A positive feedback loop between AMPK and GDF15 promotes metformin antidiabetic effects.
Por:
Aguilar-Recarte D, Barroso E, Zhang M, Rada P, Pizarro J, Peña L, Palomer FX, Valverde ÁM, Wahli W and Vazquez M
Publicada:
1 ene 2023
Ahead of Print:
23 nov 2022
Categoría:
Pharmacology
Resumen:
BACKGROUND AND AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Filiaciones:
Aguilar-Recarte D:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain
Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
Barroso E:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain
Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
Zhang M:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain
Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
Rada P:
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain
Instituto de Investigaciones Biomédicas Alberto Sols (CSIC/UAM), Madrid, Spain
Pizarro J:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain
Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
Peña L:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain
Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
Palomer FX:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain
Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
Valverde ÁM:
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain
Instituto de Investigaciones Biomédicas Alberto Sols (CSIC/UAM), Madrid, Spain
Wahli W:
Center for Integrative Genomics, University of Lausanne, CH-1015 Lausanne, Switzerland
Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 308232, Singapore
ToxAlim (Research Center in Food Toxicology), INRAE, UMR1331, F-31300 Toulouse Cedex, France
Vazquez M:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Barcelona, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Madrid, Spain
Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain. Electronic address:
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