1953;140:579–592.

    Google Scholar 

  11. Ahima RS, et al. Leptin regulation of neuroendocrine systems. Front Neuroendocrinol 2000;21: 263–307.

    Article  PubMed  CAS  Google Scholar 

  12. Cone RD, et al. The arcuate nucleus as a conduit for diverse signals relevant to energy homeostasis. Int J Obes Relat Metab Disord 2001;25(Suppl 5):S63–S67.

    Google Scholar 

  13. Elmquist JK, Elias CF, Saper CB. From lesions to leptin: hypothalamic control of food intake and body weight. Neuron 1999;22:221–232.

    Article  PubMed  CAS  Google Scholar 

  14. Schwartz MW, Woods SC, Porte D Jr, et al. Central nervous system control of food intake. Nature 2000;404:661–671.

    PubMed  CAS  Google Scholar 

  15. Havel PJ, Kasim-Karakas S, Dubuc GR, et al. Gender differences in plasma leptin concentrations. Nat Med 1996;2:949–950.

    Article  PubMed  CAS  Google Scholar 

  16. Ahren B, Mansson S, Gingerich RL, et al. Regulation of plasma leptin in mice: Influence of age, high-fat diet and fasting. Am J Physiol 1997;273:R113–R120.

    PubMed  CAS  Google Scholar 

  17. Havel PJ. Mechanisms regulating leptin production: Implications for control of energy balance. Am J Clin Nutr 1999;70:305–306.

    PubMed  CAS  Google Scholar 

  18. Buchanan C, et al. Central nervous system effects of leptin. Trends Endocrinol Metab 1998; 9:146–150.

    Article  CAS  PubMed  Google Scholar 

  19. Bjorntorp P. Metabolic implications of body fat distribution. Diabetes Care 1991;14:1132–1143.

    Article  PubMed  CAS  Google Scholar 

  20. Bjorntorp P. Abdominal fat distribution and the metabolic syndrome. J Cardiovasc Pharmacol 1992;20(Suppl 8):S26–S28.

    Google Scholar 

  21. Bjorntorp P. Body fat distribution, insulin resistance, and metabolic diseases. Nutrition 1997;13:795–803.

    Article  PubMed  CAS  Google Scholar 

  22. Woods SC, et al. Signals that regulate food intake and energy homeostasis. Science 1998;280: 1378–1383.

    Article  PubMed  CAS  Google Scholar 

  23. Schwartz MW, et al. Insulin in the brain: a hormonal regulator of energy balance. Endocri Rev 1992;13:387–414.

    Google Scholar 

  24. de Castro JM, Stroebele N. Food intake in the real world: implications for nutrition and aging. Clin Geriatr Med 2002;18:685–697.

    Article  PubMed  Google Scholar 

  25. de Castro JM. The control of eating behavior in free living humans. In: Stricker EM, Woods SC, eds. Handbook of neurobiology. Neurobiology of food and fluid intake, vol. 14, no. 2. New York: Kluwer Academic/Plenum Publishers; 2004:467–502.

    Google Scholar 

  26. de Graaf C, et al. Biomarkers of satiation and satiety. Am J Clin Nutr 2004;79:946–961.

    PubMed  Google Scholar 

  27. Mayer J. Regulation of energy intake and the body weight: The glucostatic and lipostatic hypothesis. Ann N Y Acad Sci 1955;63:14–42.

