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

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.