Central nervous control of energy and glucose balance: Focus on the central melanocortin system

Annals of the New York Academy of Sciences

Volumn 1243, Issue 1, 2011, Pages 1-14

  Xu, Yong ^a   Elmquist, Joel K ^b   Fukuda, Makoto ^b  

^a BAYLOR COLLEGE OF MEDICINE   (United States)

^b UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

Author keywords

Body weight; Estrogen; Leptin; Melanocortins; Serotonin

Indexed keywords

AGOUTI RELATED PROTEIN; ALPHA INTERMEDIN; CLOZAPINE; ESTROGEN; ESTROGEN RECEPTOR ALPHA; FENFLURAMINE; LEPTIN; LEPTIN RECEPTOR; MELANOCORTIN; MELANOCORTIN 3 RECEPTOR; MELANOCORTIN 4 RECEPTOR; NEUROPEPTIDE Y; OLANZAPINE; PROOPIOMELANOCORTIN; SEROTONIN; SEROTONIN 2C AGONIST; SEROTONIN 2C RECEPTOR; STAT3 PROTEIN; STEROIDOGENIC FACTOR 1; SUPPRESSOR OF CYTOKINE SIGNALING 3;

4 AMINOBUTYRIC ACID RELEASE; ALLELE; AMYGDALOID NUCLEUS; ANOREXIA; ARCUATE NUCLEUS; BODY WEIGHT; DORSAL RAPHE NUCLEUS; ENERGY BALANCE; ENERGY EXPENDITURE; FOOD INTAKE; GENE DELETION; GENE MUTATION; GLUCOSE HOMEOSTASIS; GLYCEMIC CONTROL; HUMAN; HYPERGLYCEMIA; HYPERINSULINEMIA; HYPERPHAGIA; HYPOTHALAMIC PARAVENTRICULAR NUCLEUS; INSULIN RELEASE; INSULIN RESISTANCE; INSULIN SENSITIVITY; INTRAABDOMINAL FAT; LIPID DIET; NONHUMAN; OBESITY; PARABRACHIAL NUCLEUS; PRADER WILLI SYNDROME; PREGANGLIONIC NERVE CELL; PRESYNAPTIC NERVE; PROTEIN EXPRESSION; REVIEW; SEX DIFFERENCE; SIDE EFFECT; SIGNAL TRANSDUCTION; SOLITARY TRACT NUCLEUS; THERMOGENESIS; WEIGHT GAIN;

EID: 84255199265     PISSN: 00778923     EISSN: 17496632     Source Type: Book Series    
DOI: 10.1111/j.1749-6632.2011.06248.x     Document Type: Review

References (171)

1. Elmquist, J.K., C.F. Elias & C.B. Saper. 1999. From lesions to leptin: hypothalamic control of food intake and body weight. Neuron 22: 221-232.
2. Cone, R.D. 2005. Anatomy and regulation of the central melanocortin system. Nat. Neurosci. 8: 571-578.
3. Williams, D.L. & M.W. Schwartz. 2005. The melanocortin system as a central integrator of direct and indirect controls of food intake. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289: R2-R3.
4. Cone, R.D. 1999. The Central Melanocortin System and Energy Homeostasis. Trends Endocrinol. Metab. 10: 211-216.
5. Huszar, D. et al. 1997. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88: 131-141.
6. Yaswen, L. et al. 1999. Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nat. Med. 5: 1066-1070.
7. Qian, S. et al. 2002. Neither agouti-related protein nor neuropeptide Y is critically required for the regulation of energy homeostasis in mice. Mol Cell Biol. 22: 5027-5035.
8. Ollmann, M.M. et al. 1997. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278: 135-138.
9. Pierroz, D.D. et al. 1996. Chronic administration of neuropeptide Y into the lateral ventricle inhibits both the pituitary-testicular axis and growth hormone and insulin-like growth factor I secretion in intact adult male rats. Endocrinology 137: 3-12.
