期刊
CELL REPORTS
卷 36, 期 6, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2021.109501
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资金
- Spanish Ministry of Economy and Competitiveness [SAF2015-64146-R, RTI2018-093999-B-100]
- European Union ERDF funds
Activation of PPAR beta/delta increases GDF15 levels, activating the AMPK and p53 pathways, thus regulating glucose and lipid metabolism. GDF15 plays a crucial role in sustaining the metabolic effects of PPAR beta/delta through AMPK activation.
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.
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