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Neuroregulation of Appetite

  • Ofer Reizes
  • Stephen C. Benoit
  • Deborah J. Clegg
Chapter

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 (CNS).

Keywords

Corticotropin Release Hormone Arcuate Nucleus Meal Size Negative Energy Balance Lateral Hypothalamic Area 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Stellar E. The physiology of motivation. Psychol Rev. 1954;61:5–22.PubMedGoogle Scholar
  2. 2.
    Powley TL. The ventromedial hypothalamic syndrome, satiety, and a cephalic phase hypothesis. Psychol Rev. 1977;84:89–126.PubMedGoogle Scholar
  3. 3.
    Sclafani A. The role of hyperinsulinema and the vagus nerve in hypothalamic hyperphagia reexamined. Diabetologia. 1981;20(Suppl):402–10.PubMedGoogle Scholar
  4. 4.
    Bray GA, Sclafani A, Novin D. Obesity-inducing hypothalamic knife cuts: effects on lipolysis and blood insulin levels. Am J Physiol. 1982;243(3):R445–9.PubMedGoogle Scholar
  5. 5.
    Aravich PF, Sclafani A. Paraventricular hypothalamic lesions and medial hypothalamic knife cuts produce similar hyperphagia syndromes. Behav Neurosci. 1983;97(6):970–83.PubMedGoogle Scholar
  6. 6.
    Grill HJ, Norgren R. Chronically decerebrate rats demonstrate satiation but not bait shyness. Science. 1978;201(4352):267–9.PubMedGoogle Scholar
  7. 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(2):281–97.PubMedGoogle Scholar
  8. 8.
    Grill HJ, Smith GP. Cholecystokinin decreases sucrose intake in chronic decerebrate rats. Am J Physiol. 1988;254:R853–6.PubMedGoogle Scholar
  9. 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(6):934–41.PubMedGoogle Scholar
  10. 10.
    Kennedy GC. The role of depot fat in the hypothalamic control of food intake in the rat. Proc R Soc Lond (Biol). 1953;140:579–92.Google Scholar
  11. 11.
    Ahima RS, et al. Leptin regulation of neuroendocrine systems. Front Neuroendocrinol. 2000;21:263–307.PubMedGoogle Scholar
  12. 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:S63–7.PubMedGoogle Scholar
  13. 13.
    Elmquist JK, Elias CF, Saper CB. From lesions to leptin: hypothalamic control of food intake and body weight. Neuron. 1999;22:221–32.PubMedGoogle Scholar
  14. 14.
    Schwartz MW, et al. Central nervous system control of food intake. Nature. 2000;404:661–71.PubMedGoogle Scholar
  15. 15.
    Havel PJ, et al. Gender differences in plasma leptin concentrations. Nat Med. 1996;2(9):949–50.PubMedGoogle Scholar
  16. 16.
    Ahren B, et al. Regulation of plasma leptin in mice: influence of age, high-fat diet and fasting. Am J Physiol. 1997;273:R113–20.PubMedGoogle Scholar
  17. 17.
    Havel PJ. Mechanisms regulating leptin production: implications for control of energy balance. Am J Clin Nutr. 1999;70:305–6.PubMedGoogle Scholar
  18. 18.
    Buchanan C, et al. Central nervous system effects of leptin. Trends Endocrinol Metab. 1998;9(4):146–50.PubMedGoogle Scholar
  19. 19.
    Bjorntorp P. Metabolic implications of body fat distribution. Diabetes Care. 1991;14(12):1132–43.PubMedGoogle Scholar
  20. 20.
    Bjorntorp P. Abdominal fat distribution and the metabolic syndrome. J Cardiovasc Pharmacol. 1992;20 Suppl 8:S26–8.PubMedGoogle Scholar
  21. 21.
    Bjorntorp P. Body fat distribution, insulin resistance, and metabolic diseases. Nutrition. 1997;13:795–803.PubMedGoogle Scholar
  22. 22.
    Woods SC, et al. Signals that regulate food intake and energy homeostasis. Science. 1998;280:1378–83.PubMedGoogle Scholar
  23. 23.
    Schwartz MW, et al. Insulin in the brain: a hormonal regulator of energy balance. Endocr Rev. 1992;13: 387–414.PubMedGoogle Scholar
  24. 24.
    de Castro JM, Stroebele N. Food intake in the real world: implications for nutrition and aging. Clin Geriatr Med. 2002;18:685–97.PubMedGoogle Scholar
  25. 25.
    de Castro JM. The control of eating behavior in free living humans. In: Stricker EM, Woods SC, editors. Handbook of neurobiology. Neurobiology of food and fluid intake, vol. 14(2). New York: Kluwer Academic, Plenum; 2004. p. 467–502.Google Scholar
  26. 26.
    de Graaf C, et al. Biomarkers of satiation and satiety. Am J Clin Nutr. 2004;79:946–61.PubMedGoogle Scholar
  27. 27.
    Mayer J. Regulation of energy intake and the body weight: the glucostatic and lipostatic hypothesis. Ann NY Acad Sci. 1955;63:14–42.Google Scholar
  28. 28.
    Mayer J, Thomas DW. Regulation of food intake and obesity. Science. 1967;156:328–37.PubMedGoogle Scholar
  29. 29.
    Friedman MI. Fuel partitioning and food intake. Am J Clin Nutr. 1998;67 Suppl 3:513S–8.PubMedGoogle Scholar
  30. 30.
    Friedman MI. An energy sensor for control of energy intake. Proc Nutr Soc. 1997;56(1A):41–50.PubMedGoogle Scholar
  31. 31.
    Langhans W. Metabolic and glucostatic control of feeding. Proc Nutr Soc. 1996;55:497–515.PubMedGoogle Scholar
  32. 32.
    Peters A, et al. The selfish brain: competition for energy resources. Neurosc Biobehav Rev. 2004;28: 143–80.Google Scholar
  33. 33.