10. Gropp, E. et al. 2005. Agouti-related peptide-expressing neurons are mandatory for feeding. Nat. Neurosci. 8: 1289-1291.
11. Xu, A.W. et al. 2005. Effects of hypothalamic neurodegeneration on energy balance. PLoS Biol. 3: e415.
12. Bewick, G.A. et al. 2005. Post-embryonic ablation of AgRP neurons in mice leads to a lean, hypophagic phenotype. FASEB J. 19: 1680-1682.
13. Aponte, Y., D. Atasoy & S.M. Sternson. 2011. AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nat. Neurosci. 14: 351-355.
14. Alexander, G.M. et al. 2009. Remote control of neuronal activity in transgenic mice expressing evolved G protein-coupled receptors. Neuron 63: 27-39.
15. Ferguson, S.M. et al. 2011. Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization. Nat. Neurosci. 14: 22-24.
16. Krashes, M.J. et al. 2011. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J. Clin. Invest. 121: 1424-1428.
17. Flier, J.S. 2006. AgRP in energy balance: will the real AgRP please stand up? Cell Metab. 3: 83-85.
18. Wojcik, S.M. et al. 2006. A shared vesicular carrier allows synaptic corelease of GABA and glycine. Neuron 50: 575-587.
19. Tong, Q. et al. 2008. Synaptic release of GABA by AgRP neurons is required for normal regulation of energy balance. Nat. Neurosci. 11: 998-1000.
20. Balthasar, N. et al. 2004. Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 42: 983-991.
21. Cowley, M.A. et al. 2001. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411: 480-484.
22. Wu, Q., M.P. Boyle & R.D. Palmiter. 2009. Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to starvation. Cell 137: 1225-1234.
23. Chen, A.S. et al. 2000. Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nat. Genet. 26: 97-102.
24. Fan, W. et al. 2000. The central melanocortin system can directly regulate serum insulin levels. Endocrinology 141: 3072-3079.
25. Butler, A.A. et al. 2000. A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. Endocrinology 141: 3518-3521.
26. Butler, A.A. 2006. The melanocortin system and energy balance. Peptides 27: 281-290.
27. Sutton, G.M. et al. 2010. Central nervous system melanocortin-3 receptors are required for synchronizing metabolism during entrainment to restricted feeding during the light cycle. FASEB J. 24: 862-872.
28. Vaisse, C. et al. 1998. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat. Genet. 20: 113-114.
29. Yeo, G.S. et al. 1998. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat. Genet. 20: 111-112.
30. Chen, A.S. et al. 2000. Role of the melanocortin-4 receptor in metabolic rate and food intake in mice. Transgenic Res. 9: 145-154.
31. Ste Marie, L. et al. 2000. A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors. Proc. Natl. Acad. Sci. USA 97: 12, 339-12, 344.
32. Nogueiras, R. et al. 2007. The central melanocortin system directly controls peripheral lipid metabolism. J. Clin. Invest. 117: 3475-3488.
33. Kishi, T. et al. 2003. Expression of melanocortin 4 receptor mRNA in the central nervous system of the rat. J. Comp. Neurol. 457: 213-235.
34. Liu, H. et al. 2003. Transgenic mice expressing green fluorescent protein under the control of the melanocortin-4 receptor promoter. J. Neurosci. 23: 7143-7154.
35. Mountjoy, K.G. et al. 1994. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol. Endocrinol. 8: 1298-1308.
36. Balthasar, N. et al. 2005. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell 123: 493-505.
37. Rossi, J. et al. 2011. Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis. Cell Metab. 13: 195-204.
38. Leibel, R.L., W.K. Chung & S.C. Chua, Jr. 1997. The molecular genetics of rodent single gene obesities. J. Biol. Chem. 272: 31, 937-31, 940.
39. Alingh Prins, A. et al. 1986. Daily rhythms of feeding in the genetically obese and lean Zucker rats. Physiol. Behav. 38: 423-426.