    Article  Google Scholar 

  28. Mayer J, Thomas DW. Regulation of food intake and obesity. Science 1967;156:328–337.

    Article  PubMed  CAS  Google Scholar 

  29. Friedman MI. Fuel partitioning and food intake. Am J Clin Nutr 1998;67(Suppl. 3):513S–518S.

    Google Scholar 

  30. Friedman MI. An energy sensor for control of energy intake. Proc Nutr Soc 1997;56:41–50.

    Article  PubMed  CAS  Google Scholar 

  31. Langhans W. Metabolic and glucostatic control of feeding. Proc Nutr Soc 1996;55:497–515.

    PubMed  CAS  Google Scholar 

  32. Peters A, et al. The selfish brain: competition for energy resources. Neurosci Biobehav Rev 2004;28:143–180.

    Article  PubMed  CAS  Google Scholar 

  33. Strubbe JH, Woods SC. The timing of meals. Psychol Rev 2004;111:128–141.

    Article  PubMed  Google Scholar 

  34. Woods SC, Strubbe JH. The psychobiology of meals. Psychonom Bull Rev 1994;1:141–155.

    Google Scholar 

  35. Woods SC, et al. Food intake and the regulation of body weight. Annu Rev Psychol 2000;51:255–277.

    Article  PubMed  CAS  Google Scholar 

  36. Davis JD, Campbell CS. Peripheral control of meal size in the rat. Effect of sham feeding on meal size and drinking rate. J Comp Physiol Psychol 1973;83:379–387.

    Article  PubMed  CAS  Google Scholar 

  37. Davis JD, Smith GP. Learning to sham feed: behavioral adjustments to loss of physiological postingestional stimuli. Am J Physiol 1990;259:R1228–R1235.

    PubMed  CAS  Google Scholar 

  38. Gibbs J, Young RC, Smith GP. Cholecystokinin elicits satiety in rats with open gastric fistulas. Nature 1973;245:323–325.

    Article  PubMed  CAS  Google Scholar 

  39. Gibbs J, Young RC, Smith GP. Cholecystokinin decreases food intake in rats. J Comp Physiol Psychol 1973;84:488–495.

    Article  PubMed  CAS  Google Scholar 

  40. Kissileff HR, et al. Cholecystokinin decreases food intake in man. Am J Clin Nutr 1981;34:154–160.

    PubMed  CAS  Google Scholar 

  41. Muurahainenn N, et al. Effects of cholecystokinin-octapeptide (CCK-8) on food intake and gastric emptying in man. Physiol Behav 1988;44:644–649.

    Article  Google Scholar 

  42. Moran TH, Schwartz GJ. Neurobiology of cholecystokinin. Crit Rev Neurobiol 1994;9:1–28.

    PubMed  CAS  Google Scholar 

  43. Smith GP, Gibbs J. The development and proof of the cholecystokinin hypothesis of satiety. In: Dourish CT, et al., eds. Multiple cholecystokinin receptors in the CNS. Oxford: Oxford University Press; 1992:166–182.

    Google Scholar 

  44. Beglinger C, et al. Loxiglumide, a CCK-A receptor antagonist, stimulates calorie intake and hunger feelings in humans. Am J Physiol 2001;280:R1149–R1154.

    CAS  Google Scholar 

  45. Hewson G, et al. The cholecystokinin receptor antagonist L364,718 increases food intake in the rat by attenuation of endogenous cholecystokinin. Br J Pharmacol 1988;93:79–84.

    PubMed  CAS  Google Scholar 

  46. Moran TH, et al. Blockade of type A, but not type B, CCK receptors postpones satiety in rhesus monkeys. Am J Physiol 1993;265:R620–R624.

    PubMed  CAS  Google Scholar 

  47. Reidelberger RD, O’Rourke MF. Potent cholecystokinin antagonist L-364,718 stimulates food intake in rats. Am J Physiol 1989;257:R1512–R1518.

    PubMed  CAS  Google Scholar 

  48. Kaplan JM, Moran TH. Gastrointestinal signaling in the control of food intake. In: Stricker EM, Woods SC, eds. Handbook of behavioral neurobiology. Neurobiology of food and fluid intake, vol. 4, no. 2. New York: Kluwer Academic/Plenum Publishing; 2004:273–303.

    Google Scholar 

  49. Smith GP, ed. Satiation: from gut to brain. New York: Oxford University Press; 1998.

    Google Scholar 

  50. Stein LJ, Woods SC. Gastrin releasing peptide reduces meal size in rats. Peptides 1982;3:833–835.

    Article  PubMed  CAS  Google Scholar 

  51. Ladenheim EE, Wirth KE, Moran TH. Receptor subtype mediation of feeding suppression by bombesin-like peptides. Pharmacol Biochem Behav 1996;54:705–711.

