Gastroenterology：黑色素4受体影响手术治疗糖尿病效果

R-en-Y式胃绕道手术可以非减轻体重依赖性的改善糖代谢，具体机制尚不清楚。黑色素皮质激素-4受体家族（MC4R）可能在此过程中发挥作用。美国德克萨斯州达拉斯德克萨斯大学西南医学部下丘脑医学研究中心的JULIET F. ZECHNER等人进行了相关研究，发现MC4R是介导R-en-Y式胃绕道手术改善糖代谢稳态的主要介质。这一结果发表在2013年3月的Gastroenterology上。

R-en-Y式胃绕道手术可以非减轻体重依赖性的改善糖代谢，具体机制尚不清楚。黑色素皮质激素-4受体家族（MC4R）也可以通过自主神经元发挥非体重减轻依赖性的调节糖代谢稳态的作用，同时也可对R-en-Y式胃绕道手术的体重减轻发挥作用。本研究发现在患者及模型鼠中其均具有非体重依赖性改善糖代谢异常的左右，所以旨在明确R-en-Y式胃绕道手术是否通过MC4Rs发挥作用。

C57BL/6小鼠利用饮食控制构建肥胖小鼠模型，并构建MC4R确实小鼠模型以及在脑干神经元特异性重新表达MC4R的小鼠模型。对于所有小鼠模型进行R-en-Y式胃绕道手术或者假手术。我们同时对进行了R-en-Y式胃绕道手术的可能携带罕见MC4R转录本的患者进行了测序。在脑干自主神经元（包括副交感迷走神经背侧运动神经元）的MC4Rs可非体重依赖性的改善糖代谢平衡。相对而言，在胆碱能节前运动神经元（交感神经及副交感神经）中的MC4Rs介导了R-en-Y式胃绕道手术引起的能量消耗增加及体重下降。R-en-Y式胃绕道手术后能量增加是其引起体重减轻及对抗高脂肪饮食引起的体重上升的主要机制，而这一作用的发挥是MC4Rs依赖性的。R-en-Y式胃绕道手术的MC4R依赖性的作用在Mc4r 单倍体的小鼠中仍然存在。而且不携带该基因的个体以及有罕见MC4R转录本的个体中，其改善早期糖尿病的作用是相似的。然而，携带有I251L这一罕见MC4R转录本的个体R-en-Y式胃绕道手术后体重减轻更为明显，在体外实验中基底活动也增加了。与非携带个体相比解决糖尿病更早而且更不依赖体重减轻。说明MC4Rs与R-en-Y式胃绕道手术发挥的作用相关。

由此可见：在人类及小鼠中，MC4Rs是介导R-en-Y式胃绕道手术发挥作用的自主神经元介质。其发挥的作用包括介导该手术非体重依赖性的改善糖代谢稳态。

Weight-independent effects of roux-en-Y gastric bypass on glucose homeostasis via melanocortin-4 receptors in mice and humans.
BACKGROUND & AIMS
Roux-en-Y gastric bypass (RYGB) improves glucose homeostasis independently of changes in body weight by unknown mechanisms. Melanocortin-4 receptors (MC4R) have weight-independent effects on glucose homeostasis, via autonomic neurons, and also might contribute to weight loss after RYGB. We investigated whether MC4Rs mediate effects of RYGB, such as its weight-independent effects on glucose homeostasis, in mice and humans.
METHODS
We studied C57BL/6 mice with diet-induced obesity, MC4R-deficient mice, and mice that re-express MC4R specifically in autonomic neurons after RYGB or sham surgeries. We also sequenced the MC4R locus in patients undergoing RYGB to investigate diabetes resolution in carriers of rare MC4R variants.
RESULTS
MC4Rs in autonomic brainstem neurons (including the parasympathetic dorsal motor vagus) mediated improved glucose homeostasis independent of changes in body weight. In contrast, MC4Rs in cholinergic preganglionic motor neurons (sympathetic and parasympathetic) mediated RYGB-induced increased energy expenditure and weight loss. Increased energy expenditure after RYGB is the predominant mechanism of weight loss and confers resistance to weight gain from a high-fat diet, the effects of which are MC4R-dependent. MC4R-dependent effects of RYGB still occurred in mice with Mc4r haplosufficiency, and early stage diabetes resolved at a similar rate in patients with rare variants of MC4R and noncarriers. However, carriers of MC4R (I251L), a rare variant associated with increased weight loss after RYGB and increased basal activity in vitro, were more likely to have early and weight-independent resolution of diabetes than noncarriers, indicating a role for MC4Rs in the effects of RYGB.
CONCLUSIONS
MC4Rs in autonomic neurons mediate beneficial effects of RYGB, including weight-independent improved glucose homeostasis, in mice and humans.