40. McLaughlin, C.L. & C.A. Baile. 1981. Ontogeny of feeding behavior in the Zucker obese rat. Physiol. Behav. 26: 607-612.
41. Trayhurn, P., P.L. Thurlby & W.P. James. 1977. Thermogenic defect in pre-obese ob/ob mice. Nature 266: 60-62.
42. Dauncey, M.J. 1986. Activity-induced thermogenesis in lean and genetically obese (ob/ob) mice. Experientia 42: 547-549.
43. Dauncey, M.J. & D. Brown. 1987. Role of activity-induced thermogenesis in twenty-four hour energy expenditure of lean and genetically obese (ob/ob) mice. Q. J. Exp. Physiol. 72: 549-559.
44. Tartaglia, L.A. 1997. The leptin receptor. J. Biol. Chem. 272: 6093-6096.
45. Halaas, J.L. et al. 1997. Physiological response to long-term peripheral and central leptin infusion in lean and obese mice. Proc. Natl. Acad. Sci. USA 94: 8878-8883.
46. Cohen, P. et al. 2001. Selective deletion of leptin receptor in neurons leads to obesity. J. Clin. Invest. 108: 1113-1121.
47. McMinn, J.E. et al. 2005. Neuronal deletion of Lepr elicits diabesity in mice without affecting cold tolerance or fertility. Am. J. Physiol. Endocrinol. Metab. 289: E403-E411.
48. Kowalski, T.J. et al. 2001. Transgenic complementation of leptin-receptor deficiency. I. Rescue of the obesity/diabetes phenotype of LEPR-null mice expressing a LEPR-B transgene. Diabetes 50: 425-435.
49. Chua, S.C., Jr. et al. 2004. 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. 286: E384-E392.
50. de Luca, C. et al. 2005. Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes. J. Clin. Invest. 115: 3484-3493.
51. Elmquist, J.K. et al. 1997. Leptin activates neurons in ventrobasal hypothalamus and brainstem. Endocrinology 138: 839-842.
52. Elmquist, J.K. et al. 1998. Leptin activates distinct projections from the dorsomedial and ventromedial hypothalamic nuclei. Proc. Natl. Acad. Sci. USA 95: 741-746.
53. Fei, H. et al. 1997. Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues. Proc. Natl. Acad. Sci. USA 94: 7001-7005.
54. Mercer, J.G. et al. 1996. 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. 387: 113-116.
55. Schwartz, M.W. et al. 1996. Identification of targets of leptin action in rat hypothalamus. J. Clin. Invest. 98: 1101-1106.
56. Scott, M.M. et al. 2009. Leptin targets in the mouse brain. J. Comp. Neurol. 514: 518-532.
57. Williams, K.W. et al. 2010. Segregation of acute leptin and insulin effects in distinct populations of arcuate proopiomelanocortin neurons. J. Neurosci. 30: 2472-2479.
58. Mizuno, T.M. et al. 1998. Hypothalamic pro-opiomelanocortin mRNA is reduced by fasting and [corrected] in ob/ob and db/db mice, but is stimulated by leptin. Diabetes 47: 294-297.
59. Schwartz, M.W. et al. 1997. Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes 46: 2119-2123.
60. Thornton, J.E. et al. 1997. Regulation of hypothalamic proopiomelanocortin mRNA by leptin in ob/ob mice. Endocrinology 138: 5063-5066.
61. Hill, J.W. et al. 2010. Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility. Cell Metab. 11: 286-297.
62. Huo, L. et al. 2009. Leptin-dependent control of glucose balance and locomotor activity by POMC neurons. Cell Metab. 9: 537-547.
63. Ikeda, Y. et al. 1995. The nuclear receptor steroidogenic factor 1 is essential for the formation of the ventromedial hypothalamic nucleus. Mol. Endocrinol. 9: 478-486.
64. Dellovade, T.L. et al. 2000. Disruption of the gene encoding SF-1 alters the distribution of hypothalamic neuronal phenotypes. J. Comp. Neurol. 423: 579-589.
