American Diabetes Association
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TRIB2-mediated modulation of AMPK promotes hepatic insulin resistance

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posted on 2024-02-23, 20:01 authored by Dan Wang, Xiaonan Kang, Lu Zhang, Yaoyao Guo, Ziyin Zhang, Huihui Ren, Gang Yuan

Insulin resistance and its linked health complications are increasing in prevalence. Recent work has caused the role of Tribbles2 (TRIB2) in metabolism and cellular signaling to be increasingly appreciated, but its role in the progression of insulin resistance has not been elucidated. Here, we explore the functions of TRIB2 in modulating insulin resistance and the mechanism involved in insulin resistance mice and palmitic acid (PA) treated HepG2 cells. We demonstrate that whole-body knockout and hepatic-specific TRIB2 deficiency protect against diet-induced insulin resistance, inflammation and ER stress. Accordingly, upregulation of TRIB2 in the liver aggravates these metabolic disturbances in HFD-induced mice and ob/ob mice. Mechanistically, TRIB2 directly binds to the αγ-SBS domain of PRKAB through its pseudokinase domain, subsequently inhibiting the formation and activity of the AMPK complex. Moreover, the results of intervention against AMPK suggest that the effects of TRIB2 depend on AMPK. Our findings reveal that TRIB2 is a novel target for the treatment of insulin resistance and its associated metabolic complications and clarify the function of TRIB2 as a regulatory component of AMPK activity.

Funding

The study was supported by the National Natural Science Foundation of China (NSFC) (No. 82270855 G.Y, No. 81770817 G.Y, No. 81974121 G.Y, and No. 82100922 H.R).

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