GDF15 mediates the metabolic effects of PPARβ/δ by activating AMPK

Cell Rep. 2021 Aug 10;36(6):109501. doi: 10.1016/j.celrep.2021.109501.

Abstract

Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) activates AMP-activated protein kinase (AMPK) and plays a crucial role in glucose and lipid metabolism. Here, we examine whether PPARβ/δ activation effects depend on growth differentiation factor 15 (GDF15), a stress response cytokine that regulates energy metabolism. Pharmacological PPARβ/δ activation increases GDF15 levels and ameliorates glucose intolerance, fatty acid oxidation, endoplasmic reticulum stress, and inflammation, and activates AMPK in HFD-fed mice, whereas these effects are abrogated by the injection of a GDF15 neutralizing antibody and in Gdf15-/- mice. The AMPK-p53 pathway is involved in the PPARβ/δ-mediated increase in GDF15, which in turn activates again AMPK. Consistently, Gdf15-/- mice show reduced AMPK activation in skeletal muscle, whereas GDF15 administration results in AMPK activation in this organ. Collectively, these data reveal a mechanism by which PPARβ/δ activation increases GDF15 levels via AMPK and p53, which in turn mediates the metabolic effects of PPARβ/δ by sustaining AMPK activation.

Keywords: AMPK; GDF15; PPARβ/δ; glucose tolerance; p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Adenylate Kinase / metabolism
  • Animals
  • Cell Line
  • Endoplasmic Reticulum Stress
  • Enzyme Activation
  • Growth Differentiation Factor 15 / deficiency
  • Growth Differentiation Factor 15 / metabolism*
  • Inflammation / pathology
  • Insulin / metabolism
  • Lipid Metabolism
  • Liver / metabolism
  • Liver / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Skeletal / metabolism
  • PPAR delta / metabolism*
  • PPAR-beta / metabolism*
  • Signal Transduction
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Growth Differentiation Factor 15
  • Insulin
  • PPAR delta
  • PPAR-beta
  • Tumor Suppressor Protein p53
  • AMP-Activated Protein Kinases
  • Adenylate Kinase