Melanocortin 4 Receptors Reciprocally Regulate Sympathetic and Parasympathetic Preganglionic Neurons

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...

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Bibliographic Details
Published in:Cell 2013-01, Vol.152 (3), p.612-619
Main Authors: Sohn, Jong-Woo, Harris, Louise E., Berglund, Eric D., Liu, Tiemin, Vong, Linh, Lowell, Bradford B., Balthasar, Nina, Williams, Kevin W., Elmquist, Joel K.
Format: Article
Language:English
Subjects:
adverse effects
agonists
Animals
autonomic nervous system
Blood Pressure
brain stem
Brain Stem - cytology
Brain Stem - metabolism
Cholinergic Neurons - metabolism
Cyclic AMP - metabolism
Electrophysiological Phenomena
energy
glucose
homeostasis
Humans
hyperinsulinemia
hypertension
insulin
Insulin - metabolism
KATP Channels - metabolism
Male
Mice
mutation
neurons
Neurons - metabolism
obesity
Obesity - metabolism
Obesity - physiopathology
Parasympathetic Nervous System - metabolism
patients
Receptor, Melanocortin, Type 4 - agonists
Receptor, Melanocortin, Type 4 - genetics
Receptor, Melanocortin, Type 4 - metabolism
receptors
spinal cord
Spinal Cord - metabolism
Sympathetic Nervous System - metabolism
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Summary: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. [Display omitted] ► MC4Rs inhibit parasympathetic preganglionic neurons in the brainstem ► MC4Rs activate sympathetic preganglionic neurons in the spinal cord ► MC4Rs expressed by cholinergic neurons regulate insulin levels ► MC4Rs expressed by cholinergic neurons contribute to obesity-induced hypertension. The CNS melanocortin 4 receptor (MC4R) and the autonomic nervous system represent key regulators of metabolism. Sohn et al. demonstrate the reciprocal regulation of sympathetic and parasympathetic tones by MC4Rs and its contribution to insulin regulation and obesity-induced hypertension.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2012.12.022