    Article  PubMed  CAS  Google Scholar 

  52. Okada S, et al. Enterostatin (Val-Pro-Asp-Pro-Arg), the activation peptide of procolipase, selectively reduces fat intake. Physiol Behav 1991;49:1185–1189.

    Article  PubMed  CAS  Google Scholar 

  53. Shargill NS, et al. Enterostatin suppresses food intake following injection into the third ventricle of rats. Brain Res 1991;544:137–140.

    Article  PubMed  CAS  Google Scholar 

  54. Lotter EC, et al. Somatostatin decreases food intake of rats and baboons. J Comp Physiol Psychol 1981;95:278–87.

    Article  PubMed  CAS  Google Scholar 

  55. Larsen PJ, et al. Systemic administration of the long-acting GLP-1 derivative NN2211 induces lasting and reversible weight loss in both normal and obese rats. Diabetes 2001;50:2530–2539.

    Article  PubMed  CAS  Google Scholar 

  56. Naslund E, et al. Energy intake and appetite are suppressed by glucagon-like peptide-1 (GLP-1) in obese men. Int J Obes Relat Metab Disord 1999;23:304–311.

    Article  PubMed  CAS  Google Scholar 

  57. Fujimoto K, et al. Effect of intravenous administration of apolipoprotein A-IV on patterns of feeding, drinking and ambulatory activity in rats. Brain Res 1993;608:233–237.

    Article  PubMed  CAS  Google Scholar 

  58. Batterham RL, et al. Gut hormone PYY(3-36) physiologically inhibits food intake. Nature 2002;418:650–654.

    Article  PubMed  CAS  Google Scholar 

  59. Chance WT, et al. Anorexia following the intrahypothalamic administration of amylin. Brain Res 1991;539:352–354.

    Article  PubMed  CAS  Google Scholar 

  60. Lutz TA, Del Prete E, Scharrer E. Reduction of food intake in rats by intraperitoneal injection of low doses of amylin. Physiol Behav 1994;55:891–895.

    Article  PubMed  Google Scholar 

  61. Geary N. Glucagon and the control of meal size. In: Smith GP, ed. Satiation. From Gut to Brain. New York: Oxford University Press: 1998:164–197.

    Google Scholar 

  62. Salter JM. Metabolic effects of glucagon in the Wistar rat. Am J Clin Nutr 1960;8:535–539.

    CAS  Google Scholar 

  63. Davison JS, Clarke GD. Mechanical properties and sensitivity to CCK of vagal gastric slowly adapting mechanoreceptors. Am J Physiol 1988;255:G55–G61.

    PubMed  CAS  Google Scholar 

  64. Lorenz DN, Goldman SA. Vagal mediation of the cholecystokinin satiety effect in rats. Physiol Behav 1982;29:599–604.

    Article  PubMed  CAS  Google Scholar 

  65. Moran TH, et al. Vagal afferent and efferent contributions to the inhibition of food intake by cholecystokinin. Am J Physiol 1997;272:R1245–R1251.

    PubMed  CAS  Google Scholar 

  66. Geary N, Le Sauter J, Noh U. Glucagon acts in the liver to control spontaneous meal size in rats. Am J Physiol 1993;264:R116–R122.

    PubMed  CAS  Google Scholar 

  67. Langhans W. Role of the liver in the metabolic control of eating: what we know – and what we do not know. Neurosci Biobehav Rev 1996;20:145–153.

    Article  PubMed  CAS  Google Scholar 

  68. Lutz TA, Del Prete E, Scharrer E. Subdiaphragmatic vagotomy does not influence the anorectic effect of amylin. Peptides 1995;16:457–462.

    Article  PubMed  Google Scholar 

  69. Lutz TA, et al. Lesion of the area postrema/nucleus of the solitary tract (AP/NTS) attenuates the anorectic effects of amylin and calcitonin gene-related peptide (CGRP) in rats. Peptides 1998;19:309–317.

