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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diet, High-Fat / adverse effects
  • Fibroblast Growth Factors / metabolism*
  • Gene Deletion
  • Insulin Resistance
  • Liver / metabolism*
  • MAP Kinase Kinase 4 / genetics
  • MAP Kinase Kinase 4 / metabolism
  • MAP Kinase Signaling System*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Obesity / etiology
  • Obesity / genetics
  • Obesity / metabolism
  • PPAR alpha / metabolism*

Substances

  • PPAR alpha
  • fibroblast growth factor 21
  • Fibroblast Growth Factors
  • MAP Kinase Kinase 4

Associated data

  • GEO/GSE55190