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
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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

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Figure 2

Deletion of Ttp in the liver results in improved glucose tolerance and insulin sensitivity after HFD.

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Deletion of Ttp in the liver results in improved glucose tolerance and i...
(A and B) Hepatic Ttp mRNA (A) and protein (B) levels in WT and lsTtp-KO mice. n = 4 for A and 3 for B. *P < 0.05 by 2-tailed unpaired Student’s t test. (C) lsTtp-KO mice have improved glucose tolerance after 8 weeks of HFD compared with WT mice fed HFD. (D) lsTtp-KO mice have improved insulin sensitivity after 9 weeks of HFD compared with WT mice fed HFD. (E) lsTtp-KO mice have less glucose-stimulated insulin secretion after 10 weeks of HFD compared with WT mice fed HFD. $P < 0.05 compared with WT mice after HFD by 1-way ANOVA with post hoc Fisher’s LSD test. NC, normal chow; HFD, high-fat diet; n = 7 for WT and lsTtp-KO fed NC, 6 for WT, and 10 for lsTtp-KO fed HFD for C and D; n = 7 for WT, 8 for lsTtp-KO fed NC, 6 for WT, and 9 for lsTtp-KO for E. (F) Adiposity as determined by fat mass percentage in WT and lsTtp-KO mice after 15 weeks of HFD. (G) Body weight of WT and lsTtp-KO mice after 15 weeks of HFD. n = 6–10 for each group for F and G. Data are presented as mean ± SEM.