Hepatic tristetraprolin promotes insulin resistance through RNA destabilization of FGF21
Konrad T. Sawicki, … , Perry J. Blackshear, Hossein Ardehali
Konrad T. Sawicki, … , Perry J. Blackshear, Hossein Ardehali
Published July 12, 2018
Citation Information: JCI Insight. 2018;3(13):e95948. https://doi.org/10.1172/jci.insight.95948.
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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 6

Hepatic deletion of Ttp activates brown and beige adipose tissue.

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Hepatic deletion of Ttp activates brown and beige adipose tissue. (A) Ad...
(A) Adipoq mRNA levels in epididymal adipose tissue (eAT) and inguinal AT (iAT) from WT and lsTtp-KO mice fed HFD (n = 5–8). (B) Soleus muscle and brown adipose tissue (bAT) glucose uptake at the end of hyperinsulinemic-euglycemic clamp studies in WT and lsTtp-KO mice fed HFD (n = 7–10). (C) Slc2a1 expression in bAT and skeletal muscle from WT and lsTtp-KO mice after HFD (n = 4–8). (D) Loss of hepatic Ttp results in a gene expression pattern in iAT consistent with beige adipose tissue browning (n = 4–7). (E) Gene expression in bAT in lsTtp-KO mice is consistent with increased brown adipose tissue activation (n = 4–7). (F) lsTtp-KO mice have increased energy expenditure after HFD (n = 6–8). (G) Food intake of WT and lsTtp-KO mice during indirect calorimetry (n = 6–8). Data are presented as mean ± SEM. *P < 0.05, #P < 0.1 by 2-tailed unpaired Student’s t test.