Hypothalamic proopiomelanocortin processing and the regulation of energy balance

European Journal of Pharmacology

Volumn 660, Issue 1, 2011, Pages 213-219

  Wardlaw, Sharon L ^a  

^a Department of Neurology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain   (United States)

Author keywords

MSH; Carboxypeptidase E; Obesity; POMC; Prohormone convertase; Proopiomelanocortin

Indexed keywords

ACYLTRANSFERASE; ALPHA INTERMEDIN; ALPHA INTERMEDIN 1-12; ALPHA INTERMEDIN 1-13; ARGONAUTE PROTEIN; CARBOXYPEPTIDASE H; CORTICOTROPIN; HELIX LOOP HELIX PROTEIN; INTERMEDIN; INTERMEDIN INHIBITING FACTOR; LEPTIN; PROLINE CARBOXYPEPTIDASE; PROOPIOMELANOCORTIN; PROPROTEIN CONVERTASE 1; TRANSCRIPTION FACTOR FKHR; UNCLASSIFIED DRUG;

AMINO TERMINAL SEQUENCE; BODY WEIGHT; ENERGY BALANCE; ENERGY EXPENDITURE; ENZYME DEFICIENCY; ENZYME DEGRADATION; EXON; FRAMESHIFT MUTATION; GENE EXPRESSION; GENE MUTATION; HOMOZYGOSITY; HORMONAL REGULATION; HUMAN; HYPOTHALAMUS; MISSENSE MUTATION; NEUROENDOCRINE SYSTEM; NONHUMAN; OBESITY; OXYGEN CONSUMPTION; PRIORITY JOURNAL; PROTEIN CLEAVAGE; PROTEIN DEGRADATION; PROTEIN PROCESSING; PROTEIN TARGETING; REVIEW; RNA INTERFERENCE; SIGNAL TRANSDUCTION; WEIGHT GAIN; WEIGHT REDUCTION;

ANIMALS; ENERGY METABOLISM; HUMANS; HYPOTHALAMUS; MUTATION; OBESITY; PRO-OPIOMELANOCORTIN;

EID: 79955938111     PISSN: 00142999     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.ejphar.2010.10.107     Document Type: Review

References (88)