    Google Scholar 

  70. Edwards GL, Ladenheim EE, Ritter RC. Dorsomedial hindbrain participation in cholecystokinin-induced satiety. Am J Physiol 1986;251:R971–R977.

    PubMed  CAS  Google Scholar 

  71. Moran TH, Ladenheim EE, Schwartz GJ. Within-meal gut feedback signaling. Int J Obes Relat Metab Disord 2001;25:S39–S41.

    Article  PubMed  CAS  Google Scholar 

  72. Moran TH, Kinzig KP. Gastrointestinal satiety signals II. Cholecystokinin. Am J Physiol Gastrointest Liver Physiol 2004;286:G183–G188.

    Article  PubMed  CAS  Google Scholar 

  73. Rinaman L, et al. Cholecystokinin activates catecholaminergic neurons in the caudal medulla that innervate the paraventricular nucleus of the hypothalamus in rats. J Comp Neurol 1995;360:246–256.

    Article  PubMed  CAS  Google Scholar 

  74. West DB, Fey D, Woods SC. Cholecystokinin persistently suppresses meal size but not food intake in free-feeding rats. Am J Physiol 1984;246:R776–R787.

    PubMed  CAS  Google Scholar 

  75. West DB, et al. Lithium chloride, cholecystokinin and meal patterns: evidence the cholecystokinin suppresses meal size in rats without causing malaise. Appetite 1987;8:221–227.

    Article  PubMed  CAS  Google Scholar 

  76. Moran TH, et al. Disordered food intake and obesity in rats lacking cholecystokinin A receptors. Am J Physiol 1998;274: R618–R625.

    PubMed  CAS  Google Scholar 

  77. Ahima RS. Central actions of adipocyte hormones. Trends Endocrinol Metab 2005;16:307–313.

    Article  PubMed  CAS  Google Scholar 

  78. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998;395:763–770.

    Article  PubMed  CAS  Google Scholar 

  79. Munzberg H, Myers MG Jr. Molecular and anatomical determinants of central leptin resistance. Nat Neurosci 2005;8:566–570.

    Article  PubMed  CAS  Google Scholar 

  80. Bates SH, Myers MG Jr. The role of leptin receptor signaling in feeding and neuroendocrine function. Trends Endocrinol Metab 2003;14:447–452.

    Article  PubMed  CAS  Google Scholar 

  81. Tartaglia LA. The leptin receptor. J Biol Chem 1997;272:6093–6096.

    PubMed  CAS  Google Scholar 

  82. White DW, et al. Leptin receptor (OB-R) signaling. Cytoplasmic domain mutational analysis and evidence for receptor homo-oligomerization. J Biol Chem 1997;272:4065–4071.

    Article  PubMed  CAS  Google Scholar 

  83. Zabeau L, et al. Leptin receptor activation depends on critical cysteine residues in its fibronectin type III subdomains. J Biol Chem 2005;280:22632–22640.

    Article  PubMed  CAS  Google Scholar 

  84. Banks AS, et al. Activation of downstream signals by the long form of the leptin receptor. J Biol Chem 2000;275:14563–14572.

    Article  PubMed  CAS  Google Scholar 

  85. Feng J, et al. Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop. Mol Cell Biol 1997;17:2497–2501.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  87. Zhang EE, et al. Neuronal Shp2 tyrosine phosphatase controls energy balance and metabolism. Proc Natl Acad Sci USA 2004;101:16064–16069.

    Article  PubMed  CAS  Google Scholar 

  88. Bjorbaek C, et al. The role of SOCS-3 in leptin signaling and leptin resistance. J Biol Chem 1999;274:30059–30065.

    Article  PubMed  CAS  Google Scholar 

  89. Bjorbaek C, et al. Activation of SOCS-3 messenger ribonucleic acid in the hypothalamus by ciliary neurotrophic factor. Endocrinology 1999;140:2035–2043.

    Article  PubMed  CAS  Google Scholar 

  90. Bates SH, et al. STAT3 signaling is required for leptin regulation of energy balance but not reproduction. Nature 2003;421:856–859.