65. Majdic, G. et al. 2002. Knockout mice lacking steroidogenic factor 1 are a novel genetic model of hypothalamic obesity. Endocrinology 143: 607-614.
66. Dhillon, H. et al. 2006. Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis. Neuron 49: 191-203.
67. Bingham, N.C. et al. 2008. Selective loss of leptin receptors in the ventromedial hypothalamic nucleus results in increased adiposity and a metabolic syndrome. Endocrinology 149: 2138-2148.
68. Morton, G.J. & M.W. Schwartz. 2011. Leptin and the central nervous system control of glucose metabolism. Physiol. Rev. 91: 389-411.
69. Kalra, S.P. 2011. Pivotal role of leptin-hypothalamus signaling in the etiology of diabetes uncovered by gene therapy: a new therapeutic intervention? Gene Ther. 18: 319-325.
70. Coppari, R. et al. 2005. The hypothalamic arcuate nucleus: a key site for mediating leptin's effects on glucose homeostasis and locomotor activity. Cell Metab. 1: 63-72.
71. Pocai, A. et al. 2005. Central leptin acutely reverses diet-induced hepatic insulin resistance. Diabetes 54: 3182-3189.
72. Hayes, M.R. et al. 2010. Endogenous leptin signaling in the caudal nucleus tractus solitarius and area postrema is required for energy balance regulation. Cell Metab. 11: 77-83.
73. Scott, M.M. et al. 2011. Leptin receptor expression in hindbrain Glp-1 neurons regulates food intake and energy balance in mice. J. Clin. Invest. 121: 2413-2421.
74. Bates, S.H. et al. 2003. STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature 421: 856-859.
75. Piper, M.L. et al. 2008. Specific physiological roles for signal transducer and activator of transcription 3 in leptin receptor-expressing neurons. Mol. Endocrinol. 22: 751-759.
76. Plum, L. et al. 2006. Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity. J. Clin. Invest. 116: 1886-1901.
77. Niswender, K.D. et al. 2003. Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus: a key mediator of insulin-induced anorexia. Diabetes 52: 227-231.
78. Hill, J.W. et al. 2008. Acute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mice. J. Clin. Invest. 118: 1796-1805.
79. Fukuda, M. et al. 2008. Monitoring FoxO1 localization in chemically identified neurons. J. Neurosci. 28: 13, 640-13, 648.
80. Cota, D. et al. 2008. The role of hypothalamic mammalian target of rapamycin complex 1 signaling in diet-induced obesity. J. Neurosci. 28: 7202-7208.
81. Blouet, C., H. Ono & G.J. Schwartz. 2008. Mediobasal hypothalamic p70 S6 kinase 1 modulates the control of energy homeostasis. Cell Metab. 8: 459-467.
82. Minokoshi, Y. et al. 2004. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428: 569-574.
83. Metlakunta, A.S., M. Sahu & A. Sahu. 2008. Hypothalamic phosphatidylinositol 3-kinase pathway of leptin signaling is impaired during the development of diet-induced obesity in FVB/N mice. Endocrinology 149: 1121-1128.
84. Xu, A.W. et al. 2005. PI3K integrates the action of insulin and leptin on hypothalamic neurons. J. Clin. Invest. 115: 951-958.
85. Xu, Y. et al. PI3K signaling in the ventromedial hypothalamic nucleus is required for normal energy homeostasis. Cell Metab. 12: 88-95.
86. Cota, D. et al. 2006. Hypothalamic mTOR signaling regulates food intake. Science 312: 927-930.
87. Bjorbaek, C. et al. 1998. Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol. Cell. 1: 619-625.
88. Cook, W.S. & R.H. Unger. 2002. Protein tyrosine phosphatase 1B: a potential leptin resistance factor of obesity. Dev. Cell. 2: 385-387.
89. Zabolotny, J.M. et al. 2002. PTP1B regulates leptin signal transduction in vivo. Dev. Cell. 2: 489-495.
90. Munzberg, H., J.S. Flier & C. Bjorbaek. 2004. Region-specific leptin resistance within the hypothalamus of diet-induced obese mice. Endocrinology 145: 4880-4889.
