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GDF15 mediates the metabolic effects of PPARβ/δ by activating AMPK Aguilar-Recarte, David Barroso Fernández, Emma Gumà i Garcia, Anna Maria Pizarro Delgado, Javier Peña, Lucía Ruart, Maria Palomer Tarridas, Francesc Xavier Wahli, Walter Vázquez Carrera, Manuel Trastorns del metabolisme dels lípids Àcids grassos Receptors nuclears (Bioquímica) Glucosa Lipid metabolism disorders Fatty acids Nuclear receptors (Biochemistry) Glucose Peroxisome proliferator-activated receptor β/ (PPARβ/) activates AMP-activated protein kinase (AMPK) and plays a crucial role in glucose and lipid metabolism. Here, we examined whether the beneficial effects of PPARβ/δ activation depended on growth differentiation factor 15 (GDF15), a stress response cytokine that regulates energy metabolism. Pharmacological PPARβ/δ activation increased GDF15 levels and ameliorated glucose intolerance, fatty acid oxidation, endoplasmic reticulum stress, inflammation and activated AMPK in HFD-fed mice, whereas these effects were abrogated by the injection of a GDF15 neutralizing antibody and in Gdf15-/- mice. The AMPK-p53 pathway was involved in the PPARβ/δ-mediated increase in GDF15, which in turn activated again AMPK. Finally, Gdf15-/- mice showed reduced AMPK activation in skeletal muscle, whereas GDF15 administration resulted in AMPK activation in this organ. Collectively, these data reveal a novel mechanism by which PPARβ/δ activation increases the levels of GDF15 via AMPK and p53, which in turn mediates the metabolic effects of PPARβ/δ by sustaining AMPK activation. Abbreviations: Acadm, acyl-CoA dehydrogenase medium chain; Acox, acyl-CoA oxidase; AMPK, AMP-activated protein kinase; ATF4, activating transcription factor 4; BiP/GRP78, Binding immunoglobulin protein/78-kDa glucose-regulated protein; CC, compound C; Chop, C/EBP homologous protein; Cpt-1, carnitine palmitoyl-transferase 1; eIF2eukaryotic translation initiation factor 2 ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; FGF21, fibroblast growth factor 21; GDF15, growth differentiation factor 15; GFRAL, glial-derived neurotrophic factor receptor α-like; HFD, high-fat diet; Pdk4, pyruvate dehydrogenase kinase 4; IRS, insulin receptor substrate; PGC-1PPAR co-activator 1 PPAR peroxisome proliferator-activated receptor; SOCS3, suppressor of cytokine signaling 3; STAT3, signal transducer and activator of transcription 3; Vldlr, very-low density lipoprotein receptor. 2021-10-07T09:22:36Z 2021-10-07T09:22:36Z 2021-07-16 2021-10-07T09:22:36Z info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Reproducció del document publicat a: https://doi.org/10.1016/j.celrep.2021.109501 Cell Reports, 2021, vol. 36, num. 6, p. 109501 https://doi.org/10.1016/j.celrep.2021.109501 cc-by (c) Aguilar-Recarte, David et al., 2021 https://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess Elsevier Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)