    Article  PubMed  CAS  Google Scholar 

  91. Bates SH, et al. LRb-STAT3 signaling is required for the neuroendocrine regulation of energy expenditure by leptin. Diabetes 2004;53:3067–3073.

    Article  PubMed  CAS  Google Scholar 

  92. Choudhury AI, et al. The role of insulin receptor substrate 2 in hypothalamic and beta cell function. J Clin Invest 2005;115:940–950.

    Article  PubMed  CAS  Google Scholar 

  93. Mercer JG, et al. Localization of leptin receptor mRNA and the long form splice variant (Ob-Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization. FEBS Lett 1996;387:113–116.

    Article  PubMed  CAS  Google Scholar 

  94. Schwartz MW, et al. Identification of hypothalamic targets of leptin action. J Clin Invest 1996;98:1101–1106.

    PubMed  CAS  Google Scholar 

  95. de Luca C, et al. Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes. J Clin Invest 2005;115:3484–3493.

    Article  PubMed  CAS  Google Scholar 

  96. Cheung CC, Clifton DK, Steiner RA. Proopiomelanocortin neurons are direct targets for leptin in the hypothalamus. Endocrinology 1997;138:4489–4492.

    Article  PubMed  CAS  Google Scholar 

  97. Marks DL, Cone RD. Central melanocortins and the regulation of weight during acute and chronic disease. Recent Prog Horm Res 2001;56:359–375.

    Article  PubMed  CAS  Google Scholar 

  98. Barsh GS, Schwartz MW. Genetic approaches to studying energy balance: perception and integration. Nat Rev Genet 2002;3:589–600.

    Article  PubMed  CAS  Google Scholar 

  99. Balthasar N, et al. Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 2004;42:983–991.

    Article  PubMed  CAS  Google Scholar 

  100. Coppari R, 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.

    Article  PubMed  CAS  Google Scholar 

  101. Hetherington AW, Ranson SW. The spontaneous activity and food intake of rats with hypothalmic lesions. Am J Physiol 1942;136:609–617.

    CAS  Google Scholar 

  102. Dellovade TL, et al. Disruption of the gene encoding SF-1 alters the distribution of hypothalamic neuronal phenotypes. J Comp Neurol 2000;423:579–589.

    Article  PubMed  CAS  Google Scholar 

  103. Majdic G, et al. Knockout mice lacking steroidogenic factor 1 are a novel genetic model of hypothalamic obesity. Endocrinology 2002;143:607–614.

    Article  PubMed  CAS  Google Scholar 

  104. Dhillon H, 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.

    Article  PubMed  CAS  Google Scholar 

  105. Elmquist JK, et al. Identifying hypothalamic pathways controlling food intake, body weight, and glucose homeostasis. J Comp Neurol 2005;493:63–71.

    Article  PubMed  CAS  Google Scholar 

  106. Birch LL, et al. The variability of young children’s energy intake. N Engl J Med 1991;324:232–235.

    Article  PubMed  CAS  Google Scholar 

  107. de Castro JM. Prior day’s intake has macronutrient-specific delayed negative feedback effects on the spontaneous food intake of free-living humans. J Nutr 1998;128:61–67.

    PubMed  Google Scholar 

  108. Gasnier A, Mayer A. Recherche sur la régulation de la nutrition. II. Mécanismes régulateurs de la nutrition chez le lapin domestique. Ann Physiol Physicochem Biol 1939;15:157–185.

    CAS  Google Scholar 

  109. Barrachina MD, et al. Synergistic interaction between leptin and cholecystokinin to reduce short-term food intake in lean mice. Proc Natl Acad Sci USA 1997;94:10455–10460.

    Article  PubMed  CAS  Google Scholar 

  110. Figlewicz DP, et al. Intraventricular insulin enhances the meal-suppressive efficacy of intraventricular cholecystokinin octapeptide in the baboon. Behav Neurosci 1995;109:567–569.

    Article  PubMed  CAS  Google Scholar 

  111. Matson CA, et al. Synergy between leptin and cholecystokinin (CCK) to control daily caloric intake. Peptides 1997;18:1275–1278.

