title: The PPARα-FGF21 hormone axis contributes to metabolic regulation by the hepatic JNK signaling pathway.
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.
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Santiago
authors.initials: S
authors.lastname: Vernia
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Howard Hughes Medical Institute, Worcester, MA 01605, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Cavanagh-Kyros
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Luisa
authors.initials: L
authors.lastname: Garcia-Haro
authors.affiliation: Department of Vascular Biology and Inflammation, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, 28029 Madrid, Spain.
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Sabio
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Howard Hughes Medical Institute, Worcester, MA 01605, USA.
authors.forename: Tamera
authors.initials: T
authors.lastname: Barrett
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Jung
authors.affiliation: 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.
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
authors.affiliation: Bioinformatics Core, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Xu
authors.affiliation: Bioinformatics Core, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Hennady P
authors.initials: HP
authors.lastname: Shulha
authors.affiliation: 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.
authors.forename: Manuel
authors.initials: M
authors.lastname: Garber
authors.affiliation: Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Guangping
authors.initials: G
authors.lastname: Gao
authors.affiliation: 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.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Davis
mesh_terms: D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D017353:Gene Deletion; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism*
chemical_list: D047493:PPAR alpha; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D048670:MAP Kinase Kinase 4