1. Appleyard, S.M., Hayward, M., Young, J.I., Butler, A.A., Cone, R.D., Rubinstein, M., Low, M.J., 2003. A role for the endogenous opioid beta-endorphin in energy homeostasis. Endocrinology 144, 1753-1760. (Pubitemid 36543312)
2. Balthasar, N., Coppari, R., McMinn, J., Liu, S.M., Lee, C.E., Tang, V., Kenny, C.D., McGovern, R.A., Chua, S.C.J., Elmquist, J.K., Lowell, B.B., 2004. Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 42, 983-991. (Pubitemid 38798236)
3. Benjannet, S., Rondeau, N., Day, R., Chretien, M., Seidah, N.G., 1991. PC1 and PC2 are proprotein convertases capable of cleaving proopiomelanocortin at distinct pairs of basic residues. Proc. Natl Acad. Sci. USA 88, 3564-3568.
4. Benoit, S.C., Air, E.L., Coolen, L.M., Strauss, R., Jackman, A., Clegg, D.J., Seeley, R.J., Woods, S.C., 2002. The catabolic action of insulin in the brain is mediated by melanocortins. J. Neurosci. 22, 9048-9052. (Pubitemid 35379074)
5. Berman, Y., Mzhavia, N., Polonskaia, A., Devi, L.A., 2001. Impaired prohormone convertases in Cpe(fat)/Cpe(fat) mice. J. Biol. Chem. 276, 1466-1473.
6. Biebermann, H., Castaneda, T.R., van Landeghem, F., von Deimling, A., Escher, F., Brabant, G., Hebebrand, J., Hinney, A., Tschop, M.H., Gruters, A., Krude, H., 2006. A role for beta-melanocyte-stimulating hormone in human body-weight regulation. Cell Metab. 3, 141-146.
7. Blouet, C., Jo, Y.H., Li, X., Schwartz, G.J., 2009. Mediobasal hypothalamic leucine sensing regulates food intake through activation of a hypothalamus-brainstem circuit. J. Neurosci. 29, 8302-8311.
8. Bodnar, R.J., 2004. Endogenous opioids and feeding behavior: a 30-year historical perspective. Peptides 25, 697-725. (Pubitemid 38681072)
9. Bouret, S.G., Draper, S.J., Simerly, R.B., 2004. Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 304, 108-110. (Pubitemid 38451467)
10. Breen, T.L., Conwell, I.M., Wardlaw, S.L., 2005. Effects of fasting, leptin, and insulin on AGRP and POMC peptide release in the hypothalamus. Brain Res. 1032, 141-148. (Pubitemid 40170319)
11. Butler, A.A., Kesterson, R.A., Khong, K., Cullen, M.J., Pelleymounter, M.A., Dekoning, J., Baetscher, M., Cone, R.D., 2000. A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. Endocrinology 141, 3518-3521. (Pubitemid 32269044)
12. Castro, M.G., Morrison, E., 1997. Post-translational processing of proopiomelanocortin in the pituitary and in the brain. Crit. Rev. Neurobiol. 11, 35-57.
13. Challis, B.G., Pritchard, L.E., Creemers, J.W., Delplanque, J., Keogh, J.M., Luan, J., Wareham, N.J., Yeo, G.S., Bhattacharyya, S., Froguel, P., White, A., Farooqi, I.S., O'Rahilly, S., 2002. A missense mutation disrupting a dibasic prohormone processing site in pro-opiomelanocortin (POMC) increases susceptibility to early-onset obesity through a novel molecular mechanism. Hum. Mol. Genet. 11, 1997-2004.
14. Challis, B.G., Coll, A.P., Yeo, G.S., Pinnock, S.B., Dickson, S.L., Thresher, R.R., Dixon, J., Zahn, D., Rochford, J.J., White, A., Oliver, R.L., Millington, G., Aparicio, S.A., Colledge, W.H., Russ, A.P., Carlton, M.B., O'Rahilly, S., 2004. Mice lacking pro-opiomelanocortin are sensitive to high-fat feeding but respond normally to the acute anorectic effects of peptide-YY(3-36). Proc. Natl Acad. Sci. USA 101, 4695-4700.
15. Chen, A.S., Marsh, D.J., Trumbauer, M.E., Frazier, E.G., Guan, X.M., Yu, H., Rosenblum, C.I., Vongs, A., Feng, Y., Cao, L., Metzger, J.M., Strack, A.M., Camacho, R.E., Mellin, T.N., Nunes, C.N., Min, W., Fisher, J., Gopal-Truter, S., MacIntyre, D.E., Chen, H.Y., Van Der Ploeg, L.H., 2000. Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nat. Genet. 26, 97-102.
