title: Molecular and cellular regulation of hypothalamic melanocortin neurons controlling food intake and energy metabolism.
abstract: The brain receives and integrates environmental and metabolic information, transforms these signals into adequate neuronal circuit activities, and generates physiological behaviors to promote energy homeostasis. The responsible neuronal circuitries show lifetime plasticity and guaranty metabolic health and survival. However, this highly evolved organization has become challenged nowadays by chronic overload with nutrients and reduced physical activity, which results in an ever-increasing number of obese individuals worldwide. Research within the last two decades has aimed to decipher the responsible molecular and cellular mechanisms for regulation of the hypothalamic melanocortin neurons, which have a key role in the control of food intake and energy metabolism. This review maps the central connections of the melanocortin system and highlights its global position and divergent character in physiological and pathological metabolic events. Moreover, recently uncovered molecular and cellular processes in hypothalamic neurons and glial cells that drive plastic morphological and physiological changes in these cells, and account for regulation of food intake and energy metabolism, are brought into focus. Finally, potential functional interactions between metabolic disorders and psychiatric diseases are discussed.
authors.affiliation: 1] Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA [2] Institute of Anatomy, University of Leipzig, Leipzig, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Koch
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: T L
authors.initials: TL
authors.lastname: Horvath
mesh_terms: D054369:Agouti-Related Protein / Q000502:physiology; D000818:Animals; D004435:Eating / Q000502:physiology*; D004734:Energy Metabolism / Q000502:physiology*; D006801:Humans; D007031:Hypothalamus / Q000502:physiology* / Q000503:physiopathology; D053486:Melanocortins / Q000502:physiology*; D001523:Mental Disorders / Q000503:physiopathology; D008959:Models, Neurological; D009457:Neuroglia / Q000502:physiology; D009474:Neurons / Q000502:physiology; D009478:Neuropeptide Y / Q000502:physiology; D015388:Organelles / Q000502:physiology; D011333:Pro-Opiomelanocortin / Q000502:physiology*
chemical_list: D054369:Agouti-Related Protein; D053486:Melanocortins; D009478:Neuropeptide Y; D011333:Pro-Opiomelanocortin
references.citation: Proc Natl Acad Sci U S A. 2012 Oct 16;109 Suppl 2:17149-53
references.pmid: 23045650
references.citation: Am J Anat. 1977 Sep;150(1):201-5
references.pmid: 337790
references.citation: Brain. 2009 Apr;132(Pt 4):889-902
references.pmid: 19293246
references.citation: Cell Metab. 2013 Apr 2;17(4):467-8
references.pmid: 23562070
references.citation: Science. 2004 Oct 15;306(5695):457-61
references.pmid: 15486293
references.citation: Mol Metab. 2012 Aug 09;1(1-2):95-100
references.pmid: 24024123
references.citation: Pharmacol Biochem Behav. 2007 May;87(1):104-14
references.pmid: 17490740
references.citation: J Neurosci Res. 2009 Sep;87(12):2718-27
references.pmid: 19382238
references.citation: Nat Neurosci. 2012 Jun 24;15(8):1108-10
references.pmid: 22729177
references.citation: Nat Neurosci. 2012 Oct;15(10):1330-5
references.pmid: 23007187
references.citation: J Diabetes Complications. 2005 Mar-Apr;19(2):113-22
references.pmid: 15745842
references.citation: Trends Neurosci. 2013 Feb;36(2):91-100
references.pmid: 23332797
references.citation: Cell Metab. 2009 Jan 7;9(1):35-51
references.pmid: 19117545
references.citation: J Chem Neuroanat. 2008 Oct;36(2):107-21
references.pmid: 18602987
references.citation: Endocrinology. 2007 Nov;148(11):5414-23
references.pmid: 17690165
references.citation: Diabetes. 2013 Aug;62(8):2629-34
references.pmid: 23881189
references.citation: Neuron. 2003 Feb 20;37(4):649-61
references.pmid: 12597862
