The PPARalpha-FGF21 hormone axis contributes to metabolic regulation by the hepatic JNK signaling pathway

UMMS Affiliation

Program in Molecular Medicine; Department of Medicine, Division of Endocrinology, Metabolism and Diabetes; Bioinformatics Core; Program in Bioinformatics; Gene Therapy Center



Document Type


Medical Subject Headings

Animals; Diet, High-Fat; Fibroblast Growth Factors; Gene Deletion; Insulin Resistance; Liver; MAP Kinase Kinase 4; *MAP Kinase Signaling System; Male; Mice; Mice, Inbred C57BL; Obesity; PPAR alpha


Biochemistry | Cell Biology | Cellular and Molecular Physiology | Molecular Biology


The cJun NH2-terminal kinase (JNK) stress signaling pathway is implicated in the metabolic response to the consumption of a high-fat diet, including the development of obesity and insulin resistance. These metabolic adaptations involve altered liver function. Here, we demonstrate that hepatic JNK potently represses the nuclear hormone receptor peroxisome proliferator-activated receptor alpha (PPARalpha). Therefore, JNK causes decreased expression of PPARalpha target genes that increase fatty acid oxidation and ketogenesis and promote the development of insulin resistance. We show that the PPARalpha target gene fibroblast growth factor 21 (Fgf21) plays a key role in this response because disruption of the hepatic PPARalpha-FGF21 hormone axis suppresses the metabolic effects of JNK deficiency. This analysis identifies the hepatokine FGF21 as a critical mediator of JNK signaling in the liver.

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Citation: Cell Metab. 2014 Sep 2;20(3):512-25. doi: 10.1016/j.cmet.2014.06.010. Epub 2014 Jul 17. Link to article on publisher's site

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