Hepatic Tristetraprolin Promotes Insulin Resistance Through RNA Destabilization of FGF21

Overview

Journal JCI Insight

Specialties Biomedical Engineering
General Medicine

Date 2018 Jul 13

PMID 29997282

Citations 17

Authors

Konrad T Sawicki

Hsiang-Chun Chang

Jason S Shapiro

Marina Bayeva

Adam De Jesus

Brian N Finck

Jason A Wertheim

Perry J Blackshear

Hossein Ardehali

Affiliations

Soon will be listed here.

Abstract

The role of posttranscriptional metabolic gene regulatory programs in diabetes is not well understood. Here, we show that the RNA-binding protein tristetraprolin (TTP) is reduced in the livers of diabetic mice and humans and is transcriptionally induced in response to insulin treatment in murine livers in vitro and in vivo. Liver-specific Ttp-KO (lsTtp-KO) mice challenged with high-fat diet (HFD) have improved glucose tolerance and peripheral insulin sensitivity compared with littermate controls. Analysis of secreted hepatic factors demonstrated that fibroblast growth factor 21 (FGF21) is posttranscriptionally repressed by TTP. Consistent with increased FGF21, lsTtp-KO mice fed HFD have increased brown fat activation, peripheral tissue glucose uptake, and adiponectin production compared with littermate controls. Downregulation of hepatic Fgf21 via an adeno-associated virus-driven shRNA in mice fed HFD reverses the insulin-sensitizing effects of hepatic Ttp deletion. Thus, hepatic TTP posttranscriptionally regulates systemic insulin sensitivity in diabetes through liver-derived FGF21.

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