Objective

Roux-en-Y gastric bypass surgery (RYGB) can achieve long-term remission of type 2 diabetes. However, the specific molecular mechanism through which this occurs has remained largely elusive. Bile acid signaling through the nuclear hormone receptor farnesoid X receptor (FXR) exerts beneficial effects after sleeve gastrectomy (VSG), which has similar effects to RYGB. Therefore, we investigated whether FXR signaling is necessary to mediate glycemic control after RYGB.

Methods

RYGB or sham surgery was performed in high-fat diet-induced obese FXR−/− (knockout) and FXR+/+ (wild type) littermates. Sham-operated mice were fed ad libitum (S-AL) or by weight matching (S-WM) to RYGB mice via caloric restriction. Body weight, body composition, food intake, energy expenditure, glucose tolerance tests, insulin tolerance tests, and homeostatic model assessment of insulin resistance were performed.

Results

RYGB surgery decreases body weight and fat mass in WT and FXR-KO mice. RYGB surgery has similar effects on food intake and energy expenditure independent of genotype. In addition, body weight-independent improvements in glucose control were attenuated in FXR −/− relative to FXR +/+ mice after RYGB. Furthermore, pharmacologic blockade of the glucagon-like peptide-1 receptor (GLP-1R) blunts the glucoregulatory effects of RYGB in FXR +/+ but not in FXR −/− mice at 4 weeks after surgery.

Conclusions

These results suggest that FXR signaling is not required for the weight loss up to 16 weeks after RYGB. Although most of the improvements in glucose homeostasis are secondary to RYGB-induced weight loss in wild type mice, FXR signaling contributes to glycemic control after RYGB in a body weight-independent manner, which might be mediated by an FXR-GLP-1 axis during the early postoperative period.

中文翻译：

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在饮食诱发的肥胖小鼠中进行Roux-en-Y胃搭桥手术后，法尼类X受体有助于血糖控制中体重无关的改善。

目的

Roux-en-Y胃搭桥手术（RYGB）可以使2型糖尿病长期缓解。但是，发生这种情况的具体分子机制仍然很难捉摸。胆囊胃切除术（VSG）后，通过核激素受体法呢类X受体（FXR）发出的胆汁酸信号发挥有益作用，其作用与RYGB类似。因此，我们调查了RYGB后是否需要FXR信号来介导血糖控制。

方法

在高脂饮食诱发的肥胖FXR-/-（敲除）和FXR + / +（野生型）同窝仔中进行RYGB或假手术。通过热量限制，对假手术小鼠自由饲喂（S-AL）或通过体重匹配（S-WM）饲喂RYGB小鼠。进行了体重，身体组成，食物摄入，能量消耗，葡萄糖耐量测试，胰岛素耐量测试以及胰岛素抵抗的稳态模型评估。

结果

RYGB手术可减轻WT和FXR-KO小鼠的体重和脂肪量。RYGB手术对饮食和能量消耗的影响与基因型无关。另外，相对于RYR后的FXR + / +小鼠，FXR-/-的血糖控制中与体重无关的改善减弱。此外，在术后4周，对胰高血糖素样肽1受体（GLP-1R）的药理作用会减弱RYGB对FXR + / +的糖调节作用，而对FXR-/-小鼠则无作用。

结论

这些结果表明，RYGB后长达16周的体重减轻不需要FXR信号。尽管葡萄糖稳态的大部分改善是在野生型小鼠中RYGB引起的体重减轻的继发性，但FXR信号以体重独立的方式有助于RYGB术后的血糖控制，这可能是由FXR-GLP-1轴介导的。术后早期。