Cell Metab：操纵大脑中特定转录因子成功防止小鼠肥胖

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德州大学西南医学中心研究人员发现了大脑特定区域中的一种转录因子在调节新陈代谢过程中起关键作用。

这项研究可能会导致开发出新的疗法来治疗肥胖和糖尿病，因为所涉及的转录因子：X盒结合蛋白 (Xbp1s)影响身体对胰岛素和瘦素信号的敏感度。胰岛素和瘦素是人体调节食物摄入量和糖处理的关键激素。

这项研究确定了连接大脑和外周内分泌组织之间的关键分子机制，研究人员发现，基因Xbp1s过度表达的小鼠被喂食高脂肪饮食后，小鼠不会患上肥胖和糖尿病，平均而言，这些小鼠比喂以同样食物的老鼠要瘦小30％。

该基因位于大脑下丘脑区域的阿黑皮素原（pro-opiomelanocortin，Pomc）神经元中，升高Pomc神经元的Xbp1s水平能模仿一个“喂”信号，提高小鼠体重，降低血糖水平，并且提高肝脏中胰岛素敏感性。

Williams 博士说，会对参与相同代谢途径的其他转录因子进行研究，以了解其他转录因子是否具有类似的效果。

doi:10.1016/j.cmet.2014.06.002
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Xbp1s in Pomc Neurons Connects ER Stress with Energy Balance and Glucose Homeostasis

Kevin W. Williams, Tiemin Liu, Xingxing Kong, Makoto Fukuda, Yingfeng Deng, Eric D. Berglund, Zhuo Deng, Yong Gao, Tianya Liu, Jong-Woo Sohn, Lin Jia, Teppei Fujikawa, Daisuke Kohno, Michael M. Scott, Syann Lee, Charlotte E. Lee, Kai Sun, Yongsheng Chang, Philipp E. Scherer, Joel K. Elmquist.

The molecular mechanisms underlying neuronal leptin and insulin resistance in obesity and diabetes remain unclear. Here we show that induction of the unfolded protein response transcription factor spliced X-box binding protein 1 (Xbp1s) in pro-opiomelanocortin (Pomc) neurons alone is sufficient to protect against diet-induced obesity as well as improve leptin and insulin sensitivity, even in the presence of strong activators of ER stress. We also demonstrate that constitutive expression of Xbp1s in Pomc neurons contributes to improved hepatic insulin sensitivity and suppression of endogenous glucose production. Notably, elevated Xbp1s levels in Pomc neurons also resulted in activation of the Xbp1s axis in the liver via a cell-nonautonomous mechanism. Together our results identify critical molecular mechanisms linking ER stress in arcuate Pomc neurons to acute leptin and insulin resistance as well as liver metabolism in diet-induced obesity and diabetes.