    Article  PubMed  CAS  Google Scholar 

  112. Matson CA, et al. Cholecystokinin and leptin act synergistically to reduce body weight. Am J Physiol 2000;278:R882–R890.

    Google Scholar 

  113. Riedy CA, et al. Central insulin enhances sensitivity to cholecystokinin. Physiol Behav 1995;58: 755–760.

    Article  PubMed  CAS  Google Scholar 

  114. Schwartz GJ, Moran TH. Sub-diaphragmatic vagal afferent integration of meal-related gastrointestinal signals. Neurosci Biobehav Rev 1996;20:47–56.

    Article  PubMed  CAS  Google Scholar 

  115. Schwartz GJ, et al. Relationships between gastric motility and gastric vagal afferent responses to CCK and GRP in rats differ. Am J Physiol 1997;272:R1726–33.

    PubMed  CAS  Google Scholar 

  116. Grill HJ, Kaplan JM. The neuroanatomical axis for control of energy balance. Front Neuroendocrinol 2002;23:2–40.

    Article  PubMed  CAS  Google Scholar 

  117. Flier JS. Obesity wars: molecular progress confronts an expanding epidemic. Cell 2004;116:337–350.

    Article  PubMed  CAS  Google Scholar 

  118. Porte DJ, et al. Obesity, diabetes and the central nervous system. Diabetologia 1998;41:863–881.

    Article  PubMed  CAS  Google Scholar 

  119. Woods SC, et al. Insulin and the blood-brain barrier. Curr Pharm Design 2003;9:795–800.

    Article  CAS  Google Scholar 

  120. Tartaglia LA, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 1995;83:1263–1271.

    Article  PubMed  CAS  Google Scholar 

  121. Bruning JC, et al. Role of brain insulin receptor in control of body weight and reproduction. Science 2000;289:2122–2125.

    Article  PubMed  CAS  Google Scholar 

  122. Seeley R, et al. Melanocortin receptors in leptin effects. Nature 1997;390:349.

    Article  PubMed  CAS  Google Scholar 

  123. Ollmann M, et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 1997;278:135–138.

    Article  PubMed  CAS  Google Scholar 

  124. Rossi M, et al. A C-terminal fragment of Agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo. Endocrinology 1998;139:4428–4431.

    Article  PubMed  CAS  Google Scholar 

  125. Hagan MM, et al. Long-term orexigenic effects of AgRP-(83-132) involve mechanisms other than melanocortin receptor blockade. Am J Physiol 2000;279:R47–R52.

    CAS  Google Scholar 

  126. Fan W, et al. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 1997;385:165–168.

    Article  PubMed  CAS  Google Scholar 

  127. Hagan M, et al. Role of the CNS melanocortin system in the response to overfeeding. J Neurosci 1999;19:2362–2367.

    PubMed  CAS  Google Scholar 

  128. Niswender KD, Schwartz MW. Insulin and leptin revisited: adiposity signals with overlapping physiological and intracellular signaling capabilities. Front Neuroendocrinol 2003;24:1–10.

    Article  PubMed  CAS  Google Scholar 

  129. Vaisse C, et al. Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nat Genet 1996;14:95–7.

    Article  PubMed  CAS  Google Scholar 

  130. Cohen B, Novick D, Rubinstein M. Modulation of insulin activities by leptin. Science 1996;274:1185–1188.

    Article  PubMed  CAS  Google Scholar 

  131. Van Dijk G, Thiele TE, Donahey JC, Campfield LA, Smith FJ, Burn P, Bernstein IL, Woods SC, Seeley RJ. Central infusions of leptin and GLP-1-(7-36) amide differentially stimulate c-FLI in the rat brain. Am J Physiol 1996;271:R1096–R1100.

    PubMed  Google Scholar 

  132. Ainscow EK, et al. Dynamic imaging of free cytosolic ATP concentration during fuel sensing by rat hypothalamic neurones: evidence for ATP-independent control of ATP-sensitive K(+) channels. J Physiol 2002;544:429–445.