    Strubbe JH, Woods SC. The timing of meals. Psychol Rev. 2004;111:128–41.PubMedGoogle Scholar
  34. 34.
    Woods SC, Strubbe JH. The psychobiology of meals. Psychon Bull Rev. 1994;1:141–55.PubMedGoogle Scholar
  35. 35.
    Woods SC, et al. Food intake and the regulation of body weight. Annu Rev Psychol. 2000;51:255–77.PubMedGoogle Scholar
  36. 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(3):379–87.PubMedGoogle Scholar
  37. 37.
    Davis JD, Smith GP. Learning to sham feed: behavioral adjustments to loss of physiological postingestional stimuli. Am J Physiol. 1990;259(6 Pt 2): R1228–35.PubMedGoogle Scholar
  38. 38.
    Gibbs J, Young RC, Smith GP. Cholecystokinin elicits satiety in rats with open gastric fistulas. Nature. 1973;245:323–5.PubMedGoogle Scholar
  39. 39.
    Gibbs J, Young RC, Smith GP. Cholecystokinin decreases food intake in rats. J Comp Physiol Psychol. 1973;84:488–95.PubMedGoogle Scholar
  40. 40.
    Kissileff HR, et al. Cholecystokinin decreases food intake in man. Am J Clin Nutr. 1981;34:154–60.PubMedGoogle Scholar
  41. 41.
    Muurahainenn N, et al. Effects of cholecystokinin-octapeptide (CCK-8) on food intake and gastric emptying in man. Physiol Behav. 1988;44:644–9.Google Scholar
  42. 42.
    Moran TH, Schwartz GJ. Neurobiology of cholecystokinin. Crit Rev Neurobiol. 1994;9:1–28.PubMedGoogle Scholar
  43. 43.
    Smith GP, Gibbs J. The development and proof of the cholecystokinin hypothesis of satiety. In: Dourish CT et al., editors. Multiple cholecystokinin receptors in the CNS. Oxford: Oxford University Press; 1992. p. 166–82.Google Scholar
  44. 44.
    Beglinger C, et al. Loxiglumide, a CCK-A receptor antagonist, stimulates calorie intake and hunger feelings in humans. Am J Physiol. 2001;280:R1149–54.Google Scholar
  45. 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.PubMedCentralPubMedGoogle Scholar
  46. 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:R620–4.PubMedGoogle Scholar
  47. 47.
    Reidelberger RD, O’Rourke MF. Potent cholecystokinin antagonist L-364,718 stimulates food intake in rats. Am J Physiol. 1989;257:R1512–8.PubMedGoogle Scholar
  48. 48.
    Kaplan JM, Moran TH. Gastrointestinal signaling in the control of food intake. In: Stricker M, Woods SC, editors. Handbook of behavioral neurobiology. Neurobiology of food and fluid intake, vol. 4(2). New York: Kluwer Academic, Plenum; 2004. p. 273–303.Google Scholar
  49. 49.
    Smith GP, editor. Satiation: from gut to brain. New York: Oxford University Press; 1998.Google Scholar
  50. 50.
    Stein LJ, Woods SC. Gastrin releasing peptide reduces meal size in rats. Peptides. 1982;3(5):833–5.PubMedGoogle Scholar
  51. 51.
    Ladenheim EE, Wirth KE, Moran TH. Receptor subtype mediation of feeding suppression by bombesin-like peptides. Pharmacol Biochem Behav. 1996;54(4):705–11.PubMedGoogle Scholar
  52. 52.
    Okada S, et al. Enterostatin (Val-Pro-Asp-Pro-Arg), the activation peptide of procolipase, selectively reduces fat intake. Physiol Behav. 1991;49:1185–9.PubMedGoogle Scholar
  53. 53.
    Shargill NS, et al. Enterostatin suppresses food intake following injection into the third ventricle of rats. Brain Res. 1991;544:137–40.PubMedGoogle Scholar
  54. 54.
    Lotter EC, et al. Somatostatin decreases food intake of rats and baboons. J Comp Physiol Psychol. 1981;95(2):278–87.PubMedGoogle Scholar
  55. 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;50:2530–9.PubMedGoogle Scholar
  56. 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(3): 304–11.PubMedGoogle Scholar
  57. 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;608:233–7.PubMedGoogle Scholar
  58. 58.
    Batterham RL, et al. Gut hormone PYY(3-36) physiologically inhibits food intake. Nature. 2002; 418(6898):650–4.PubMedGoogle Scholar
  59. 59.
    Chance WT, et al. Anorexia following the intrahypothalamic administration of amylin. Brain Res. 1991;539(2):352–4.PubMedGoogle Scholar
  60. 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(5):891–5.PubMedGoogle Scholar
  61. 61.
    Geary N. Glucagon and the control of meal size. In: Smith GP, editor. Satiation: from gut to brain. New York: Oxford University Press; 1998. p. 164–97.Google Scholar
  62. 62.
    Salter JM. Metabolic effects of glucagon in the Wistar rat. Am J Clin Nutr. 1960;8:535–9.Google Scholar
  63. 63.
    Davison JS, Clarke GD. Mechanical properties and sensitivity to CCK of vagal gastric slowly adapting mechanoreceptors. Am J Physiol. 1988;255(1 Pt 1): G55–61.PubMedGoogle Scholar
  64. 64.
    Lorenz DN, Goldman SA. Vagal mediation of the cholecystokinin satiety effect in rats. Physiol Behav. 1982;29(4):599–604.PubMedGoogle Scholar
  65. 65.
    Moran TH, et al. Vagal afferent and efferent contributions to the inhibition of food intake by cholecystokinin. Am J Physiol. 1997;272(4 Pt 2):R1245–51.PubMedGoogle Scholar
  66. 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:R116–22.PubMedGoogle Scholar
  67. 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;20:145–53.PubMedGoogle Scholar
  68. 68.
    Lutz TA, Del Prete E, Scharrer E. Subdiaphragmatic vagotomy does not influence the anorectic effect of amylin. Peptides. 1995;16(3):457–62.PubMedGoogle Scholar
  69. 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(2):309–17.PubMedGoogle Scholar
  70. 70.
