Several human genetic studies have identified TRIB2 variants, such as rs1057001 was associated with thermogenesis, fat accumulation, and human migration related to environmental temperature.

We used Trib2 konck mice to explore the mechanism by which it regulates thermogenesis and fat accumulation.

Uncoupling protein 1 (UCP1) is a key regulator of thermogenesis and energy expenditure. Here, we demonstrate that Trib2 knockout (KO) protects mice from diet-induced obesity, attenuates hepatic steatosis, and improves glucose tolerance and insulin sensitivity. Trib2 KO mice exhibited elevated UCP1 expression in brown adipose tissue, resulting in enhanced thermogenesis and increased energy expenditure. Mechanistically, TRIB2 functions as a scaffold protein that binds UCP1 via its pseudokinase domain and recruits the E3 ligase MYCBP2, thereby promoting UCP1 ubiquitination and subsequent proteasomal degradation. Furthermore, we demonstrated that the A allele of rs1057001 at the 3’UTR of TRIB2, which was associated with enhanced thermogenesis causes instability of TRIB2 RNA.

Collectively, our findings reveal a new regulatory mechanism of UCP1 by E3 ligase-mediated degradation and highlight TRIB2 as a potential therapeutic target for obesity and related metabolic disorders.