The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-specific FGF21 Signaling

TY - JOUR

T1 - The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-specific FGF21 Signaling

AU - Jager, Jennifer

AU - Wang, Fenfen

AU - Fang, Bin

AU - Lim, Hee-Woong

AU - Peed, Lindsey C

AU - Steger, David J

AU - Won, Kyoung-Jae

AU - Kharitonenkov, Alexei

AU - Adams, Andrew C

AU - Lazar, Mitchell A

N1 - © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

PY - 2016/5/13

Y1 - 2016/5/13

N2 - FGF21 is an atypical member of the FGF family that functions as a hormone to regulate carbohydrate and lipid metabolism. Here we demonstrate that the actions of FGF21 in mouse adipose tissue, but not in liver, are modulated by the nuclear receptor Rev-erbα, a potent transcriptional repressor. Interrogation of genes induced in the absence of Rev-erbα for Rev-erbα-binding sites identified βKlotho, an essential coreceptor for FGF21, as a direct target gene of Rev-erbα in white adipose tissue but not liver. Rev-erbα ablation led to the robust elevated expression of βKlotho. Consequently, the effects of FGF21 were markedly enhanced in the white adipose tissue of mice lacking Rev-erbα. A major Rev-erbα-controlled enhancer at the Klb locus was also bound by the adipocytic transcription factor peroxisome proliferator-activated receptor (PPAR) γ, which regulates its activity in the opposite direction. These findings establish Rev-erbα as a specific modulator of FGF21 signaling in adipose tissue.

AB - FGF21 is an atypical member of the FGF family that functions as a hormone to regulate carbohydrate and lipid metabolism. Here we demonstrate that the actions of FGF21 in mouse adipose tissue, but not in liver, are modulated by the nuclear receptor Rev-erbα, a potent transcriptional repressor. Interrogation of genes induced in the absence of Rev-erbα for Rev-erbα-binding sites identified βKlotho, an essential coreceptor for FGF21, as a direct target gene of Rev-erbα in white adipose tissue but not liver. Rev-erbα ablation led to the robust elevated expression of βKlotho. Consequently, the effects of FGF21 were markedly enhanced in the white adipose tissue of mice lacking Rev-erbα. A major Rev-erbα-controlled enhancer at the Klb locus was also bound by the adipocytic transcription factor peroxisome proliferator-activated receptor (PPAR) γ, which regulates its activity in the opposite direction. These findings establish Rev-erbα as a specific modulator of FGF21 signaling in adipose tissue.

KW - Adipocytes/cytology

KW - Adipose Tissue/cytology

KW - Animals

KW - Female

KW - Fibroblast Growth Factors/genetics

KW - Male

KW - Membrane Proteins/genetics

KW - Mice

KW - Mice, Knockout

KW - Nuclear Receptor Subfamily 1, Group D, Member 1/genetics

KW - PPAR gamma/genetics

KW - Signal Transduction/physiology

U2 - 10.1074/jbc.m116.719120

DO - 10.1074/jbc.m116.719120

M3 - Journal article

C2 - 27002153

SN - 0021-9258

VL - 291

SP - 10867

EP - 10875

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 20

ER -