Fibroblast Growth Factor 21 Mediates Glycemic Regulation by Hepatic JNK

Santiago Vernia; Julie Cavanagh-Kyros; Tamera Barrett; Cathy Tournier; Roger J Davis

doi:10.1016/j.celrep.2016.02.026

Fibroblast Growth Factor 21 Mediates Glycemic Regulation by Hepatic JNK

Cell Rep. 2016 Mar 15;14(10):2273-80. doi: 10.1016/j.celrep.2016.02.026. Epub 2016 Mar 3.

Authors

Santiago Vernia¹, Julie Cavanagh-Kyros², Tamera Barrett², Cathy Tournier³, Roger J Davis⁴

Affiliations

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 Faculty of Life Sciences, Manchester University, Manchester M13 9PL, UK.
⁴ 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)-signaling pathway is implicated in metabolic syndrome, including dysregulated blood glucose concentration and insulin resistance. Fibroblast growth factor 21 (FGF21) is a target of the hepatic JNK-signaling pathway and may contribute to the regulation of glycemia. To test the role of FGF21, we established mice with selective ablation of the Fgf21 gene in hepatocytes. FGF21 deficiency in the liver caused marked loss of FGF21 protein circulating in the blood. Moreover, the protective effects of hepatic JNK deficiency to suppress metabolic syndrome in high-fat diet-fed mice were not observed in mice with hepatocyte-specific FGF21 deficiency, including reduced blood glucose concentration and reduced intolerance to glucose and insulin. Furthermore, we show that JNK contributes to the regulation of hepatic FGF21 expression during fasting/feeding cycles. These data demonstrate that the hepatokine FGF21 is a key mediator of JNK-regulated metabolic syndrome.

Publication types

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

MeSH terms

Adipose Tissue / metabolism
Adipose Tissue / pathology
Animals
Blood Glucose / analysis
Cells, Cultured
Diet, High-Fat
Fibroblast Growth Factors / antagonists & inhibitors
Fibroblast Growth Factors / genetics
Fibroblast Growth Factors / metabolism*
Gene Expression Regulation / drug effects
Hepatocytes / cytology
Hepatocytes / metabolism
Insulin / blood
JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
JNK Mitogen-Activated Protein Kinases / genetics
JNK Mitogen-Activated Protein Kinases / metabolism*
Leptin / blood
MAP Kinase Kinase Kinases / deficiency
MAP Kinase Kinase Kinases / genetics
Male
Metabolic Diseases / etiology*
Metabolic Diseases / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitogen-Activated Protein Kinase Kinase Kinase 11
Obesity / etiology
Obesity / metabolism
Peroxisomal Bifunctional Enzyme / genetics
Peroxisomal Bifunctional Enzyme / metabolism
Protein Kinase Inhibitors / pharmacology
Real-Time Polymerase Chain Reaction
Resistin / blood
Signal Transduction

Substances

Blood Glucose
Insulin
Leptin
Protein Kinase Inhibitors
Resistin
fibroblast growth factor 21
Fibroblast Growth Factors
JNK Mitogen-Activated Protein Kinases
MAP Kinase Kinase Kinases
Ehhadh protein, mouse
Peroxisomal Bifunctional Enzyme

Abstract

Publication types

MeSH terms

Substances

Grants and funding