16. Chen, H., Jawahar, S., Qian, Y., Duong, Q., Chan, G., Parker, A., Meyer, J.M., Moore, K.J., Chayen, S., Gross, D.J., Glaser, B., Permutt, M.A., Fricker, L.D., 2001. Missense polymorphism in the human carboxypeptidase E gene alters enzymatic activity. Hum. Mutat. 18, 120-131.
17. Clement, K., Dubern, B., Mencarelli, M., Czernichow, P., Ito, S., Wakamatsu, K., Barsh, G.S., Vaisse, C., Leger, J., 2008.Unexpected endocrine features and normal pigmentation in a young adult patient carrying a novel homozygousmutation in the POMC gene. J. Clin. Endocrinol. Metab. 93, 4955-4962.
18. Coll, A.P., Farooqi, I.S., Challis, B.G., Yeo, G.S., O'Rahilly, S., 2004. Proopiomelanocortin and energy balance: insights from human and murine genetics. J. Clin. Endocrinol. Metab. 89, 2557-2562.
19. Coll, A.P., Challis, B.G., Lopez, M., Piper, S., Yeo, G.S., O'Rahilly, S., 2005. Proopiomelanocortin-deficient mice are hypersensitive to the adverse metabolic effects of glucocorticoids. Diabetes 54, 2269-2276. (Pubitemid 41134252)
20. Comuzzie, A.G., Hixson, J.E., Almasy, L., Mitchell, B.D., Mahaney, M.C., Dyer, T.D., Stern, M.P., MacCluer, J.W., Blangero, J., 1997. A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2. Nat. Genet. 15, 273-276.
21. Contreras, P.C., Takemori, A.E., 1984. Antagonism of morphine-induced analgesia, tolerance and dependence by alpha-melanocyte-stimulating hormone. J. Pharmacol. Exp. Ther. 229, 21-26.
22. Cool, D.R., Normant, E., Shen, F., Chen, H.C., Pannell, L., Zhang, Y., Loh, Y.P., 1997. Carboxypeptidase E is a regulated secretory pathway sorting receptor: genetic obliteration leads to endocrine disorders in Cpe(fat) mice. Cell 88, 73-83. (Pubitemid 27180332)
23. Cota, D., Proulx, K., Smith, K.A., Kozma, S.C., Thomas, G., Woods, S.C., Seeley, R.J., 2006. Hypothalamic mTOR signaling regulates food intake. Science 312, 927-930. (Pubitemid 43727328)
24. Cowley, M.A., Pronchuk, N., Fan, W., Dinulescu, D.M., Colmers, W.F., Cone, R.D., 1999. Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat. Neuron 24, 155-163. (Pubitemid 29466155)
25. Cowley, M.A., Smart, J.L., Rubinstein, M., Cerdan, M.G., Diano, S., Horvath, T.L., Cone, R.D., Low, M.J., 2001. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411, 480-484. (Pubitemid 32494394)
26. Creemers, J.W., Pritchard, L.E., Gyte, A., Le Rouzic, P., Meulemans, S., Wardlaw, S.L., Zhu, X., Steiner, D.F., Davies, N., Armstrong, D., Lawrence, C.B., Luckman, S.M., Schmitz, C.A., Davies, R.A., Brennand, J.C., White, A., 2006. Agouti-related protein is posttranslationally cleaved by proprotein convertase 1 to generate agouti-related protein (AGRP)83-132: interaction between AGRP83-132 and melanocortin receptors cannot be influenced by syndecan-3. Endocrinology 147, 1621-1631.
27. Creemers, J.W., Lee, Y.S., Oliver, R.L., Bahceci, M., Tuzcu, A., Gokalp, D., Keogh, J., Herber, S., White, A., O'Rahilly, S., Farooqi, I.S., 2008. Mutations in the amino-terminal region of proopiomelanocortin (POMC) in patients with early-onset obesity impair POMC sorting to the regulated secretory pathway. J. Clin. Endocrinol. Metab. 93, 4494-4499.
28. Dubern, B., Lubrano-Berthelier, C., Mencarelli, M., Ersoy, B., Frelut, M.L., Bougle, D., Costes, B., Simon, C., Tounian, P., Vaisse, C., Clement, K., 2008. Mutational analysis of the pro-opiomelanocortin gene in French obese children led to the identification of a novel deleterious heterozygous mutation located in the alpha-melanocyte stimulating hormone domain. Pediatr. Res. 63, 211-216.
