Toronto General Hospital Research Institute, UHN, Toronto, ON M5G1L7, Canada.
Toronto General Hospital Research Institute, UHN, Toronto, ON M5G1L7, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S1A8, Canada.
Cell Metab. 2023 May 2;35(5):875-886.e5. doi: 10.1016/j.cmet.2023.03.014. Epub 2023 Apr 14.
Metformin, the most widely prescribed medication for obesity-associated type 2 diabetes (T2D), lowers plasma glucose levels, food intake, and body weight in rodents and humans, but the mechanistic site(s) of action remain elusive. Metformin increases plasma growth/differentiation factor 15 (GDF15) levels to regulate energy balance, while GDF15 administration activates GDNF family receptor α-like (GFRAL) that is highly expressed in the area postrema (AP) and the nucleus of the solitary tract (NTS) of the hindbrain to lower food intake and body weight. However, the tissue-specific contribution of plasma GDF15 levels after metformin treatment is still under debate. Here, we found that metformin increased plasma GDF15 levels in high-fat (HF) fed male rats through the upregulation of GDF15 synthesis in the kidney. Importantly, the kidney-specific knockdown of GDF15 expression as well as the AP-specific knockdown of GFRAL expression negated the ability of metformin to lower food intake and body weight gain. Taken together, we unveil the kidney as a target of metformin to regulate energy homeostasis through a kidney GDF15-dependent AP axis.
二甲双胍是治疗肥胖相关 2 型糖尿病（T2D）最常用的药物，它可降低啮齿动物和人类的血浆葡萄糖水平、食物摄入量和体重，但作用机制仍不清楚。二甲双胍可增加血浆生长/分化因子 15（GDF15）水平，以调节能量平衡，而 GDF15 的给药可激活在延髓后区（AP）和孤束核（NTS）中高度表达的 GDNF 家族受体 α样（GFRAL），从而降低食物摄入量和体重。然而，关于二甲双胍治疗后血浆 GDF15 水平的组织特异性贡献仍存在争议。在这里，我们发现二甲双胍通过上调肾脏中 GDF15 的合成，增加了高脂肪（HF）喂养雄性大鼠的血浆 GDF15 水平。重要的是，肾脏特异性敲低 GDF15 表达以及 AP 特异性敲低 GFRAL 表达，均可消除二甲双胍降低食物摄入和体重增加的能力。总之，我们揭示了肾脏是二甲双胍通过肾脏 GDF15 依赖的 AP 轴来调节能量平衡的靶点。
