GDF15 regulates energy balance and glucose homeostasis in rodents by activating its receptor GFRAL expressed in the area postrema of the brain. However, whether GDF15-GFRAL signaling in the area postrema regulates glucose tolerance independent of changes in food intake and weight and contributes to the glucose-lowering effect of metformin remain unknown. Herein, we report that direct acute GDF15 infusion into the area postrema of high fat fed rats increased intravenous glucose tolerance and insulin sensitivity to lower hepatic glucose production independent of changes in food intake, weight, and plasma insulin levels under conscious, unrestrained, and non-stressed conditions. In parallel, metformin infusion concurrently increased plasma GDF15 levels and glucose tolerance. Finally, a knockdown of GFRAL expression in the area postrema not only negated administration of GDF15 but also metformin to increase glucose tolerance independent of changes in food intake, weight, and plasma insulin levels. In summary, activation of GFRAL in the area postrema contributes to glucose regulation of GDF15 and metformin in vivo.

中文翻译：

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后区 GFRAL 的急性激活有助于独立于体重的葡萄糖调节。

GDF15 通过激活其在大脑后部区域表达的受体 GFRAL 来调节啮齿类动物的能量平衡和葡萄糖稳态。然而，后区的 GDF15-GFRAL 信号传导是否能够独立于食物摄入和体重的变化来调节葡萄糖耐量，并有助于二甲双胍的降血糖作用，目前仍不清楚。在此，我们报告，直接将 GDF15 急性输注到高脂肪喂养的大鼠的尾部，可增加静脉内葡萄糖耐量和胰岛素敏感性，从而降低肝葡萄糖的产生，而与在有意识、无限制和无意识的情况下食物摄入量、体重和血浆胰岛素水平的变化无关。 - 压力条件。与此同时，二甲双胍输注同时增加了血浆 GDF15 水平和葡萄糖耐量。最后，后区 GFRAL 表达的敲低不仅使 GDF15 无效，而且使二甲双胍无法增加葡萄糖耐量，而与食物摄入量、体重和血浆胰岛素水平的变化无关。总之，后区 GFRAL 的激活有助于体内 GDF15 和二甲双胍的葡萄糖调节。