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Cell Metab. 2014 Sep 2;20(3):512-25. doi: 10.1016/j.cmet.2014.06.010. Epub 2014 Jul 17.

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

Author information

1
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
2
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Howard Hughes Medical Institute, Worcester, MA 01605, USA.
3
Department of Vascular Biology and Inflammation, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, 28029 Madrid, Spain.
4
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Massachusetts Medical School, Worcester, MA 01605, USA.
5
Bioinformatics Core, University of Massachusetts Medical School, Worcester, MA 01605, USA.
6
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Program in Bioinformatics, University of Massachusetts Medical School, Worcester, MA 01605, USA.
7
Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA.
8
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Howard Hughes Medical Institute, Worcester, MA 01605, USA. Electronic address: roger.davis@umassmed.edu.

Abstract

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 α (PPARα). Therefore, JNK causes decreased expression of PPARα target genes that increase fatty acid oxidation and ketogenesis and promote the development of insulin resistance. We show that the PPARα target gene fibroblast growth factor 21 (Fgf21) plays a key role in this response because disruption of the hepatic PPARα-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.

PMID:
25043817
PMCID:
PMC4156535
DOI:
10.1016/j.cmet.2014.06.010
[Indexed for MEDLINE]
Free PMC Article
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