29. Elias, C.F., Aschkenasi, C., Lee, C., Kelly, J., Ahima, R.S., Bjorbaek, C., Flier, J.S., Saper, C.B., Elmquist, J.K., 1999. Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 23, 775-786. (Pubitemid 29411566)
30. Elmquist, J.K., Elias, C.F., Saper, C.B., 1999. From lesions to leptin: hypothalamic control of food intake and body weight. Neuron 22, 221-232. (Pubitemid 29109657)
31. Emeson, R.B., Eipper, B.A., 1986. Characterization of pro-ACTH/endorphin-derived peptides in rat hypothalamus. J. Neurosci. 6, 837-849. (Pubitemid 16134922)
32. Farooqi, I.S., Drop, S., Clements, A., Keogh, J.M., Biernacka, J., Lowenbein, S., Challis, B.G., O'Rahilly, S., 2006. Heterozygosity for a POMC-null mutation and increased obesity risk in humans. Diabetes 55, 2549-2553. (Pubitemid 44871155)
33. Fox, D.L., Vella, K.R., Good, D.J., 2007. Energy balance pathways converging on the Nhlh2 transcription factor. Front. Biosci. 12, 3983-3993.
34. Fukuda, M., Jones, J.E., Olson, D., Hill, J., Lee, C.E., Gautron, L., Choi, M., Zigman, J.M., Lowell, B.B., Elmquist, J.K., 2008. Monitoring FoxO1 localization in chemically identified neurons. J. Neurosci. 28, 13640-13648.
35. Furuta, M., Yano, H., Zhou, A., Rouille, Y., Holst, J.J., Carroll, R., Ravazzola, M., Orci, L., Furuta, H., Steiner, D.F., 1997. Defective prohormone processing and altered pancreatic islet morphology in mice lacking active SPC2. Proc. Natl Acad. Sci. USA 94, 6646-6651.
36. Graham, M., Shutter, J.R., Sarmiento, U., Sarosi, I., Stark, K.L., 1997. Overexpression of Agrt leads to obesity in transgenic mice. Nat. Genet. 17, 273-274.
37. Grossman, H.C., Hadjimarkou, M.M., Silva, R.M., Giraudo, S.Q., Bodnar, R.J., 2003. Interrelationships between mu opioid and melanocortin receptors in mediating food intake in rats. Brain Res. 991, 240-244. (Pubitemid 37297953)
38. Guo, L., Munzberg, H., Stuart, R.C., Nillni, E.A., Bjorbaek, C., 2004. N-acetylation of hypothalamic alpha-melanocyte-stimulating hormone and regulation by leptin. Proc. Natl Acad. Sci. USA 101, 11797-11802.
39. Hager, J., Dina, C., Francke, S., Dubois, S., Houari, M., Vatin, V., Vaillant, E., Lorentz, N., Basdevant, A., Clement, K., Guy-Grand, B., Froguel, P., 1998. A genome-wide scan for human obesity genes reveals a major susceptibility locus on chromosome 10. Nat. Genet. 20, 304-308.
40. Hill, J.W., Elias, C.F., Fukuda, M., Williams, K.W., Berglund, E.D., Holland, W.L., Cho, Y.R., Chuang, J.C., Xu, Y., Choi, M., Lauzon, D., Lee, C.E., Coppari, R., Richardson, J.A., Zigman, J.M., Chua, S., Scherer, P.E., Lowell, B.B., Bruning, J.C., Elmquist, J.K., 2010. Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility. Cell Metab. 11, 286-297.
41. Huszar, D., Lynch, C.A., Fairchild-Huntress, V., Dunmore, J.H., Fang, Q., Berkemeier, L.R., Gu, W., Kesterson, R.A., Boston, B.A., Cone, R.D., Smith, F.J., Campfield, L.A., Burn, P., Lee, F., 1997. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131-141. (Pubitemid 27180337)
42. Ibrahim, N., Bosch, M.A., Smart, J.L., Qiu, J., Rubinstein, M., Ronnekleiv, O.K., Low, M.J., Kelly, M.J., 2003. Hypothalamic proopiomelanocortin neurons are glucose responsive and express K(ATP) channels. Endocrinology 144, 1331-1340. (Pubitemid 36428475)
43. Jackson, R.S., Creemers, J.W., Ohagi, S., Raffin-Sanson, M.L., Sanders, L., Montague, C.T., Hutton, J.C., O'Rahilly, S., 1997. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat. Genet. 16, 303-306.