    Edwards GL, Ladenheim EE, Ritter RC. Dorsomedial hindbrain participation in cholecystokinin-induced satiety. Am J Physiol. 1986;251:R971–7.PubMedGoogle Scholar
  71. 71.
    Moran TH, Ladenheim EE, Schwartz GJ. Within-meal gut feedback signaling. Int J Obes Relat Metab Disord. 2001;25 Suppl 5:S39–41.PubMedGoogle Scholar
  72. 72.
    Moran TH, Kinzig KP. Gastrointestinal satiety signals. II. Cholecystokinin. Am J Physiol Gastrointest Liver Physiol. 2004;286(2):G183–8.PubMedGoogle Scholar
  73. 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;360:246–56.PubMedGoogle Scholar
  74. 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:R776–87.PubMedGoogle Scholar
  75. 75.
    West DB, et al. Lithium chloride, cholecystokinin and meal patterns: evidence that cholecystokinin suppresses meal size in rats without causing malaise. Appetite. 1987;8:221–7.PubMedGoogle Scholar
  76. 76.
    Moran TH, et al. Disordered food intake and obesity in rats lacking cholecystokinin A receptors. Am J Physiol. 1998;274(3 Pt 2):R618–25.PubMedGoogle Scholar
  77. 77.
    Birch LL, et al. The variability of young children’s energy intake. N Engl J Med. 1991;324:232–5.PubMedGoogle Scholar
  78. 78.
    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;128:61–7.PubMedGoogle Scholar
  79. 79.
    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;15:157–85.Google Scholar
  80. 80.
    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;94:10455–60.PubMedCentralPubMedGoogle Scholar
  81. 81.
    Figlewicz DP, et al. Intraventricular insulin enhances the meal-suppressive efficacy of intraventricular cholecystokinin octapeptide in the baboon. Behav Neurosci. 1995;109:567–9.PubMedGoogle Scholar
  82. 82.
    Matson CA, et al. Synergy between leptin and cholecystokinin (CCK) to control daily caloric intake. Peptides. 1997;18:1275–8.PubMedGoogle Scholar
  83. 83.
    Matson CA, et al. Cholecystokinin and leptin act synergistically to reduce body weight. Am J Physiol. 2000;278:R882–90.Google Scholar
  84. 84.
    Riedy CA, et al. Central insulin enhances sensitivity to cholecystokinin. Physiol Behav. 1995;58:755–60.PubMedGoogle Scholar
  85. 85.
    Schwartz GJ, Moran TH. Sub-diaphragmatic vagal afferent integration of meal-related gastrointestinal signals. Neurosci Biobehav Rev. 1996;20:47–56.PubMedGoogle Scholar
  86. 86.
    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(6 Pt 2):R1726–33.PubMedGoogle Scholar
  87. 87.
    Grill HJ, Kaplan JM. The neuroanatomical axis for control of energy balance. Front Neuroendocrinol. 2002;23(1):2–40.PubMedGoogle Scholar
  88. 88.
    Flier JS. Obesity wars: molecular progress confronts an expanding epidemic. Cell. 2004;116:337–50.PubMedGoogle Scholar
  89. 89.
    Porte DJ, et al. Obesity, diabetes and the central nervous system. Diabetologia. 1998;41:863–81.PubMedGoogle Scholar
  90. 90.
    Woods SC, et al. Insulin and the blood-brain barrier. Curr Pharm Des. 2003;9:795–800.PubMedGoogle Scholar
  91. 91.
    Tartaglia LA, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell. 1995;83:1263–71.PubMedGoogle Scholar
  92. 92.
    Bruning JC, et al. Role of brain insulin receptor in control of body weight and reproduction. Science. 2000;289(5487):2122–5.PubMedGoogle Scholar
  93. 93.
    Seeley R, et al. Melanocortin receptors in leptin effects. Nature. 1997;390:349.PubMedGoogle Scholar
  94. 94.
    Ollmann M, et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science. 1997;278(5335):135–8.PubMedGoogle Scholar
  95. 95.
    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;139:4428–31.PubMedGoogle Scholar
  96. 96.
    Hagan MM, et al. Long-term orexigenic effects of AgRP-(83-132) involve mechanisms other than melanocortin receptor blockade. Am J Physiol. 2000;279:R47–52.Google Scholar
  97. 97.
    Fan W, et al. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature. 1997;385:165–8.PubMedGoogle Scholar
  98. 98.
    Hagan M, et al. Role of the CNS melanocortin system in the response to overfeeding. J Neurosci. 1999;19:2362–7.PubMedGoogle Scholar
  99. 99.
    Niswender KD, Schwartz MW. Insulin and leptin revisited: adiposity signals with overlapping physiological and intracellular signaling capabilities. Front Neuroendocrinol. 2003;24:1–10.PubMedGoogle Scholar
  100. 100.
    Tartaglia LA. The leptin receptor. J Biol Chem. 1997;272:6093–6.PubMedGoogle Scholar
  101. 101.
    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(1):95–7.PubMedGoogle Scholar
  102. 102.
    Cohen B, Novick D, Rubinstein M. Modulation of insulin activities by leptin. Science. 1996;274(5290): 1185–8.PubMedGoogle Scholar
  103. 103.
    Benoit SC, et al. Palmitic acid mediates hypothalamic insulin resistance by altering PKC-theta subcellular localization in rodents. J Clin Invest. 2009;119(9):2577–89.PubMedCentralPubMedGoogle Scholar
  104. 104.
    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;544:429–45.PubMedCentralPubMedGoogle Scholar
  105. 105.
    Even P, Nicolaidis S. Spontaneous and 2DG-induced metabolic changes and feeding: the ischymetric hypothesis. Brain Res Bull. 1985;15:429–35.PubMedGoogle Scholar
  106. 106.