references.citation: Nat Med. 2011 Aug 28;17(9):1121-7
references.pmid: 21873987
references.citation: Nature. 2008 Aug 14;454(7206):846-51
references.pmid: 18668043
references.citation: Cell. 2005 Nov 4;123(3):493-505
references.pmid: 16269339
references.citation: Cell Metab. 2013 Sep 3;18(3):309-11
references.pmid: 24011068
references.citation: Brain Behav Immun. 2010 Mar;24(3):358-65
references.pmid: 19922787
references.citation: Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14875-80
references.pmid: 20679202
references.citation: Acta Psychiatr Scand. 2008 Jul;118(1):4-18
references.pmid: 18498432
references.citation: Cell. 2009 Jun 26;137(7):1225-34
references.pmid: 19563755
references.citation: Mol Endocrinol. 1994 Oct;8(10):1298-308
references.pmid: 7854347
references.citation: JAMA. 2002 Jan 16;287(3):356-9
references.pmid: 11790215
references.citation: Physiol Rev. 2009 Jul;89(3):1025-78
references.pmid: 19584320
references.citation: J Clin Invest. 2012 Nov;122(11):3900-13
references.pmid: 23064363
references.citation: J Clin Invest. 2012 Jan;122(1):153-62
references.pmid: 22201683
references.citation: Cell Metab. 2013 Oct 1;18(4):588-95
references.pmid: 24093681
references.citation: Nat Neurosci. 2008 Sep;11(9):998-1000
references.pmid: 19160495
references.citation: Cell Metab. 2013 Apr 2;17(4):607-17
references.pmid: 23562080
references.citation: Trends Neurosci. 2013 Feb;36(2):65-73
references.pmid: 23318157
references.citation: Nature. 1996 May 30;381(6581):415-21
references.pmid: 8632796
references.citation: Nat Neurosci. 2011 Mar;14(3):351-5
references.pmid: 21209617
references.citation: Nat Rev Drug Discov. 2012 Sep;11(9):675-91
references.pmid: 22858652
references.citation: J Neuroendocrinol. 2011 Apr;23(4):365-70
references.pmid: 21314736
references.citation: Cell. 2011 Sep 16;146(6):992-1003
references.pmid: 21925320
references.citation: Physiol Rev. 2011 Apr;91(2):389-411
references.pmid: 21527729
references.citation: J Neurosci. 2013 Feb 20;33(8):3624-32
references.pmid: 23426689
references.citation: Cell Metab. 2007 Jun;5(6):438-49
references.pmid: 17550779
references.citation: Nature. 2004 Apr 1;428(6982):569-74
references.pmid: 15058305
references.citation: Nurs Stand. 2008 Aug 6-12;22(48):43-8
references.pmid: 18727355
references.citation: Trends Endocrinol Metab. 2009 Mar;20(2):78-87
references.pmid: 19084428
references.citation: Nat Genet. 1998 Oct;20(2):113-4
references.pmid: 9771699
references.citation: Nat Neurosci. 2012 Oct;15(10):1336-42
references.pmid: 23007188
references.citation: Nature. 2007 Sep 13;449(7159):228-32
references.pmid: 17728716
references.citation: Nature. 1997 Jan 9;385(6612):165-8
references.pmid: 8990120
references.citation: Cell Metab. 2010 Apr 7;11(4):286-97
references.pmid: 20374961
references.citation: Nat Rev Neurosci. 2004 Aug;5(8):662-7
references.pmid: 15263896
references.citation: Nat Neurosci. 2012 Oct;15(10):1350-5
references.pmid: 23007190
references.citation: Physiol Behav. 2009 Aug 4;98(1-2):223-8
references.pmid: 19481557
references.citation: Diabetes Care. 2007 Apr;30(4):872-7
references.pmid: 17392548
references.citation: JAMA. 2005 Aug 3;294(5):621-3
references.pmid: 16077059
references.citation: Aging (Albany NY). 2013 May;5(5):332-4
references.pmid: 23667132
references.citation: Cell. 1997 Jan 10;88(1):131-41
references.pmid: 9019399
references.citation: F1000 Biol Rep. 2012;4:14
references.pmid: 22802875
references.citation: Cell Metab. 2012 Dec 5;16(6):706-22
references.pmid: 23168220
references.citation: Brain Res. 1986 Feb 26;366(1-2):131-6
references.pmid: 3697673
references.citation: Nat Med. 2007 Jan;13(1):89-94
references.pmid: 17195839
references.citation: Nat Rev Neurosci. 2007 May;8(5):355-67
references.pmid: 17453016
references.citation: Cell. 2009 Jun 26;137(7):1177-9
references.pmid: 19563747
references.citation: J Neuroendocrinol. 2008 Jul;20(7):942-51
references.pmid: 18445126
references.citation: Science. 2004 Apr 2;304(5667):110-5