91. Enriori, P.J. et al. 2007. Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons. Cell Metab. 5: 181-194.
92. White, C.L. et al. 2008. HF diets increase hypothalamic PTP1B and induce leptin resistance through both leptin-dependent and independent mechanisms. Am. J. Physiol. Endocrinol. Metab. 296: E291-E299.
93. Mori, H. et al. 2004. Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nat. Med. 10: 739-743.
94. Howard, J.K. et al. 2004. Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3. Nat. Med. 10: 734-738.
95. Bence, K.K. et al. 2006. Neuronal PTP1B regulates body weight, adiposity and leptin action. Nat. Med. 12: 917-924.
96. Kievit, P. et al. 2006. Enhanced leptin sensitivity and improved glucose homeostasis in mice lacking suppressor of cytokine signaling-3 in POMC-expressing cells. Cell Metab. 4: 123-132.
97. Banno, R. et al. 2010. PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in mice. J. Clin. Invest. 120: 720-734.
98. Briancon, N. et al. 2010. Combined neural inactivation of suppressor of cytokine signaling-3 and protein-tyrosine phosphatase-1B reveals additive, synergistic, and factor-specific roles in the regulation of body energy balance. Diabetes 59: 3074-3084.
99. Carr, M.C. 2003. The emergence of the metabolic syndrome with menopause. J. Clin. Endocrinol. Metab. 88: 2404-2411.
100. Flegal, K.M. et al. 2002. Prevalence and trends in obesity among US adults, 1999-2000. JAMA 288: 1723-1727.
101. Freedman, D.S. et al. 2002. Trends and correlates of class 3 obesity in the United States from 1990 through 2000. JAMA 288: 1758-1761.
102. Drewett, R.F. 1973. Sexual behaviour and sexual motivation in the female rat. Nature 242: 476-477.
103. Blaustein, J.D. & G.N. Wade. 1976. Ovarian influences on the meal patterns of female rats. Physiol. Behav. 17: 201-208.
104. Wallen, W.J., M.P. Belanger & C. Wittnich. 2001. Sex hormones and the selective estrogen receptor modulator tamoxifen modulate weekly body weights and food intakes in adolescent and adult rats. J. Nutr. 131: 2351-2357.
105. Roy, E.J. & G.N. Wade. 1977. Role of food intake in estradiol-induced body weight changes in female rats. Horm. Behav. 8: 265-274.
106. Mueller, K. & S. Hsiao. 1980. Estrus- and ovariectomy-induced body weight changes: evidence for two estrogenic mechanisms. J. Comp. Physiol. Psychol. 94: 1126-1134.
107. Gao, Q. et al. 2007. Anorectic estrogen mimics leptin's effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals. Nat. Med. 13: 89-94.
108. Bjorntorp, P. 1997. Hormonal control of regional fat distribution. Hum. Reprod. 1(12 Suppl): 21-25.
109. Bjorntorp, P. 1997. Obesity. Lancet 350: 423-426.
110. Bjorntorp, P. 1997. Body fat distribution, insulin resistance, and metabolic diseases. Nutrition 13: 795-803.
111. Kotani, K. et al. 1994. Sexual dimorphism of age-related changes in whole-body fat distribution in the obese. Int. J. Obes. Relat. Metab. Disord. 18: 207-212.
112. Heine, P.A. et al. 2000. Increased adipose tissue in male and female estrogen receptor-alpha knockout mice. Proc. Natl. Acad. Sci. USA 97: 12, 729-12, 734.
113. Ohlsson, C. et al. 2000. Obesity and disturbed lipoprotein profile in estrogen receptor-alpha-deficient male mice. Biochem. Biophys. Res. Commun. 278: 640-645.
114. Geary, N. et al. 2001. Deficits in E2-dependent control of feeding, weight gain, and cholecystokinin satiation in ER-alpha null mice. Endocrinology 142: 4751-4757.