    Article  PubMed  CAS  Google Scholar 

  133. Even P, Nicolaidis S. Spontaneous and 2DG-induced metabolic changes and feeding: The ischymetric hypothesis. Brain Res Bull 1985;15:429–435.

    Article  PubMed  CAS  Google Scholar 

  134. Nicolaidis S, Even P. Mesure du métabolisme de fond en relation avec la prise alimentaire: hypothese iscymétrique. Comptes Rendus Academie de Sciences, Paris 1984;298:295–300.

    CAS  Google Scholar 

  135. Clegg, DJ, et al. Comparison of central and peripheral administration of C75 on food intake, body weight, and conditioned taste aversion. Diabetes 2002;51:3196–201.

    Article  PubMed  CAS  Google Scholar 

  136. Kumar MV, et al. Differential effects of a centrally acting fatty acid synthase inhibitor in lean and obese mice. Proc Natl Acad Sci USA 2002;99:1921–1925.

    Article  PubMed  CAS  Google Scholar 

  137. Loftus TM, et al. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 2000;288:2299–2300.

    Article  Google Scholar 

  138. Obici S, et al. Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nat Med 2003;9:756–761.

    Article  PubMed  CAS  Google Scholar 

  139. Wortman MD, et al. C75 inhibits food intake by increasing CNS glucose metabolism. Nat Med 2003;9:483–485.

    Article  PubMed  CAS  Google Scholar 

  140. Obici S, et al. Central administration of oleic acid inhibits glucose production and food intake. Diabetes 2002;51:271–275.

    Article  PubMed  CAS  Google Scholar 

  141. Nicolaidis S. Mecanisme nerveux de l’equilibre energetique. Journees Annuelles de Diabetologie de l’Hotel-Dieu 1978;1:152–156.

    Google Scholar 

  142. Levin BE, Dunn-Meynell AA, Routh VH. Brain glucose sensing and body energy homeostasis: role in obesity and diabetes. Am J Physiol 1999; 276:R1223–R1231.

    PubMed  CAS  Google Scholar 

  143. Levin BE. Glucosensing neurons as integrators of metabolic signals. European Winter Conference on Brain Research (EWCBR) 2002;22:67.

    Google Scholar 

  144. Bernstein IL, Lotter EC, Kulkosky PJ. Effect of force-feeding upon basal insulin levels in rats. Proc Soc Exp Biol Med 1975;150:546–548.

    PubMed  CAS  Google Scholar 

  145. Seeley RJ, et al. Behavioral, endocrine and hypothalamic responses to involuntary overfeeding. Am J Physiol 1996;271:R819–R823.

    PubMed  CAS  Google Scholar 

  146. Ettinger MP, et al. Recombinant variant of ciliary neurotrophic factor for weight loss in obese adults: a randomized, dose-ranging study. JAMA 2003;289:1826–1832.

    Article  PubMed  CAS  Google Scholar 

  147. Anderson KD, et al. Activation of the hypothalamic arcuate nucleus predicts the anorectic actions of ciliary neurotrophic factor and leptin in intact and gold thioglucose-lesioned mice. J Neuroendocrinol 2003;15:649–660.

    Article  PubMed  CAS  Google Scholar 

  148. Kelly JF, et al. Ciliary neurotrophic factor and leptin induce distinct patterns of immediate early gene expression in the brain. Diabetes 2004;53:911–920.

    Article  PubMed  CAS  Google Scholar 

  149. Kokoeva MV, Yin H, Flier JS. Neurogenesis in the hypothalamus of adult mice: potential role in energy balance. Science 2005;310:679–683.

    Article  PubMed  CAS  Google Scholar 

  150. Pu S, et al. Neuropeptide Y counteracts the anorectic and weight reducing effects of ciliary neurotropic factor. J Neuroendocrinol 2000;12:827–832.