    Nicolaidis S, Even P. Mesure du métabolisme de fond en relation avec la prise alimentaire: Hypothese iscymétrique. C R Acad Sci Paris. 1984;298: 295–300.PubMedGoogle Scholar
  107. 107.
    Clegg DJ, et al. Comparison of central and peripheral administration of C75 on food intake, body weight, and conditioned taste aversion. Diabetes. 2002;51(11):3196–201.PubMedGoogle Scholar
  108. 108.
    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;99:1921–5.PubMedCentralPubMedGoogle Scholar
  109. 109.
    Loftus TM, et al. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science. 2000;288:2299–300.Google Scholar
  110. 110.
    Obici S, et al. Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nat Med. 2003;9:756–61.PubMedGoogle Scholar
  111. 111.
    Wortman MD, et al. C75 inhibits food intake by increasing CNS glucose metabolism. Nat Med. 2003;9:483–5.PubMedGoogle Scholar
  112. 112.
    Obici S, et al. Central administration of oleic acid inhibits glucose production and food intake. Diabetes. 2002;51(2):271–5.PubMedGoogle Scholar
  113. 113.
    Nicolaidis S. Mecanisme nerveux de l’equilibre energetique. Journees Annuelles de Diabetologie de l’Hotel-Dieu. 1978;1:152–6.Google Scholar
  114. 114.
    Levin BE, Dunn-Meynell AA, Routh VH. Brain glucose sensing and body energy homeostasis: role in obesity and diabetes. Am J Physiol. 1999;276: R1223–31.PubMedGoogle Scholar
  115. 115.
    Levin BE. Glucosensing neurons as integrators of metabolic signals. EWCBR. 2002;22:67.Google Scholar
  116. 116.
    Clark JT, et al. Neuropeptide Y and human pancreatic polypeptide stimulate feeding behavior in rats. Endocrinology. 1984;115(1):427–9.PubMedGoogle Scholar
  117. 117.
    Stanley BG, Leibowitz SF. Neuropeptide Y injected into the paraventricular hypothalamus: a powerful stimulant of feeding behavior. Proc Natl Acad Sci USA. 1984;82:3940–3.Google Scholar
  118. 118.
    Seeley RJ, Payne CJ, Woods SC. Neuropeptide Y fails to increase intraoral intake in rats. Am J Physiol. 1995;268:R423–7.PubMedGoogle Scholar
  119. 119.
    Allen YS, et al. Neuropeptide Y distribution in the rat brain. Science. 1983;221:877–9.PubMedGoogle Scholar
  120. 120.
    Minth CD, Andrews PC, Dixon JE. Characterization, sequence and expression of the cloned human neuropeptide Y gene. J Biol Chem. 1986;261(26): 11975–9.Google Scholar
  121. 121.
    Mizuno TM, et al. Fasting regulates hypothalamic neuropeptide Y, agouti-related peptide, and proopiomelanocortin in diabetic mice independent of changes in leptin or insulin. Endocrinology. 1999; 140(10):4551–7.PubMedGoogle Scholar
  122. 122.
    Sahu A, et al. Neuropeptide Y release from the parventricular nucleus increases in association with hyperphagia in streptozotocin-induced diabetic rats. Endocrinology. 1992;131(6):2979–85.PubMedGoogle Scholar
  123. 123.
    Marks JL, et al. Effect of fasting on regional levels of neuropeptide Y mRNA and insulin receptors in the rat hypothalamus: an autoradiographic study. Mol Cell Neurosci. 1992;3:199–205.PubMedGoogle Scholar
  124. 124.
    Sahu A, et al. Neuropeptide Y concentration in microdissected hypothalamic regions and in vitro release from the medial basal hypothalamus-preoptic area of streptozotocin-diabetic rats with and without insulin substitution therapy. Endocrinology. 1990; 126:192–8.PubMedGoogle Scholar
  125. 125.
    Kalra SP, et al. Neuropeptide Y secretion increases in the paraventricular nucleus in association with increased appetite for food. Proc Natl Acad Sci USA. 1991;88:10931–5.PubMedCentralPubMedGoogle Scholar
  126. 126.
    Sahu A, Kalra PS, Kalra SP. Food deprivation and ingestion induce reciprocal changes in neuropeptide Y concentrations in the paraventricular nucleus. Peptides. 1988;9:83–6.PubMedGoogle Scholar
  127. 127.
    Stanley BG, et al. Neuropeptide Y chronically injected into the hypothalamus: a powerful neurochemical inducer of hyperphagia and obesity. Peptides. 1986;7:1189–92.PubMedGoogle Scholar
  128. 128.
    McMinn JE, et al. NPY-induced overfeeding suppresses hypothalamic NPY mRNA expression: potential roles of plasma insulin and leptin. Regul Pept. 1998;75–76:425–31.PubMedGoogle Scholar
  129. 129.
    Sipols AJ, Baskin DG, Schwartz MW. Effect of intracerebroventricular insulin infusion on diabetic hyperphagia and hypothalamic neuropeptide gene expression. Diabetes. 1995;44:147–51.PubMedGoogle Scholar
  130. 130.
    Sipols AJ, Baskin DG, Schwartz MW. The importance of central nervous system insulin deficiency to diabetic hyperphagia. Diabetes. 1993;42 Suppl 1:152.Google Scholar
  131. 131.
    Stephens TW, et al. The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature. 1995;377:530–4.PubMedGoogle Scholar
  132. 132.
    Schwartz MW, et al. Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice. Diabetes. 1996;45:531–5.PubMedGoogle Scholar
  133. 133.
    Bernardis LL, Bellinger LL. The dorsomedial hypothalamic nucleus revisited: 1998 update. Proc Soc Exp Biol Med. 1998;218(4):284–306.PubMedGoogle Scholar
  134. 134.
    Kesterson RA, et al. Induction of neuropeptide Y gene expression in the dorsal medial hypothalamic nucleus in two models of the agouti obesity syndrome. Mol Endocrinol. 1997;11(5):630–7.PubMedGoogle Scholar
  135. 135.