115. Osterlund, M. et al. 1998. Differential distribution and regulation of estrogen receptor-alpha and -beta mRNA within the female rat brain. Brain Res. Mol. Brain Res. 54: 175-180.
116. Merchenthaler, I. et al. 2004. Distribution of estrogen receptor alpha and beta in the mouse central nervous system: in vivo autoradiographic and immunocytochemical analyses. J. Comp. Neurol. 473: 270-291.
117. Butera, P.C. & R.J. Beikirch. 1989. Central implants of diluted estradiol: independent effects on ingestive and reproductive behaviors of ovariectomized rats. Brain Res. 491: 266-273.
118. Palmer, K. & J.M. Gray. 1986. Central vs. peripheral effects of estrogen on food intake and lipoprotein lipase activity in ovariectomized rats. Physiol. Behav. 37: 187-189.
119. Butera, P.C., D.M. Willard & S.A. Raymond. 1992. Effects of PVN lesions on the responsiveness of female rats to estradiol. Brain Res. 576: 304-310.
120. Hrupka, B.J., G.P. Smith & N. Geary. 2002. Hypothalamic implants of dilute estradiol fail to reduce feeding in ovariectomized rats. Physiol. Behav. 77: 233-241.
121. Dagnault, A. & D. Richard. 1994. Lesions of hypothalamic paraventricular nuclei do not prevent the effect of estradiol on energy and fat balance. Am. J. Physiol. 267: E32-E38.
122. Wade, G.N. & I. Zucker. 1970. Modulation of food intake and locomotor activity in female rats by diencephalic hormone implants. J. Comp. Physiol. Psychol. 72: 328-336.
123. Musatov, S. et al. 2007. Silencing of estrogen receptor alpha in the ventromedial nucleus of hypothalamus leads to metabolic syndrome. Proc. Natl. Acad. Sci. USA 104: 2501-2506.
124. Xu, Y. et al. 2011. Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction. Cell Metab. 14: 453-465.
125. Olofsson, L.E., A.A. Pierce & A.W. Xu. 2009. Functional requirement of AgRP and NPY neurons in ovarian cycle-dependent regulation of food intake. Proc. Natl. Acad. Sci. USA 106: 15, 932-15, 937.
126. Miller, M.M. et al. 1995. Effects of age and long-term ovariectomy on the estrogen-receptor containing subpopulations of beta-endorphin-immunoreactive neurons in the arcuate nucleus of female C57BL/6J mice. Neuroendocrinology 61: 542-551.
127. de Souza, F.S. et al. 2011. The estrogen receptor alpha colocalizes with proopiomelanocortin in hypothalamic neurons and binds to a conserved motif present in the neuron-specific enhancer nPE2. Eur. J. Pharmacol. 660: 181-187.
128. Malyala, A. et al. 2008. PI3K signaling effects in hypothalamic neurons mediated by estrogen. J. Comp. Neurol. 506: 895-911.
129. Lechin, F., B. van der Dijs & G. Hernandez-Adrian. 2006. Dorsal raphe vs. median raphe serotonergic antagonism. Anatomical, physiological, behavioral, neuroendocrinological, neuropharmacological and clinical evidences: relevance for neuropharmacological therapy. Prog. Neuropsychopharmacol. Biol. Psychiatry 30: 565-585.
130. De Fanti, B.A., J.S. Hamilton & B.A. Horwitz. 2001. Meal-induced changes in extracellular 5-HT in medial hypothalamus of lean (Fa/Fa) and obese (fa/fa) Zucker rats. Brain Res. 902: 164-170.
131. Rowland, N.E. & J. Carlton. 1986. Neurobiology of an anorectic drug: fenfluramine. Prog. Neurobiol. 27: 13-62.
132. Foltin, R.W. & T.H. Moran. 1989. Food intake in baboons: effects of a long-acting cholecystokinin analog. Appetite 12: 145-152.