44. Jackson, R.S., Creemers, J.W., Farooqi, I.S., Raffin-Sanson, M.L., Varro, A., Dockray, G.J., Holst, J.J., Brubaker, P.L., Corvol, P., Polonsky, K.S., Ostrega, D., Becker, K.L., Bertagna, X., Hutton, J.C., White, A., Dattani, M.T., Hussain, K., Middleton, S.J., Nicole, T.M., Milla, P.J., Lindley, K.J., O'Rahilly, S., 2003. Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency. J. Clin. Investig. 112, 1550-1560.
45. Jing, E., Nillni, E.A., Sanchez, V.C., Stuart, R.C., Good, D.J., 2004. Deletion of the Nhlh2 transcription factor decreases the levels of the anorexigenic peptides alpha melanocyte-stimulating hormone and thyrotropin-releasing hormone and implicates prohormone convertases I and II in obesity. Endocrinology 145, 1503-1513. (Pubitemid 38402353)
46. Jobst, E.E., Enriori, P.J., Cowley, M.A., 2004. The electrophysiology of feeding circuits. Trends Endocrinol. Metab. TEM 15, 488-499.
47. Koegler, F.H., Grove, K.L., Schiffmacher, A., Smith, M.S., Cameron, J.L., 2001. Central melanocortin receptors mediate changes in food intake in the rhesus macaque. Endocrinology 142, 2586-2592. (Pubitemid 32473114)
48. Korner, J., Chua Jr., S.C., Williams, J.A., Leibel, R.L., Wardlaw, S.L., 1999. Regulation of hypothalamic proopiomelanocortin by leptin in lean and obese rats. Neuroendocrinology 70, 377-383. (Pubitemid 30009026)
49. Krude, H., Biebermann, H., Luck, W., Horn, R., Brabant, G., Gruters, A., 1998. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat. Genet. 19, 155-157.
50. Krude, H., Biebermann, H., Schnabel, D., Tansek, M.Z., Theunissen, P., Mullis, P.E., Gruters, A., 2003. Obesity due to proopiomelanocortin deficiency: three new cases and treatment trials with thyroid hormone and ACTH4-10. J. Clin. Endocrinol. Metab. 88, 4633-4640.
51. Lee, M., Wardlaw, S.L., 2007. The central melanocortin system and the regulation of energy balance. Front. Biosci. 12, 3994-4010.
52. Lee, Y.S., Challis, B.G., Thompson, D.A., Yeo, G.S., Keogh, J.M., Madonna, M.E., Wraight, V., Sims, M., Vatin, V., Meyre, D., Shield, J., Burren, C., Ibrahim, Z., Cheetham, T., Swift, P., Blackwood, A., Hung, C.C., Wareham, N.J., Froguel, P., Millhauser, G.L., O'Rahilly, S., Farooqi, I.S., 2006. A POMC variant implicates beta-melanocyte-stimulating hormone in the control of human energy balance. Cell Metab. 3, 135-140.
53. Lee, M., Kim, A., Chua Jr., S.C., Obici, S., Wardlaw, S.L., 2007. Transgenic MSH overexpression attenuates the metabolic effects of a high-fat diet. Am. J. Physiol. 293, E121-E131.
54. Li, J.Y., Finniss, S., Yang, Y.K., Zeng, Q., Qu, S.Y., Barsh, G., Dickinson, C., Gantz, I., 2000. Agouti-related protein-like immunoreactivity: characterization of release from hypothalamic tissue and presence in serum. Endocrinology 141, 1942-1950. (Pubitemid 32274341)
55. Li, G., Mobbs, C.V., Scarpace, P.J., 2003. Central pro-opiomelanocortin gene delivery results in hypophagia, reduced visceral adiposity, and improved insulin sensitivity in genetically obese Zucker rats. Diabetes 52, 1951-1957. (Pubitemid 36919786)
56. Lloyd, D.J., Bohan, S., Gekakis, N., 2006. Obesity, hyperphagia and increased metabolic efficiency in Pc1 mutant mice. Hum. Mol. Genet. 15, 1884-1893.
57. Low, M.J., Hayward, M.D., Appleyard, S.M., Rubinstein, M., 2003. State-dependent modulation of feeding behavior by proopiomelanocortin-derived beta-endorphin. Ann. NY Acad. Sci. 994, 192-201.
