A positive feedback loop between AMPK and GDF15 promotes metformin antidiabetic effects

二甲双胍 安普克 AMP活化蛋白激酶 药理学 GDF15型 医学 内科学 能量稳态 内分泌学 糖尿病 受体 生物 细胞生物学 蛋白激酶A 激酶
作者
David Aguilar-Recarte,Emma Barroso,Meijian Zhang,Patricia Rada,Javier Pizarro‐Delgado,Lucía Peña,Xavier Palomer,Ángela M. Valverde,Walter Wahli,Manuel Vázquez‐Carrera
出处
期刊:Pharmacological Research [Elsevier]
卷期号:187: 106578-106578 被引量:13
标识
DOI:10.1016/j.phrs.2022.106578
摘要

Metformin, the most prescribed drug for the treatment of type 2 diabetes mellitus, has been recently reported to promote weight loss by upregulating the anorectic cytokine growth differentiation factor 15 (GDF15). Since the antidiabetic effects of metformin are mostly mediated by the activation of AMPK, a key metabolic sensor in energy homeostasis, we examined whether the activation of this kinase by metformin was dependent on GDF15.Cultured hepatocytes and myotubes, and wild-type and Gdf15-/- mice were utilized in a series of studies to investigate the involvement of GDF15 in the activation of AMPK by metformin.A low dose of metformin increased GDF15 levels without significantly reducing body weight or food intake, but it ameliorated glucose intolerance and activated AMPK in the liver and skeletal muscle of wild-type mice but not Gdf15-/- mice fed a high-fat diet. Cultured hepatocytes and myotubes treated with metformin showed AMPK-mediated increases in GDF15 levels independently of its central receptor GFRAL, while Gdf15 knockdown blunted the effect of metformin on AMPK activation, suggesting that AMPK is required for the metformin-mediated increase in GDF15, which in turn is needed to sustain the full activation of this kinase independently of the CNS.Overall, these findings uncover a novel mechanism through which GDF15 upregulation by metformin is involved in achieving and sustaining full AMPK activation by this drug independently of the CNS.
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