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

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.
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https://hal.inrae.fr/hal-03321289
Contributor : Hélène Lesur Connect in order to contact the contributor
Submitted on : Tuesday, August 17, 2021 - 1:49:20 PM
Last modification on : Monday, August 30, 2021 - 8:18:00 AM

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David Aguilar-Recarte, Emma Barroso, Anna Gumà, Javier Pizarro-Delgado, Lucía Peña, et al.. GDF15 mediates the metabolic effects of PPARβ/δ by activating AMPK. Cell Reports, Elsevier Inc, 2021, 36 (6), ⟨10.1016/j.celrep.2021.109501⟩. ⟨hal-03321289⟩

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