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PPARβ/δ contributes to the antidiabetic effect and the increase in GDF15 caused by metformin

Acta Pharmacologica Sinica (2026)Cite this article

Abstract

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)β/δ 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 β-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 β-arrestin 1 and PCSK6 in the kidneys of WT mice, but not Ppard−/− mice. Furthermore, treatment of mice with a PPARβ/δ 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 PPARβ/δ antagonist GSK0660 (50 µM) prevented the increase in GDF15, β-arrestin 1, and PCSK6 levels caused by metformin in cultured podocytes. Collectively, these data uncover a regulatory axis wherein metformin, via PPARβ/δ, orchestrates glucose tolerance, AMPK activity, and GDF15 maturation.

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Fig. 1: The antidiabetic effect of metformin is abolished in Ppard−/− mice.
Fig. 2: Metformin increases the expression of the genes involved in fatty acid oxidation in the livers of WT mice, but not Ppard−/− mice.
Fig. 3: Metformin increases the hepatic and circulating levels of GDF15 in WT mice, but not in Ppard−/− mice.
Fig. 4: Metformin increases the levels of PPARβ/δ and AMPK in the kidneys of WT mice, but not Ppard−/− mice.
Fig. 5: Metformin increases the levels of GDF15 and of the proteins involved in its maturation in the kidneys of WT mice, but not Ppard−/− mice.
Fig. 6: PPARβ/δ activation increases phosphorylated AMPK, GDF15, β-arrestin 1, and PCSK6 protein levels in the liver and kidneys of mice.
Fig. 7: Metformin increases GDF15 levels and secretion via the PPARβ/δ-AMPK pathway in podocytes.
Fig. 8: The PPARβ/δ-AMPK pathway increases GDF15 secretion and the levels of proteins involved in GDF15 maturation.

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Acknowledgements

We are indebted to the Biobank core facility of the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) for the technical help. We would like to thank the Language Services of the University of Barcelona for revising the manuscript. EB is a Serra Hunter fellow. This study was supported by the grants PID2024-155124OB-I00 and PID2021-122116OB-I00 (MVC and XP), PID2021-122766OB-I00 (AMV), and PRE2019-089839 funded by MICIU/AEI/10.13039/501100011033 and “ERDF, A Way of Making Europe”. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) is a Carlos III Health Institute project. Support was also received from the CERCA Programme/Generalitat de Catalunya.

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Authors and Affiliations

  1. Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028, Barcelona, Spain

    Javier Jurado-Aguilar, Emma Barroso, Mona Peyman, Adel Rostami, Xavier Palomer & Manuel Vázquez-Carrera

  2. Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028, Barcelona, Spain

    Javier Jurado-Aguilar, Emma Barroso, Mona Peyman, Adel Rostami, Xavier Palomer & Manuel Vázquez-Carrera

  3. Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029, Madrid, Spain

    Javier Jurado-Aguilar, Emma Barroso, Patricia Rada, Mona Peyman, Adel Rostami, Jesús Balsinde, Ángela M. Valverde, Xavier Palomer & Manuel Vázquez-Carrera

  4. Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain

    Javier Jurado-Aguilar, Emma Barroso, Mona Peyman, Adel Rostami, Xavier Palomer & Manuel Vázquez-Carrera

  5. Instituto de Investigaciones Biomédicas Sols-Morreale (CSIC/UAM), Madrid, Spain

    Patricia Rada & Ángela M. Valverde

  6. Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Valladolid, Spain

    Jesús Balsinde

  7. Center for Integrative Genomics, University of Lausanne, CH-, Lausanne, Switzerland

    Walter Wahli

  8. ToxAlim (Research Center in Food Toxicology), INRAE UMR1331, F-31300, Toulouse Cedex, France

    Walter Wahli

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  1. Javier Jurado-Aguilar
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Contributions

JJA, EB, PR, MP, AR, and MVC performed the experiments and collected the data. JJA, JB, AMV, WW, XP, and MVC analyzed and interpreted the data. WW and XP drafted and revised the manuscript. MVC designed the experiments, interpreted the results, and wrote the manuscript. All authors have read and approved the final manuscript.

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Correspondence to Manuel Vázquez-Carrera.

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Jurado-Aguilar, J., Barroso, E., Rada, P. et al. PPARβ/δ contributes to the antidiabetic effect and the increase in GDF15 caused by metformin. Acta Pharmacol Sin (2026). https://doi.org/10.1038/s41401-025-01705-5

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