133. McGuirk, J. et al. 1991. Differential effects of d-fenfluramine, l-fenfluramine and d-amphetamine on the microstructure of human eating behaviour. Behav. Pharmacol. 2: 113-119.
134. Rogers, P.J. & J.E. Blundell. 1979. Effect of anorexic drugs on food intake and the micro-structure of eating in human subjects. Psychopharmacology (Berl) 66: 159-165.
135. Blundell, J.E. & M.B. Leshem. 1974. Central action of anorexic agents: effects of amphetamine and fenfluramine in rats with lateral hypothalamic lesions. Eur. J. Pharmacol. 28: 81-88.
136. Geyer, M.A. et al. 1976. Behavioral studies following lesions of the mesolimbic and mesostriatal serotonergic pathways. Brain Res. 106: 257-269.
137. Ghosh, M.N. & S. Parvathy. 1973. The effect of cyproheptadine on water and food intake and on body weight in the fasted adult and weanling rats. Br. J. Pharmacol. 48: 328P-329P.
138. Saller, C.F. & E.M. Stricker. 1976. Hyperphagia and increased growth in rats after intraventricular injection of 5, 7-dihydroxytryptamine. Science 192: 385-387.
139. Vickers, S.P. & C.T. Dourish. 2004. Serotonin receptor ligands and the treatment of obesity. Curr. Opin. Investig. Drugs 5: 377-388.
140. Vickers, S.P. et al. 1999. Reduced satiating effect of d-fenfluramine in serotonin 5-HT(2C) receptor mutant mice. Psychopharmacology (Berl) 143: 309-314.
141. Kennett, G.A. & G. Curzon. 1991. Potencies of antagonists indicate that 5-HT1C receptors mediate 1-3(chlorophenyl)piperazine-induced hypophagia. Br. J. Pharmacol. 103: 2016-2020.
142. Kennett, G.A. et al. 1997. SB 242084, a selective and brain penetrant 5-HT2C receptor antagonist. Neuropharmacology 36: 609-620.
143. Clifton, P.G., M.D. Lee & C.T. Dourish. 2000. Similarities in the action of Ro 60-0175, a 5-HT2C receptor agonist and d-fenfluramine on feeding patterns in the rat. Psychopharmacology (Berl). 152: 256-267.
144. Tecott, L.H. et al. 1995. Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors. Nature 374: 542-546.
145. Nonogaki, K. et al. 1998. Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene. Nat. Med. 4: 1152-1156.
146. Templeman, L.A. et al. 2005. Polymorphisms of the 5-HT2C receptor and leptin genes are associated with antipsychotic drug-induced weight gain in Caucasian subjects with a first-episode psychosis. Pharmacogenet. Genomics 15: 195-200.
147. Reynolds, G.P., Z.J. Zhang & X.B. Zhang. 2002. Association of antipsychotic drug-induced weight gain with a 5-HT2C receptor gene polymorphism. Lancet 359: 2086-2087.
148. Kishore, S. & S. Stamm. 2006. The snoRNA HBII-52 regulates alternative splicing of the serotonin receptor 2C. Science 311: 230-232.
149. Wade, J.M. et al. 2008. Synergistic impairment of glucose homeostasis in ob/ob mice lacking functional serotonin 2C receptors. Endocrinology 149: 955-961.
150. Zhou, L. et al. 2007. Serotonin 2C receptor agonists improve type 2 diabetes via melanocortin-4 receptor signaling pathways. Cell Metab. 6: 398-405.
151. Molineaux, S.M. et al. 1989. 5-HT1c receptor is a prominent serotonin receptor subtype in the central nervous system. Proc. Natl. Acad. Sci. USA 86: 6793-6797.
152. Heisler, L.K. et al. 2002. Activation of central melanocortin pathways by fenfluramine. Science 297: 609-611.
153. Kiss, J., C. Leranth & B. Halasz. 1984. Serotoninergic endings on VIP-neurons in the suprachiasmatic nucleus and on ACTH-neurons in the arcuate nucleus of the rat hypothalamus. A combination of high resolution autoradiography and electron microscopic immunocytochemistry. Neurosci. Lett. 44: 119-124.