    Guan XM, et al. Induction of neuropeptide Y expression in dorsomedial hypothalamus of diet-induced obese mice. Neuroreport. 1998;9(15):3415–9.PubMedGoogle Scholar
  136. 136.
    Bi S, Ladenheim EE, Moran TH. Elevated neuropeptide Y expression in the dorsomedial hypothalamic nucleus may contribute to the hyperphagia and obesity in OLETF rats with CCKA receptor deficit. In Annual Meeting for the Society for Neuroscience, New Orleans, LA. 2000.Google Scholar
  137. 137.
    Erickson JC, Clegg KE, Palmiter RD. Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y. Nature. 1996;381:415–8.PubMedGoogle Scholar
  138. 138.
    Erickson JC, Hollopeter G, Palmiter RD. Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y. Science. 1996;274(5293):1704–7.PubMedGoogle Scholar
  139. 139.
    Hollopeter G, Erickson JC, Palmiter RD. Role of neuropeptide Y in diet-, chemical- and genetic-induced obesity of mice. Int J Obes Relat Metab Disord. 1998;22(6):506–12.PubMedGoogle Scholar
  140. 140.
    Palmiter RD, et al. Life without neuropeptide Y. Recent Prog Horm Res. 1998;53:163–99.PubMedGoogle Scholar
  141. 141.
    Woods SC, et al. NPY and food intake: discrepancies in the model. Regul Pept. 1998;75–76:403–8.PubMedGoogle Scholar
  142. 142.
    Gropp E, et al. Agouti-related peptide-expressing neurons are mandatory for feeding. Nat Neurosci. 2005;8(10):1289–91.PubMedGoogle Scholar
  143. 143.
    Criscione L, et al. Food intake in free-feeding and energy-deprived lean rats is mediated by the neuropeptide Y5 receptor. J Clin Invest. 1998;102(12): 2136–45.PubMedCentralPubMedGoogle Scholar
  144. 144.
    Marsh DJ, et al. Role of the Y5 neuropeptide Y receptor in feeding and obesity [see comments]. Nat Med. 1998;4(6):718–21.PubMedGoogle Scholar
  145. 145.
    Kanatani A, et al. Role of the Y1 receptor in the regulation of neuropeptide Y-mediated feeding: comparison of wild-type, Y1 receptor-deficient, and Y5 receptor-deficient mice. Endocrinology. 2000;141(3):1011–6.PubMedGoogle Scholar
  146. 146.
    Tang-Christensen M, et al. Central administration of Y5 receptor antisense decreases spontaneous food intake and attenuates feeding in response to exogenous neuropeptide Y. J Endocrinol. 1998;159(2):307–12.PubMedGoogle Scholar
  147. 147.
    Larsen PJ, et al. Activation of central neuropeptide Y Y1 receptors potently stimulates food intake in male rhesus monkeys [In Process Citation]. J Clin Endocrinol Metab. 1999;84(10):3781–91.PubMedGoogle Scholar
  148. 148.
    Hellig M, et al. In vivo downregulation of neuropeptide Y (NPY) Y1-receptors by i.c.v. antisense oligodeoxynucleotide administration is associated with signs of anxiety in rats. Soc Neurosci Abst. 1992;18:1539.Google Scholar
  149. 149.
    O’Shea D, et al. Neuropeptide Y induced feeding in the rat is mediated by a novel receptor. Endocrinology. 1997;138(1):196–202.PubMedGoogle Scholar
  150. 150.
    Zimanyi IA, Fathi Z, Poindexter GS. Central control of feeding behavior by neuropeptide Y. Curr Pharm Des. 1998;4(4):349–66.PubMedGoogle Scholar
  151. 151.
    Levens NR, Della-Zuana O. Neuropeptide Y Y5 receptor antagonists as anti-obesity drugs. Curr Opin Investig Drugs. 2003;4(10):1198–204.PubMedGoogle Scholar
  152. 152.
    Qu D, et al. A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature. 1996;380(6571):243–7.PubMedGoogle Scholar
  153. 153.
    Ludwig D, et al. Melanin-concentrating hormone: a functional melanocortin antagonist in the hypothalamus. Am J Physiol. 1998;274:E627–33.PubMedGoogle Scholar
  154. 154.
    Sanchez M, Baker B, Celis M. Melanin-concentrating hormone (MCH) antagonizes the effects of alpha-MSH and neuropeptide E-I on grooming and locomotor activities in the rat. Peptides. 1997;18:393–6.PubMedGoogle Scholar
  155. 155.
    Clegg DJ, et al. Intraventricular melanin-concentrating hormone stimulates water intake independent of food intake. Am J Physiol Regul Integr Comp Physiol. 2003;284(2):R494–9.PubMedGoogle Scholar
  156. 156.
    Rossi M, et al. Melanin-concentrating hormone acutely stimulates feeding, but chronic administration has no effect on body weight. Endocrinology. 1997;138(1):351–5.PubMedGoogle Scholar
  157. 157.
    Shimada M, et al. Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature. 1998;396:670–4.PubMedGoogle Scholar
  158. 158.
    Mystkowski P, et al. Hypothalamic melanin-concentrating hormone and estrogen-induced weight loss [In Process Citation]. J Neurosci. 2000;20(22): 8637–42.PubMedGoogle Scholar
  159. 159.
    Mashiko S, et al. Antiobesity effect of a melanin-concentrating hormone 1 receptor antagonist in diet-induced obese mice. Endocrinology. 2005;146(7): 3080–6.PubMedGoogle Scholar
  160. 160.
    Takekawa S, et al. T-226296: a novel, orally active and selective melanin-concentrating hormone receptor antagonist. Eur J Pharmacol. 2002;438(3): 129–35.PubMedGoogle Scholar
  161. 161.
    de Lecea L, et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA. 1998;95:322–7.PubMedCentralPubMedGoogle Scholar
  162. 162.
    Sakurai T, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell. 1998;92(4):573–85.PubMedGoogle Scholar
  163. 163.
