Melanocortin 4 receptors reciprocally regulate sympathetic and parasympathetic preganglionic neurons

Jong Woo Sohn, Louise E. Harris, Eric D. Berglund, Tiemin Liu, Linh Vong, Bradford B. Lowell, Nina Balthasar, Kevin W. Williams, Joel K. Elmquist

Research output: Contribution to journalArticle

115 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)612-619
Number of pages8
JournalCell
Volume152
Issue number3
DOIs
StatePublished - Jan 31 2013

Fingerprint

Receptor, Melanocortin, Type 4
Neurons
Cholinergic Neurons
Cholinergic Agents
Obesity
Hypertension
Neurology
Autonomic Agents
Insulin
Autonomic Nervous System
Brain Stem
Spinal Cord
Homeostasis
Central Nervous System

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Melanocortin 4 receptors reciprocally regulate sympathetic and parasympathetic preganglionic neurons. / Sohn, Jong Woo; Harris, Louise E.; Berglund, Eric D.; Liu, Tiemin; Vong, Linh; Lowell, Bradford B.; Balthasar, Nina; Williams, Kevin W.; Elmquist, Joel K.

In: Cell, Vol. 152, No. 3, 31.01.2013, p. 612-619.

Research output: Contribution to journalArticle

Sohn, Jong Woo ; Harris, Louise E. ; Berglund, Eric D. ; Liu, Tiemin ; Vong, Linh ; Lowell, Bradford B. ; Balthasar, Nina ; Williams, Kevin W. ; Elmquist, Joel K. / Melanocortin 4 receptors reciprocally regulate sympathetic and parasympathetic preganglionic neurons. In: Cell. 2013 ; Vol. 152, No. 3. pp. 612-619.
@article{2df8c8c2769b42f08f1a5149d5138603,
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.",
author = "Sohn, {Jong Woo} and Harris, {Louise E.} and Berglund, {Eric D.} and Tiemin Liu and Linh Vong and Lowell, {Bradford B.} and Nina Balthasar and Williams, {Kevin W.} and Elmquist, {Joel K.}",
year = "2013",
month = "1",
day = "31",
doi = "10.1016/j.cell.2012.12.022",
language = "English (US)",
volume = "152",
pages = "612--619",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "3",

}

TY - JOUR

T1 - Melanocortin 4 receptors reciprocally regulate sympathetic and parasympathetic preganglionic neurons

AU - Sohn, Jong Woo

AU - Harris, Louise E.

AU - Berglund, Eric D.

AU - Liu, Tiemin

AU - Vong, Linh

AU - Lowell, Bradford B.

AU - Balthasar, Nina

AU - Williams, Kevin W.

AU - Elmquist, Joel K.

PY - 2013/1/31

Y1 - 2013/1/31

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84873301711&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84873301711&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2012.12.022

DO - 10.1016/j.cell.2012.12.022

M3 - Article

VL - 152

SP - 612

EP - 619

JO - Cell

JF - Cell

SN - 0092-8674

IS - 3

ER -