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. Display omitted •Activation of the AMPK-p53 pathway by PPARβ/δ agonists increases GDF15•Many metabolic effects mediated by PPARβ/δ activation are abrogated in Gdf15−/− mice•GDF15 is required for the activation of AMPK by ligand-activated PPARβ/δ•In skeletal muscle, GDF15 activates AMPK in the absence of the GDF15 receptor GFRAL GDF15 is a stress response cytokine that regulates energy metabolism. Aguilar-Recarte et al. show that PPARβ/δ activation increases GDF15 levels, which contributes to the metabolic effect of this receptor and activates AMPK in skeletal muscle independently of GDF15 receptor GFRAL.