    Broberger C, et al. Hypocretin/orexin- and melanin-concentrating hormone-expressing cells form distinct populations in the rodent lateral hypothalamus: relationship to the neuropeptide Y and agouti gene-related protein systems. J Comp Neurol. 1998;402: 460–74.PubMedGoogle Scholar
  164. 164.
    Yamanaka A, et al. Orexin-induced food intake involves neuropeptide Y pathway. Brain Res. 2000;859(2):404–9.PubMedGoogle Scholar
  165. 165.
    Rauch M, et al. Orexin A activates leptin-responsive neurons in the arcuate nucleus [In Process Citation]. Pflugers Arch. 2000;440(5):699–703.PubMedGoogle Scholar
  166. 166.
    Peyron C, et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci. 1998;18:9996–10015.PubMedGoogle Scholar
  167. 167.
    Kilduff TS, Peyron C. The hypocretin/orexin ligand-receptor system: implications for sleep and sleep disorders. Trends Neurosci. 2000;23(8):359–65.PubMedGoogle Scholar
  168. 168.
    Elias CF, et al. Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area. J Comp Neurol. 1998;402(4): 442–59.PubMedGoogle Scholar
  169. 169.
    Tritos NA, et al. Functional interactions between melanin-concentrating hormone, neuropeptide Y, and anorectic neuropeptides in the rat hypothalamus. Diabetes. 1998;47:1687–92.PubMedGoogle Scholar
  170. 170.
    Jain MR, et al. Evidence that NPY Y1 receptors are involved in stimulation of feeding by orexins (hypocretins) in sated rats. Regul Pept. 2000;87(1–3): 19–24.PubMedGoogle Scholar
  171. 171.
    Sergeyev V, et al. Effect of 2-mercaptoacetate and 2-deoxy-D-glucose administration on the expression of NPY, AGRP, POMC, MCH and hypocretin/orexin in the rat hypothalamus. Neuroreport. 2000;11(1): 117–21.PubMedGoogle Scholar
  172. 172.
    Choi DL, et al. Orexin signaling in the paraventricular thalamic nucleus modulates mesolimbic dopamine and hedonic feeding in the rat. Neuroscience. 2012;210:243–8.PubMedCentralPubMedGoogle Scholar
  173. 173.
    Kojima M, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656–60.PubMedGoogle Scholar
  174. 174.
    Kojima M, Hosoda H, Kangawa K. Purification and distribution of ghrelin: the natural endogenous ligand for the growth hormone secretagogue receptor. Horm Res. 2001;56 Suppl 1:93–7.PubMedGoogle Scholar
  175. 175.
    Tschöp M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature. 2000;407(6806): 908–13.PubMedGoogle Scholar
  176. 176.
    Kamegai J, et al. Central effect of ghrelin, an endogenous growth hormone secretagogue, on hypothalamic peptide gene expression. Endocrinology. 2000;141(12):4797–800.PubMedGoogle Scholar
  177. 177.
    Wren AM, et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab. 2001;86(12):5992.PubMedGoogle Scholar
  178. 178.
    Horvath TL, et al. Minireview: Ghrelin and the regulation of energy balance–a hypothalamic perspective. Endocrinology. 2001;142(10):4163–9.PubMedGoogle Scholar
  179. 179.
    Asakawa A, et al. Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin. Gastroenterology. 2001;120(2):337–45.PubMedGoogle Scholar
  180. 180.
    Kamegai J, et al. Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and Agouti-related protein mRNA levels and body weight in rats. Diabetes. 2001;50(11):2438–43.PubMedGoogle Scholar
  181. 181.
    Nakazato M, et al. A role for ghrelin in the central regulation of feeding. Nature. 2001;409(6817): 194–8.PubMedGoogle Scholar
  182. 182.
    Wang L, Saint-Pierre DH, Tache Y. Peripheral ghrelin selectively increases Fos expression in neuropeptide Y - synthesizing neurons in mouse hypothalamic arcuate nucleus. Neurosci Lett. 2002;325(1):47–51.PubMedGoogle Scholar
  183. 183.
    Tschöp M, et al. Circulating ghrelin levels are decreased in human obesity. Diabetes. 2001;50(4): 707–9.PubMedGoogle Scholar
  184. 184.
    Cummings DE, et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med. 2002;346(21):1623–30.PubMedGoogle Scholar
  185. 185.
    Tong J, et al. Acute administration of unacylated ghrelin has no effect on basal or stimulated insulin secretion in healthy humans. Diabetes. 2014.Google Scholar
  186. 186.
    Davis JF, et al. GOAT induced ghrelin acylation regulates hedonic feeding. Horm Behav. 2012;62(5): 598–604.PubMedCentralPubMedGoogle Scholar
  187. 187.
    Yi CX, et al. The GOAT-ghrelin system is not essential for hypoglycemia prevention during prolonged calorie restriction. PLoS One. 2012;7(2):e32100.PubMedCentralPubMedGoogle Scholar
  188. 188.
    Horvath TL, Diano S, Tschop M. Ghrelin in hypothalamic regulation of energy balance. Curr Top Med Chem. 2003;3(8):921–7.PubMedGoogle Scholar
  189. 189.
    Asakawa A, et al. Antagonism of ghrelin receptor reduces food intake and body weight gain in mice. Gut. 2003;52(7):947–52.PubMedCentralPubMedGoogle Scholar
  190. 190.
    Beck B, Richy S, Stricker-Krongrad A. Feeding response to ghrelin agonist and antagonist in lean and obese Zucker rats. Life Sci. 2004;76(4):473–8.PubMedGoogle Scholar
  191. 191.
    Bernstein IL, Lotter EC, Kulkosky PJ. Effect of force-feeding upon basal insulin levels in rats. Proc Soc Exp Biol Med. 1975;150:546–8.PubMedGoogle Scholar
  192. 192.
    Seeley RJ, et al. Behavioral, endocrine and hypothalamic responses to involuntary overfeeding. Am J Physiol. 1996;271:R819–23.PubMedGoogle Scholar
  193. 193.
