Hepatic tristetraprolin promotes insulin resistance through RNA destabilization of FGF21
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
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
View: Text | PDF
Research Article Metabolism

Hepatic tristetraprolin promotes insulin resistance through RNA destabilization of FGF21

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.

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

×

Figure 4

Liver-specific Ttp-KO mice have increased peripheral tissue insulin sensitivity after high-fat diet.

Options: View larger image (or click on image) Download as PowerPoint
Liver-specific Ttp-KO mice have increased peripheral tissue insulin sens...
(A–D) lsTtp-KO mice have improved insulin sensitivity in adipose tissue (A and B) and skeletal muscle (C and D) after 12 weeks of HFD compared with control mice, as assessed by phosphorylated AKT S473 (pAKT) to total AKT (tAKT) ratio after injection of insulin (0.0075 U/kg) or saline (n = 6–9). Representative Western blotting results are shown in A and C, and densitometry analyses are provided in B and D. (E) lsTtp-KO mice fed HFD have significantly lower insulin levels at baseline and during hyperinsulinemic-euglycemic clamp studies. Data are presented as mean ± SEM. *P < 0.05 by 2-tailed unpaired Student’s t test.