Hypothalamic bile acid-TGR5 signaling protects from obesity
Hypothalamic bile acid-TGR5 signaling protects from obesity
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DOI：
10.1016/j.cmet.2021.04.009
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发表时间：
2021-07-06
期刊：
影响因子：
29
通讯作者：
Cota, Daniela
中科院分区：
文献类型：
--
作者：
Castellanos-Jankiewicz, Ashley;Guzman-Quevedo, Omar;Cota, Daniela
胆汁酸（BA）通过激活外周组织中的Takeda G蛋白偶联受体5（TGR 5）改善代谢并发挥抗肥胖作用。TGR 5也存在于大脑下丘脑中，但下丘脑BA信号传导是否与体重控制和肥胖病理生理学有关仍不清楚。在这里，我们表明，下丘脑BA含量减少饮食诱导的肥胖小鼠。在这些动物中中枢施用BA或特异性TGR 5激动剂通过激活交感神经系统降低体重和脂肪量，从而促进负能量平衡。相反，下丘脑中基底核TGR 5表达的遗传下调有利于肥胖的发展，并通过钝化交感神经活动来抑制已建立的肥胖。最后，下丘脑TGR 5信号传导是膳食BA补充剂的抗肥胖作用所必需的。总之，这些发现将下丘脑TGR 5信号传导确定为抵消饮食诱导的肥胖的自上而下神经机制的关键介质。
Bile acids (BAs) improve metabolism and exert anti-obesity effects through the activation of the Takeda G protein-coupled receptor 5 (TGR5) in peripheral tissues. TGR5 is also found in the brain hypothalamus, but whether hypothalamic BA signaling is implicated in body weight control and obesity pathophysiology remains unknown. Here we show that hypothalamic BA content is reduced in diet-induced obese mice. Central administration of BAs or a specific TGR5 agonist in these animals decreases body weight and fat mass by activating the sympathetic nervous system, thereby promoting negative energy balance. Conversely, genetic downregulation of hypothalamic TGR5 expression in the mediobasal hypothalamus favors the development of obesity and worsens established obesity by blunting sympathetic activity. Lastly, hypothalamic TGR5 signaling is required for the anti-obesity action of dietary BA supplementation. Together, these findings identify hypothalamic TGR5 signaling as a key mediator of a top-down neural mechanism that counteracts diet induced obesity.