    Elias CF, et al. Leptin activates hypothalamic CART neurons projecting to the spinal cord. Neuron. 1998; 21:1375–85.PubMedGoogle Scholar
  194. 194.
    Kristensen P, et al. Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature. 1998; 393:72–6.PubMedGoogle Scholar
  195. 195.
    Lambert PD, et al. CART peptides in the central control of feeding and interactions with neuropeptide Y. Synapse. 1998;29:293–8.PubMedGoogle Scholar
  196. 196.
    Vrang N, et al. Recombinant CART peptide induces c-Fos expression in central areas involved in control of feeding behaviour. Brain Res. 1999;818:499–509.PubMedGoogle Scholar
  197. 197.
    Kask A, et al. Anorexigenic cocaine- and amphetamine-regulated transcript peptide intensifies fear reactions in rats. Brain Res. 2000;857(1–2): 283–5.PubMedGoogle Scholar
  198. 198.
    Abbott CR, et al. Evidence of an orexigenic role for cocaine- and amphetamine-regulated transcript after administration into discrete hypothalamic nuclei. Endocrinology. 2001;142(8):3457–63.PubMedGoogle Scholar
  199. 199.
    Krahn DD, Gosnell BA. Behavioral effects of corticotropin-releasing factor: localization and characterization of central effects. Brain Res. 1988;443: 63–9.PubMedGoogle Scholar
  200. 200.
    Arase K, et al. Effects of corticotropin releasing factor on food intake and brown adipose tissue thermogenesis in rats. Am J Physiol. 1988;255:E255–9.PubMedGoogle Scholar
  201. 201.
    Heinrichs S, et al. Corticotropin-releasing factor-binding protein ligand inhibitor blunts excessive weight gain in genetically obese Zucker rats and rats during nicotine withdrawal. Proc Natl Acad Sci USA. 1996;93:15475–80.PubMedCentralPubMedGoogle Scholar
  202. 202.
    Spina M, et al. Appetite-suppressing effects of urocortin, a CRF-related neuropeptide. Science. 1996; 273:1561–4.PubMedGoogle Scholar
  203. 203.
    Vaughan J, et al. Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor [see comments]. Nature. 1995;378: 287–92.PubMedGoogle Scholar
  204. 204.
    Richard D, Huang Q, Timofeeva E. The corticotropin-releasing hormone system in the regulation of energy balance in obesity. Int J Obes Relat Metab Disord. 2000;24 Suppl 2:S36–9.PubMedGoogle Scholar
  205. 205.
    Heinrichs SC, Richard D. The role of corticotropin-releasing factor and urocortin in the modulation of ingestive behavior. Neuropeptides. 1999;33(5):350–9.PubMedGoogle Scholar
  206. 206.
    D’Alessio DA, et al. Elimination of the action of glucagon-like peptide 1 causes an impairment of glucose tolerance after nutrient ingestion by healthy baboons. J Clin Invest. 1996;97(1):133–8.PubMedCentralPubMedGoogle Scholar
  207. 207.
    Drucker DJ, et al. Biologic properties and therapeutic potential of glucagon-like peptide-2. JPEN J Parenter Enteral Nutr. 1999;23(5 Suppl):S98–100.PubMedGoogle Scholar
  208. 208.
    Drucker DJ. Glucagon-like peptides. Diabetes. 1998;47(2):159–69.PubMedGoogle Scholar
  209. 209.
    van Dijk G, Thiele TE. Glucagon-like peptide-1 (7-36) amide: a central regulator of satiety and interoceptive stress. Neuropeptides. 1999;33(5):406–14.PubMedGoogle Scholar
  210. 210.
    Goldstone AP, et al. Effect of leptin on hypothalamic GLP-1 peptide and brain-stem pre-proglucagon mRNA. Biochem Biophys Res Commun. 2000; 269(2):331–5.PubMedGoogle Scholar
  211. 211.
    Elmquist JK, et al. Leptin activates neurons in ventrobasal hypothalamus and brainstem. Endocrinology. 1997;138:839–42.PubMedGoogle Scholar
  212. 212.
    Turton MD, et al. A role for glucagon-like peptide-1 in the central regulation of feeding [see comments]. Nature. 1996;379(6560):69–72.PubMedGoogle Scholar
  213. 213.
    Tang-Christensen M, et al. Central administration of GLP-1-(7-36) amide inhibits food and water intake in rats. Am J Physiol. 1996;271(4 Pt 2):R848–56.PubMedGoogle Scholar
  214. 214.
    Van Dijk G, et al. Central infusions of leptin and GLP-1-(7-36) amide differentially stimulate c-FLI in the rat brain. Am J Physiol. 1996;271(4 Pt 2): R1096–100.PubMedGoogle Scholar
  215. 215.
    Thiele TE, et al. Central infusion of GLP-1, but not leptin, produces conditioned taste aversions in rats. Am J Physiol. 1997;272(2 Pt 2):R726–30.PubMedGoogle Scholar
  216. 216.
    Thiele TE, et al. Central infusion of glucagon-like peptide-1-(7-36) amide (GLP-1) receptor antagonist attenuates lithium chloride-induced c-Fos induction in rat brainstem. Brain Res. 1998;801(1–2):164–70.PubMedGoogle Scholar
  217. 217.
    Seeley RJ, et al. The role of CNS GLP-1-(7-36) amide receptors in mediating the visceral illness effects of lithium chloride. J Neurosci. 2000;20:1616–21.PubMedGoogle Scholar
  218. 218.
    Tang-Christensen M, et al. The proglucagon-derived peptide, glucagon-like peptide-2, is a neurotransmitter involved in the regulation of food intake. Nat Med. 2000;6(7):802–7.PubMedGoogle Scholar
  219. 219.
    Halford JC, et al. Serotonin (5-HT) drugs: effects on appetite expression and use for the treatment of obesity. Curr Drug Targets. 2005;6(2):201–13.PubMedGoogle Scholar
  220. 220.
