Nature2014-06-18 2:50 PM

减肥手术的工作原理 FXR is a molecular target for the effects of vertical sleeve gastrectomy


侵入性手术(创伤手术)作为控制肥胖和相关疾病的方法的使用和误用存在很大争议。不管它有什么好处,相关成本和风险都意味着在很多情况下这种方法是不合适的。这项研究向以下观点提出了挑战:这种手术纯粹通过使身体难以摄取或吸收热量来产生减肥效果,同时也提出这样一个可能性:也许有可能研究出能够达到同样目的而又不需要动手术的治疗方法来。“垂直袖状胃切除手术”(VSG)(在这种手术中,大约80%的胃被切除,形成一个与食管和十二指肠相接触的胃“袖”)已知能诱导体重降低和脂肪减少,改善人类和啮齿类的葡萄糖耐受性。在这项研究中,Randy Seeley及同事发现,VSG对小鼠的疗效不是来自较小的胃所产生的机械限制作用,而是来自循环胆汁酸水平由于胃变小的增加和肠道微生物群落的变化。而且,在没有核胆汁酸受体FXR的情况下,VSG降低体重和改善葡萄糖耐受性的能力被大大削弱。


Bariatric surgical procedures, such as vertical sleeve gastrectomy (VSG), are at present the most effective therapy for the treatment of obesity, and are associated with considerable improvements in co-morbidities, including type-2 diabetes mellitus. The underlying molecular mechanisms contributing to these benefits remain largely undetermined, despite offering the potential to reveal new targets for therapeutic intervention. Substantial changes in circulating total bile acids are known to occur after VSG. Moreover, bile acids are known to regulate metabolism by binding to the nuclear receptor FXR (farsenoid-X receptor, also known as NR1H4). We therefore examined the results of VSG surgery applied to mice with diet-induced obesity and targeted genetic disruption of FXR. Here we demonstrate that the therapeutic value of VSG does not result from mechanical restriction imposed by a smaller stomach. Rather, VSG is associated with increased circulating bile acids, and associated changes to gut microbial communities. Moreover, in the absence of FXR, the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced. These results point to bile acids and FXR signalling as an important molecular underpinning for the beneficial effects of this weight-loss surgery.






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