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

Peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta) activates AMP-activated protein kinase (AMPK) and plays a crucial role in glucose and lipid metabolism. Here, we examine whether PPAR beta/delta activation effects depend on growth differentiation factor 15 (GDF15), a stress response cytokine that regulates energy metabolism. Pharmacological PPAR beta/delta 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 PPAR beta/delta-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 PPAR beta/delta activation increases GDF15 levels via AMPK and p53, which in turn mediates the metabolic effects of PPAR beta/delta by sustaining AMPK activation.