    Lawton CL, Blundell JE. The effect of d-fenfluramine on intake of carbohydrate supplements is influenced by the hydration of the test diets. Behav Pharmacol. 1992;3(5):517–23.PubMedGoogle Scholar
  221. 221.
    Leibowitz SF, Alexander JT. Hypothalamic serotonin in control of eating behavior, meal size, and body weight. Biol Psychiatry. 1998;44(9):851–64.PubMedGoogle Scholar
  222. 222.
    Pierce PA, et al. 5-Hydroxytryptamine receptor subtype messenger RNAs in human dorsal root ganglia: a polymerase chain reaction study. Neuroscience. 1997;81(3):813–9.PubMedGoogle Scholar
  223. 223.
    Miller KJ. Serotonin 5-ht2c receptor agonists: potential for the treatment of obesity. Mol Interv. 2005;5(5):282–91.PubMedGoogle Scholar
  224. 224.
    Nonogaki K, et al. Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene. Nat Med. 1998;4(10): 1152–6.PubMedGoogle Scholar
  225. 225.
    Heisler LK, et al. Activation of central melanocortin pathways by fenfluramine. Science. 2002; 297(5581):609–11.PubMedGoogle Scholar
  226. 226.
    Ettinger MP, et al. Recombinant variant of ciliary neurotrophic factor for weight loss in obese adults: a randomized, dose-ranging study. JAMA. 2003; 289(14):1826–32.PubMedGoogle Scholar
  227. 227.
    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(7):649–60.PubMedGoogle Scholar
  228. 228.
    Kelly JF, et al. Ciliary neurotrophic factor and leptin induce distinct patterns of immediate early gene expression in the brain. Diabetes. 2004;53(4): 911–20.PubMedGoogle Scholar
  229. 229.
    Kokoeva MV, Yin H, Flier JS. Neurogenesis in the hypothalamus of adult mice: potential role in energy balance. Science. 2005;310(5748):679–83.PubMedGoogle Scholar
  230. 230.
    Pu S, et al. Neuropeptide Y counteracts the anorectic and weight reducing effects of ciliary neurotropic factor. J Neuroendocrinol. 2000;12(9):827–32.PubMedGoogle Scholar
  231. 231.
    Cone RD. Anatomy and regulation of the central melanocortin system. Nat Neurosci. 2005;8(5): 571–8.PubMedGoogle Scholar
  232. 232.
    Yen T, et al. Obesity, diabetes, and neoplasia in yellow A(vy)/- mice: ectopic expression of the agouti gene. FASEB J. 1994;8:479–88.PubMedGoogle Scholar
  233. 233.
    Zimanyi IA, Pelleymounter MA. The role of melanocortin peptides and receptors in regulation of energy balance. Curr Pharm Des. 2003;9(8): 627–41.PubMedGoogle Scholar
  234. 234.
    Stutz AM, Morrison CD, Argyropoulos G. The Agouti-related protein and its role in energy homeostasis. Peptides. 2005;26(10):1771–81.PubMedGoogle Scholar
  235. 235.
    Yaswen L, et al. Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nat Med. 1999;5(9):1066–70.PubMedGoogle Scholar
  236. 236.
    Krude H, et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet. 1998;19(2): 155–7.PubMedGoogle Scholar
  237. 237.
    Huszar D, et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell. 1997;88(1):131–41.PubMedGoogle Scholar
  238. 238.
    Cone RD, et al. The melanocortin receptors: agonists, antagonists, and the hormonal control of pigmentation. Recent Prog Horm Res. 1996;51: 287–320.PubMedGoogle Scholar
  239. 239.
    Seeley RJ, Drazen DL, Clegg DJ. The critical role of the melanocortin system in the control of energy balance. Annu Rev Nutr. 2004;24:133–49.PubMedGoogle Scholar
  240. 240.
    Boyce RS, Duhl DM. Melanocortin-4 receptor agonists for the treatment of obesity. Curr Opin Investig Drugs. 2004;5(10):1063–71.PubMedGoogle Scholar
  241. 241.
    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(11):2787–96.PubMedGoogle Scholar
  242. 242.
    Dorr RT, et al. Evaluation of melanotan-II, a superpotent cyclic melanotropic peptide in a pilot phase-I clinical study. Life Sci. 1996;58(20):1777–84.PubMedGoogle Scholar
  243. 243.
    Davis JF, Choi DL, Benoit SC. Insulin, leptin and reward. Trends Endocrinol Metab. 2010;21(2):68–74.PubMedCentralPubMedGoogle Scholar
  244. 244.
    Figlewicz DP, et al. Moderate high fat diet increases sucrose self-administration in young rats. Appetite. 2013;61(1):19–29.PubMedCentralPubMedGoogle Scholar
  245. 245.
    Choi DL, et al. The role of orexin-A in food motivation, reward-based feeding behavior and food-induced neuronal activation in rats. Neuroscience. 2010;167(1):11–20.PubMedGoogle Scholar
  246. 246.
    Benoit SC, et al. Novel functions of orexigenic hypothalamic peptides: from genes to behavior. Nutrition. 2008;24(9):843–7.PubMedCentralPubMedGoogle Scholar
  247. 247.
    Davis JF, et al. Role for dopamine-3 receptor in the hyperphagia of an unanticipated high-fat meal in rats. Pharmacol Biochem Behav. 2006;85(1):190–7.PubMedGoogle Scholar
  248. 248.
    Davis JF, et al. Leptin regulates energy balance and motivation through action at distinct neural circuits. Biol Psychiatry. 2011;69(7):668–74.PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Ofer Reizes
    • 1
  • Stephen C. Benoit
    • 2
  • Deborah J. Clegg
    • 3
  1. 1.Cellular & Molecular MedicineCleveland Clinic FoundationClevelandUSA
  2. 2.Department of Psychiatry & Behavioral Neuroscience, Obesity Research CenterUniversity of CincinnatiCincinnatiUSA
  3. 3.Internal MedicineUniversity of Texas Southwestern Medical CenterDallasUSA

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