期刊
CELL METABOLISM
卷 13, 期 2, 页码 195-204出版社
CELL PRESS
DOI: 10.1016/j.cmet.2011.01.010
关键词
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资金
- University of Texas Southwestern Medical Center [PL1 DK081182-01, UL1RR024923]
- BNORC [P30 DK46200]
- BADERC [P30 DK057521]
- Sigrid Juselius Foundation
- Academy of Finland
- Finnish Cultural Foundation
- British Heart Foundation [FS/05/057]
- ADA-EASD Transatlantic Fellowship
- BONRC [P30DK046200, K08DK071561, K99DK024719-02]
- TORS-Interdisciplinary Research Training Program [5TL1DK081181, RO1DK075632, R01DK53301, DK071320, RL1DK081185]
- American Diabetes Association
- Smith Family Foundation
- Engineering and Physical Sciences Research Council [EP/E500110/1] Funding Source: researchfish
Melanocortin-4 receptor (MC4R) mutations cause dysregulation of energy balance and hyperinsulinemia. We have used mouse models to study the physiological roles of extrahypothalamic MC4Rs. Re-expression of MC4Rs in cholinergic neurons (ChAT-Cre, loxTB MC4R mice) modestly reduced body weight gain without altering food intake and was sufficient to normalize energy expenditure and attenuate hyperglycemia and hyperinsulinemia. In contrast, restoration of MC4R expression in brain-stem neurons including those in the dorsal motor nucleus of the vagus (Phox2b-Cre, loxTB MC4R mice) was sufficient to attenuate hyperinsulinemia, while the hyperglycemia and energy balance were not normalized. Additionally, hepatic insulin action and insulin-mediated suppression of hepatic glucose production were improved in ChAT-Cre, loxTB MC4R mice. These findings suggest that MC4R5 expressed by cholinergic neurons regulate energy expenditure and hepatic glucose production. Our results also provide further evidence of the dissociation in pathways mediating the effects of melanocortins on energy balance and glucose homeostasis.
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