PPARß/d contributes to the antidiabetic effect and the increase in GDF15 caused by metformin
Por:
Jurado-Aguilar J, Barroso E, Rada P, Peyman M, Rostami A, Balsinde J, Valverde ÁM, Wahli W, Palomer FX and Vazquez M
Publicada:
1 may 2026
Ahead of Print:
1 ene 2026
Resumen:
Metformin, the most prescribed drug for the treatment of type 2 diabetes mellitus, increases the circulating levels of the metabolic regulator growth differentiation factor 15 (GDF15) via transcriptional regulation, with the kidneys being responsible for this increase. Since peroxisome proliferator-activated receptor (PPAR)beta/delta agonists mimic many of the effects of metformin, including the rise in circulating GDF15 levels, we herein investigated whether the metformin-mediated antidiabetic effects and GDF15 upregulation were dependent on this nuclear receptor. Male Ppard-/- and wild-type (WT) mice received a western-type high-fat diet (HFD) for 12 weeks and were treated with metformin (200 mg kg-1 d-1, i.g.) in the last 3 weeks. At the end of the treatment, the mice were sacrificed, and the skeletal muscle, kidney, and liver samples were collected for analyses. We showed that metformin treatment ameliorated glucose intolerance and increased hepatic and circulating GDF15 levels in WT mice, but not in Ppard-/- mice fed a HFD. In the kidneys, metformin treatment increased the expression levels of phosphorylated AMPK and GDF15 in the WT mice, which was abolished in the Ppard-/- mice. Both beta-arrestin 1 and proprotein convertase subtilisin/kexin type 6 (PCSK6) are involved in the posttranslational maturation of GDF15. Likewise, metformin treatment increased the levels of beta-arrestin 1 and PCSK6 in the kidneys of WT mice, but not Ppard-/- mice. Furthermore, treatment of mice with a PPAR beta/delta activator, GW501516 (3 mg kg-1 d-1, i.g., for 7 days), increased the levels of these proteins in the kidneys and liver. In contrast, a PPAR beta/delta antagonist GSK0660 (50 mu M) prevented the increase in GDF15, beta-arrestin 1, and PCSK6 levels caused by metformin in cultured podocytes. Collectively, these data uncover a regulatory axis wherein metformin, via PPAR beta/delta, orchestrates glucose tolerance, AMPK activity, and GDF15 maturation.
Filiaciones:
Jurado-Aguilar J:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028, Barcelona, Spain
Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028, Barcelona, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029, Madrid, Spain
Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
Barroso E:
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029, Madrid, Spain
Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028, Barcelona, Spain
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028, Barcelona, Spain
Rada P:
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029, Madrid, Spain
Instituto de Investigaciones Biomédicas Sols-Morreale (CSIC/UAM), Madrid, Spain
Peyman M:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028, Barcelona, Spain
Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028, Barcelona, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029, Madrid, Spain
Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
Rostami A:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028, Barcelona, Spain
Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028, Barcelona, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029, Madrid, Spain
Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
Balsinde J:
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029, Madrid, Spain
Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Valladolid, Spain
Valverde ÁM:
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029, Madrid, Spain
Instituto de Investigaciones Biomédicas Sols-Morreale (CSIC/UAM), Madrid, Spain
Wahli W:
Center for Integrative Genomics, University of Lausanne, CH-, Lausanne, Switzerland
ToxAlim (Research Center in Food Toxicology), INRAE UMR1331, F-31300, Toulouse Cedex, France
Palomer FX:
Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028, Barcelona, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029, Madrid, Spain
Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028, Barcelona, Spain
Vazquez M:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028, Barcelona, Spain
Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028, Barcelona, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029, Madrid, Spain
Green Accepted
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