58. McMinn, J.E., Wilkinson, C.W., Havel, P.J., Woods, S.C., Schwartz, M.W., 2000. Effect of intracerebroventricular alpha-MSH on food intake, adiposity, c-Fos induction, and neuropeptide expression. Am. J. Physiol. Regul. Integr. Comp. Physiol. 279, R695-R703.
59. Mizuno, T.M., Kelley, K.A., Pasinetti, G.M., Roberts, J.L., Mobbs, C.V., 2003. Transgenic neuronal expression of proopiomelanocortin attenuates hyperphagic response to fasting and reverses metabolic impairments in leptin-deficient obese mice. Diabetes 52, 2675-2683. (Pubitemid 37339696)
60. Munzberg, H., Huo, L., Nillni, E.A., Hollenberg, A.N., Bjorbaek, C., 2003. Role of signal transducer and activator of transcription 3 in regulation of hypothalamic proopiomelanocortin gene expression by leptin. Endocrinology 144, 2121-2131. (Pubitemid 36543352)
61. Naggert, J.K., Fricker, L.D., Varlamov, O., Nishina, P.M., Rouille, Y., Steiner, D.F., Carroll, R.J., Paigen, B.J., Leiter, E.H., 1995. Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity. Nat. Genet. 10, 135-142.
62. Nicolas, P., Li, C.H., 1985. Beta-endorphin-(1-27) is a naturally occurring antagonist to etorphine-induced analgesia. Proc. Natl Acad. Sci. USA 82, 3178-3181.
63. Ollmann, M.M., Wilson, B.D., Yang, Y.K., Kerns, J.A., Chen, Y., Gantz, I., Barsh, G.S., 1997. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278, 135-138. (Pubitemid 27446294)
64. Olszewski, P.K., Wirth, M.M., Grace, M.K., Levine, A.S., Giraudo, S.Q., 2001. Evidence of interactions between melanocortin and opioid systems in regulation of feeding. NeuroReport 12, 1727-1730. (Pubitemid 32521495)
65. Perello, M., Stuart, R.C., Nillni, E.A., 2007. Differential effects of fasting and leptin on proopiomelanocortin peptides in the arcuate nucleus and in the nucleus of the solitary tarct. Am. J. Physiol. 292, E1348-E1357.
66. Pinto, S., Roseberry, A.G., Liu, H., Diano, S., Shanabrough, M., Cai, X., Friedman, J.M., Horvath, T.L., 2004. Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304, 110-115. (Pubitemid 38451468)
67. Plum, L., Lin, H.V., Dutia, R., Tanaka, J., Aizawa, K.S., Matsumoto, M., Kim, A.J., Cawley, N.X., Paik, J.H., Loh, Y.P., Depinho, R.A., Wardlaw, S.L., Accili, D., 2009. The obesity susceptibility gene Cpe links FoxO1 signaling in hypothalamic pro-opiomelanocortin neurons with regulation of food intake. Nat. Med. 15, 1195-1201.
68. Pritchard, L.E., White, A., 2007. Neuropeptide processing and its impact on melanocortin pathways. Endocrinology 148, 4201-4207. (Pubitemid 47295669)
69. Pritchard, L.E., Oliver, R.L., McLoughlin, J.D., Birtles, S., Lawrence, C.B., Turnbull, A.V., White, A., 2003. Proopiomelanocortin-derived peptides in rat cerebrospinal fluid and hypothalamic extracts: evidence that secretion is regulated with respect to energy balance. Endocrinology 144, 760-766. (Pubitemid 36262843)
70. Rossi, M., Kim, M.S., Morgan, D.G., Small, C.J., Edwards, C.M., Sunter, D., Abusnana, S., Goldstone, A.P., Russell, S.H., Stanley, S.A., Smith, D.M., Yagaloff, K., Ghatei, M.A., Bloom, S.R., 1998. A C-terminal fragment of Agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo. Endocrinology 139, 4428-4431. (Pubitemid 28513735)
71. Rotimi, C.N., Comuzzie, A.G., Lowe, W.L., Luke, A., Blangero, J., Cooper, R.S., 1999. The quantitative trait locus on chromosome 2 for serum leptin levels is confirmed in African-Americans. Diabetes 48, 643-644. (Pubitemid 29106883)
72. Sanchez, V.C., Goldstein, J., Stuart, R.C., Hovanesian, V., Huo, L., Munzberg, H., Friedman, T.C., Bjorbaek, C., Nillni, E.A., 2004. Regulation of hypothalamic prohormone convertases 1 and 2 and effects on processing of prothyrotropin-releasing hormone. J. Clin. Investig. 114, 357-369.
