Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Cell Metab. 2011 Feb 2;13(2):195-204. doi: 10.1016/j.cmet.2011.01.010.
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 brainstem 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 MC4Rs 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.
黑皮质素-4 受体（MC4R）突变导致能量平衡失调和高胰岛素血症。我们使用小鼠模型来研究下丘脑外 MC4R 的生理作用。MC4R 在胆碱能神经元中的重新表达（ChAT-Cre，loxTB MC4R 小鼠）适度减轻了体重增加，而不改变食物摄入，足以使能量消耗正常化，并减轻高血糖和高胰岛素血症。相比之下，恢复包括迷走神经背核神经元在内的脑干神经元中的 MC4R 表达（Phox2b-Cre，loxTB MC4R 小鼠）足以减轻高胰岛素血症，而高血糖和能量平衡未恢复正常。此外，ChAT-Cre，loxTB MC4R 小鼠的肝胰岛素作用和胰岛素介导的肝葡萄糖生成抑制得到改善。这些发现表明，胆碱能神经元表达的 MC4R 调节能量消耗和肝葡萄糖生成。我们的结果还进一步证明了调节黑皮质素对能量平衡和葡萄糖稳态影响的途径的分离。
