2026-04-14T06:49:40Zhttps://recercat.cat/oai/request
oai:recercat.cat:2445/1804742025-11-19T10:49:07Zcom_2072_1057col_2072_478781col_2072_478816col_2072_478917
RECERCAT author Aguilar-Recarte, David author Barroso Fernández, Emma author Gumà i Garcia, Anna Maria author Pizarro Delgado, Javier author Peña, Lucía author Ruart, Maria author Palomer Tarridas, Francesc Xavier author Wahli, Walter author Vázquez Carrera, Manuel 2021-10-07T09:22:36Z2021-10-07T09:22:36Z2021-07-162021-10-07T09:22:36Z 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. cc-by (c) Aguilar-Recarte, David et al., 2021 https://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess Trastorns del metabolisme dels lípids Àcids grassos Receptors nuclears (Bioquímica) Glucosa Lipid metabolism disorders Fatty acids Nuclear receptors (Biochemistry) Glucose GDF15 mediates the metabolic effects of PPARβ/δ by activating AMPK info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion