title: Melanocortin 4 receptors reciprocally regulate sympathetic and parasympathetic preganglionic neurons.
abstract: Melanocortin 4 receptors (MC4Rs) in the central nervous system are key regulators of energy and glucose homeostasis. Notably, obese patients with MC4R mutations are hyperinsulinemic and resistant to obesity-induced hypertension. Although these effects are probably dependent upon the activity of the autonomic nervous system, the cellular effects of MC4Rs on parasympathetic and sympathetic neurons remain undefined. Here, we show that MC4R agonists inhibit parasympathetic preganglionic neurons in the brainstem. In contrast, MC4R agonists activate sympathetic preganglionic neurons in the spinal cord. Deletion of MC4Rs in cholinergic neurons resulted in elevated levels of insulin. Furthermore, re-expression of MC4Rs specifically in cholinergic neurons (including sympathetic preganglionic neurons) restores obesity-associated hypertension in MC4R null mice. These findings provide a cellular correlate of the autonomic side effects associated with MC4R agonists and demonstrate a role for MC4Rs expressed in cholinergic neurons in the regulation of insulin levels and in the development of obesity-induced hypertension.
authors: Department of Internal Medicine, Division of Hypothalamic Research, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
authors: Jong-Woo
authors: JW
authors: Sohn
authors: Louise E
authors: LE
authors: Harris
authors: Eric D
authors: ED
authors: Berglund
authors: Tiemin
authors: T
authors: Liu
authors: Linh
authors: L
authors: Vong
authors: Bradford B
authors: BB
authors: Lowell
authors: Nina
authors: N
authors: Balthasar
authors: Kevin W
authors: KW
authors: Williams
authors: Joel K
authors: JK
authors: Elmquist
mesh_terms: D000818:Animals; D001794:Blood Pressure; D001933:Brain Stem / Q000166:cytology / Q000378:metabolism*; D059329:Cholinergic Neurons / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D055724:Electrophysiological Phenomena; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D054086:KATP Channels / Q000378:metabolism; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology; D010275:Parasympathetic Nervous System / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000378:metabolism
chemical_list: D007328:Insulin; D054086:KATP Channels; D044105:Receptor, Melanocortin, Type 4; D000242:Cyclic AMP
references: Am J Physiol Gastrointest Liver Physiol. 2007 Jun;292(6):G1474-82
references: 17322063
references: Endocrinology. 2000 Sep;141(9):3072-9
references: 10965876
references: J Neurosci. 2003 May 15;23(10):4173-81
references: 12764105
references: Cell. 2005 Nov 4;123(3):493-505
references: 16269339
references: Endocrinology. 2007 Apr;148(4):1868-81
references: 17194747
references: Nat Genet. 1998 Oct;20(2):113-4
references: 9771699
references: Physiol Rev. 2010 Jul;90(3):799-829
references: 20664073
references: Cell Metab. 2011 Feb 2;13(2):195-204
references: 21284986
references: J Physiol. 2007 Jan 15;578(Pt 2):425-38
references: 17068101
references: J Neurosci. 2008 Nov 19;28(47):12445-52
references: 19020037
references: Nature. 2011 Dec 07;481(7379):71-5
references: 22158102
references: Circ Res. 2004 May 28;94(10):1359-66
references: 15087422
references: Mol Endocrinol. 1994 Oct;8(10):1298-308
references: 7854347
references: J Clin Invest. 2001 Oct;108(7):1079-85
references: 11581309
references: Nat Neurosci. 2005 May;8(5):571-8
references: 15856065
references: N Engl J Med. 2003 Mar 20;348(12):1085-95
references: 12646665
references: J Neurosci. 2004 Mar 24;24(12):2905-13
references: 15044529
references: J Neurosci. 2003 Aug 6;23(18):7143-54
references: 12904474
references: Nature. 1997 Jan 9;385(6612):165-8
references: 8990120
references: J Neurosci. 2008 May 7;28(19):4957-66
references: 18463249
references: Cell. 1997 Jan 10;88(1):131-41
references: 9019399
references: Hypertension. 2005 Aug;46(2):326-32
references: 16027245
references: J Clin Invest. 2008 May;118(5):1796-805
references: 18382766
references: J Hypertens. 2006 Nov;24(11):2239-46
references: 17053546
references: J Physiol. 2006 Jun 1;573(Pt 2):395-412
references: 16581866
references: Nat Genet. 1998 Oct;20(2):111-2
references: 9771698
references: J Neurosci. 2004 Sep 15;24(37):8141-52
references: 15371515
references: N Engl J Med. 2009 Jan 1;360(1):44-52
references: 19092146
references: Hypertension. 2004 Feb;43(2):370-5
references: 14707160