期刊
CELL
卷 152, 期 3, 页码 612-619出版社
CELL PRESS
DOI: 10.1016/j.cell.2012.12.022
关键词
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资金
- American Diabetes Association [07-11-MN-16]
- American Heart Association [12POST8860007]
- British Heart Foundation [FS/06/057]
- Lister Institute for Preventive Medicine
- National Institutes of Health [F32 DK092083, K01 DK087780, P01 DK088761, RL1 DK081185, R37 DK053301, F32 DK078478, R01 DK075632, P30 DK046200, P30 DK057521]
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.
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