    Article  PubMed  CAS  Google Scholar 

  151. Cone RD. Anatomy and regulation of the central melanocortin system. Nat Neurosci 2005;8:571–578.

    Article  PubMed  CAS  Google Scholar 

  152. Yen T, et al. Obesity, diabetes, and neoplasia in yellow A(vy)/- mice: ectopic expression of the agouti gene. FASEB J 1994;8:479–488.

    PubMed  CAS  Google Scholar 

  153. Zimanyi IA, Pelleymounter MA. The role of melanocortin peptides and receptors in regulation of energy balance. Curr Pharm Des 2003;9:627–41.

    Article  PubMed  CAS  Google Scholar 

  154. Stutz AM, Morrison CD, Argyropoulos G. The Agouti-related protein and its role in energy homeostasis. Peptides 2005;26:1771–1781.

    Article  PubMed  CAS  Google Scholar 

  155. Yaswen L, et al. Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nat Med 1999;5:1066–1070.

    Article  PubMed  CAS  Google Scholar 

  156. Krude H, et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 1998;19:155–157.

    Article  PubMed  CAS  Google Scholar 

  157. Huszar D, et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 1997;88:131–141.

    Article  PubMed  CAS  Google Scholar 

  158. Ollmann MM, et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 1997;278:135–138.

    Article  PubMed  CAS  Google Scholar 

  159. Cone RD, et al. The melanocortin receptors: agonists, antagonists, and the hormonal control of pigmentation. Recent Prog Hormone Res 1996; 51:287–320.

    CAS  Google Scholar 

  160. Seeley RJ, Drazen DL, Clegg DJ. The critical role of the melanocortin system in the control of energy balance. Annu Rev Nutr 2004;24:133–149.

    Article  PubMed  CAS  Google Scholar 

  161. Boyce RS, Duhl DM. Melanocortin-4 receptor agonists for the treatment of obesity. Curr Opin Invest Drugs 2004;5:1063–1071.

    CAS  Google Scholar 

  162. Bluher S, et al. Ciliary neurotrophic factorAx15 alters energy homeostasis, decreases body weight, and improves metabolic control in diet-induced obese and UCP1-DTA mice. Diabetes 2004;53:2787–2796.

    Article  PubMed  Google Scholar 

  163. Dorr RT, et al. Evaluation of melanotan-II, a superpotent cyclic melanotropic peptide in a pilot phase-I clinical study. Life Sci 1996;58:1777–1784.

    Article  PubMed  CAS  Google Scholar 

  164. Bouret SG, Draper SJ, Simerly RB. Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 2004;304:108–110.

    Article  PubMed  CAS  Google Scholar 

  165. Pinto S, et al. Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 2004;304:110–115.

    Article  PubMed  CAS  Google Scholar 

  166. Shanley LJ, Irving AJ, Harvey J. Leptin enhances NMDA receptor function and modulates hippocampal synaptic plasticity. J Neurosci 2001;21:RC186.

    PubMed  CAS  Google Scholar 

  167. Wayner MJ, et al. Orexin-A (hypocretin-1) and leptin enhance LTP in the dentate gyrus of rats in vivo. Peptides 2004;25:991–996.

    Article  PubMed  CAS  Google Scholar 

  168. Ohta R, et al. Conditioned taste aversion learning in leptin-receptor-deficient db/db mice. Neurobiol Learn Mem 2003;80:105–112.

    Article  PubMed  CAS  Google Scholar 

  169. Li XL, et al. Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents. Neuroscience 2002;113:607–615.

    Article  PubMed  CAS  Google Scholar 

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Authors
  1. Ofer Reizes
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  2. Stephen C. Benoit
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  3. Deborah J. Clegg
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Editors and Affiliations

  1. University of lowa, lowa City, IA

    Patricia A. Donohoue MD

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Reizes, O., Benoit, S.C., Clegg, D.J. (2007). Leptin Signaling In the Brain. In: Donohoue, P.A. (eds) Energy Metabolism and Obesity. Contemporary Endocrinology. Humana Press. https://doi.org/10.1007/978-1-60327-139-4_2

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  • DOI: https://doi.org/10.1007/978-1-60327-139-4_2

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