73. Sandman, C.A., Kastin, A.J., 1981. Intraventricular administration of MSH induces hyperalgesia in rats. Peptides 2, 231-233. (Pubitemid 11030849)
74. Savontaus, E., Breen, T.L., Kim, A., Yang, L.M., Chua, S.C.J., Wardlaw, S.L., 2004. Metabolic effects of transgenic melanocyte-stimulating hormone overexpression in lean and obese mice. Endocrinology 145, 3881-3891. (Pubitemid 39037577)
75. Schwartz, M.W., Seeley, R.J., Woods, S.C., Weigle, D.S., Campfield, L.A., Burn, P., Baskin, D.G., 1997. Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes 46, 2119-2123. (Pubitemid 27512108)
76. Shalts, E., Feng, Y.J., Ferin, M., Wardlaw, S.L., 1992. Alpha-melanocyte-stimulating hormone antagonizes the neuroendocrine effects of corticotropin-releasing factor and interleukin-1 alpha in the primate. Endocrinology 131, 132-138.
77. Smart, J.L., Tolle, V., Low, M.J., 2006. Glucocorticoids exacerbate obesity and insulin resistance in neuron-specific proopiomelanocortin-deficient mice. J. Clin. Investig. 116, 495-505.
78. Smith, A.I., Funder, J.W., 1988. Proopiomelanocortin processing in the pituitary, central nervous system, and peripheral tissues. Endocr Rev 9, 159-179.
79. Wallingford, N., Perroud, B., Gao, Q., Coppola, A., Gyengesi, E., Liu, Z.W., Gao, X.B., Diament, A., Haus, K.A., Shariat-Madar, Z., Mahdi, F., Wardlaw, S.L., Schmaier, A.H., Warden, C.H., Diano, S., 2009. Prolylcarboxypeptidase regulates food intake by inactivating alpha-MSH in rodents. J. Clin. Investig. 119, 2291-2303.
80. Wardlaw, S.L., Ferin, M., 1990. Interaction between beta-endorphin and alpha-melanocyte-stimulating hormone in the control of prolactin and luteinizing hormone secretion in the primate. Endocrinology 126, 2035-2040. (Pubitemid 20139751)
81. Wardlaw, S.L., Smeal, M.M., Markowitz, C.E., 1986. Antagonism of beta-endorphin-induced prolactin release by alpha-melanocyte-stimulating hormone and corticotropin-like intermediate lobe peptide. Endocrinology 119, 112-118. (Pubitemid 16100715)
82. Wilkinson, C.W., 2006. Roles of acetylation and other post-translational modifications in melanocortin function and interactions with endorphins. Peptides 27, 453-471. (Pubitemid 43162918)
83. Williams, K.W., Margatho, L.O., Lee, C.E., Choi, M., Lee, S., Scott, M.M., Elias, C.F., Elmquist, J.K., 2010. Segregation of acute leptin and insulin effects in distinct populations of arcuate proopiomelanocortin neurons. J. Neurosci. 30, 2472-2479.
84. Xiao, E., Kim, A.J., Dutia, R., Conwell, I., Ferin, M., Wardlaw, S.L., 2010. Effects of estradiol on cerebrospinal fluid levels of agouti-related protein in ovariectomized rhesus monkeys. Endocrinology 151, 1002-1009.
85. Xu, A.W., Kaelin, C.B., Morton, G.J., Ogimoto, K., Stanhope, K., Graham, J., Baskin, D.G., Havel, P., Schwartz, M.W., Barsh, G.S., 2005a. Effects of hypothalamic neurodegeneration on energy balance. PLoS Biol. 3, e415.
86. Xu, A.W., Kaelin, C.B., Takeda, K., Akira, S., Schwartz, M.W., Barsh, G.S., 2005b. PI3K integrates the action of insulin and leptin on hypothalamic neurons. J. Clin. Investig. 115, 951-958.
87. Yaswen, L., Diehl, N., Brennan, M.B., Hochgeschwender, U., 1999. Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nat. Med. 5, 1066-1070.
88. Zhu, X., Zhou, A., Dey, A., Norrbom, C., Carroll, R., Zhang, C., Laurent, V., Lindberg, I., Ugleholdt, R., Holst, J.J., Steiner, D.F., 2002. Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects. Proc. Natl Acad. Sci. USA 99, 10293-10298.