154. Qiu, J. et al. 2007. Serotonin 5-hydroxytryptamine2C receptor signaling in hypothalamic proopiomelanocortin neurons: role in energy homeostasis in females. Mol. Pharmacol. 72: 885-896.
155. Lam, D.D. et al. 2008. Serotonin 5-HT2C receptor agonist promotes hypophagia via downstream activation of melanocortin 4 receptors. Endocrinology 149: 1323-1328.
156. Heisler, L.K. et al. 2006. Serotonin reciprocally regulates melanocortin neurons to modulate food intake. Neuron 51: 239-249.
157. Zigman, J.M. et al. 2005. Mice lacking ghrelin receptors resist the development of diet-induced obesity. J. Clin. Invest. 115: 3564-3572.
158. Xu, Y. et al. 2008. 5-HT2CRs expressed by pro-opiomelanocortin neurons regulate energy homeostasis. Neuron 60: 582-589.
159. Xu, Y. et al. 2010. A serotonin and melanocortin circuit mediates d-fenfluramine anorexia. J. Neurosci. 30: 14, 630-14, 634.
160. Xu, Y. et al. 2010. 5-HT(2C)Rs expressed by pro-opiomelanocortin neurons regulate insulin sensitivity in liver. Nat. Neurosci. 13: 1457-1459.
161. Halford, J.C. & J.E. Blundell. 1996. The 5-HT1B receptor agonist CP-94, 253 reduces food intake and preserves the behavioural satiety sequence. Physiol. Behav. 60: 933-939.
162. Lee, M.D. & K.J. Simansky. 1997. CP-94, 253: a selective serotonin1B (5-HT1B) agonist that promotes satiety. Psychopharmacology (Berl) 131: 264-270.
163. Lee, M.D. et al. 1998. Infusion of the serotonin1B (5-HT1B) agonist CP-93, 129 into the parabrachial nucleus potently and selectively reduces food intake in rats. Psychopharmacology (Berl) 136: 304-307.
164. Bouwknecht, J.A. et al. 2001. Male and female 5-HT(1B) receptor knockout mice have higher body weights than wildtypes. Physiol. Behav. 74: 507-516.
165. Lucas, J.J. et al. 1998. Absence of fenfluramine-induced anorexia and reduced c-Fos induction in the hypothalamus and central amygdaloid complex of serotonin 1B receptor knock-out mice. J. Neurosci. 18: 5537-5544.
166. Bonaventure, P. et al. 1998. Detailed mapping of serotonin 5-HT1B and 5-HT1D receptor messenger RNA and ligand binding sites in guinea-pig brain and trigeminal ganglion: clues for function. Neuroscience 82: 469-484.
167. Bruinvels, A.T. et al. 1994. Localization of 5-HT1B, 5-HT1D alpha, 5-HT1E and 5-HT1F receptor messenger RNA in rodent and primate brain. Neuropharmacology 33: 367-386.
168. Roseberry, A.G. et al. 2004. Neuropeptide Y-mediated inhibition of proopiomelanocortin neurons in the arcuate nucleus shows enhanced desensitization in ob/ob mice. Neuron 41: 711-722.
169. Chadha, A. et al. 2000. The 5HT(1B) receptor agonist, CP-93129, inhibits [(3)H]-GABA release from rat globus pallidus slices and reverses akinesia following intrapallidal injection in the reserpine-treated rat. Br. J. Pharmacol. 130: 1927-1932.
170. Stanford, I.M. & M.G. Lacey. 1996. Differential actions of serotonin, mediated by 5-HT1B and 5-HT2C receptors, on GABA-mediated synaptic input to rat substantia nigra pars reticulata neurons in vitro. J. Neurosci. 16: 7566-7573.
171. Sohn, J.W. et al. 2011. Serotonin 2C receptor activates a dinstinct population of arcuate pro-opiomelanocortin neurons via TRPC channels. Neuron 71: 488-497.