references.pmid: 15064421
references.citation: Mol Cell Biol. 2002 Jul;22(14):5027-35
references.pmid: 12077332
references.citation: Nat Med. 2004 Jul;10(7):739-43
references.pmid: 15208705
references.citation: Psychosom Med. 2007 May;69(4):297-9
references.pmid: 17517972
references.citation: Ann Clin Psychiatry. 2011 May;23(2):131-40
references.pmid: 21547274
references.citation: Science. 2013 Jul 19;341(6143):275-8
references.pmid: 23869016
references.citation: Cell Metab. 2011 Feb 2;13(2):195-204
references.pmid: 21284986
references.citation: Diabetes. 1998 Feb;47(2):294-7
references.pmid: 9519731
references.citation: Cell. 2013 Jan 31;152(3):612-9
references.pmid: 23374353
references.citation: Nat Rev Neurosci. 2013 Jan;14(1):24-37
references.pmid: 23232606
references.citation: Cell Metab. 2012 Sep 5;16(3):296-309
references.pmid: 22902836
references.citation: Endocrinol Metab Clin North Am. 2013 Mar;42(1):57-66
references.pmid: 23391239
references.citation: Cell. 2014 Jan 30;156(3):495-509
references.pmid: 24462248
references.citation: Curr Opin Clin Nutr Metab Care. 2002 Sep;5(5):561-8
references.pmid: 12172481
references.citation: Cell. 2013 Sep 26;155(1):172-87
references.pmid: 24074867
references.citation: Nat Med. 1999 Sep;5(9):1066-70
references.pmid: 10470087
references.citation: J Clin Endocrinol Metab. 2003 Apr;88(4):1748-52
references.pmid: 12679468
references.citation: Cell. 2013 Sep 26;155(1):188-99
references.pmid: 24074868
references.citation: Nature. 2012 Aug 9;488(7410):172-7
references.pmid: 22801496
references.citation: JAMA. 2005 Aug 3;294(5):557-62
references.pmid: 16077049
references.citation: Nat Neurosci. 2012 Apr 25;15(5):651-3
references.pmid: 22534576
references.citation: Brain Res. 1997 May 9;756(1-2):283-6
references.pmid: 9187344
references.citation: Nat Neurosci. 1998 Aug;1(4):271-2
references.pmid: 10195157
references.citation: Endocrinology. 2011 Jul;152(7):2552-7
references.pmid: 21521751
references.citation: Trends Mol Med. 2012 Jan;18(1):52-8
references.pmid: 21917523
references.citation: J Clin Invest. 2011 Apr;121(4):1424-8
references.pmid: 21364278
references.citation: Science. 2013 Jul 19;341(6143):278-81
references.pmid: 23869017
references.citation: Nature. 2012 Mar 14;483(7391):594-7
references.pmid: 22419158
references.citation: Am J Psychiatry. 2001 Oct;158(10):1719-22
references.pmid: 11579009
references.citation: Front Physiol. 2013 Sep 26;4:268
references.pmid: 24133452
references.citation: Nature. 2013 Nov 7;503(7474):111-4
references.pmid: 24121436
references.citation: Curr Opin Drug Discov Devel. 2009 Sep;12(5):597-606
references.pmid: 19736619
references.citation: J Biol Chem. 1993 Jul 15;268(20):15174-9
references.pmid: 8392067
references.citation: Eur J Pharmacol. 2013 Oct 15;718(1-3):376-82
references.pmid: 23973646
references.citation: Psychoneuroendocrinology. 2011 Oct;36(9):1396-406
references.pmid: 21531082
references.citation: Nat Neurosci. 2012 Jul 26;15(8):1060-1
references.pmid: 22837033
references.citation: Nature. 2001 May 24;411(6836):480-4
references.pmid: 11373681
references.citation: Ann N Y Acad Sci. 2011 Dec;1243:1-14
references.pmid: 22211889
references.citation: Nat Neurosci. 2012 Mar 25;15(5):700-2
references.pmid: 22446882
references.citation: JAMA. 2005 Dec 21;294(23):2968; discussion 2968-9
references.pmid: 16414938
references.citation: J Affect Disord. 2006 Jan;90(1):21-7
references.pmid: 16324751
references.citation: Prog Brain Res. 2012;198:47-64
references.pmid: 22813969
references.citation: Endocrinology. 2010 Apr;151(4):1622-32
references.pmid: 20176722
references.citation: PLoS One. 2012;7(3):e33548
references.pmid: 22438946
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2687-92
references.pmid: 18272480
references.citation: J Clin Invest. 2007 Nov;117(11):3475-88
references.pmid: 17885689
references.citation: Cell Metab. 2007 Mar;5(3):181-94
references.pmid: 17339026