Diet-induced obesity and aging-induced upregulation of Trib3 interfere with energy homeostasis by downregulating the thermogenic capacity of BAT

Characterized by UCP1 expression and abundant mitochondria, brown adipose tissue (BAT) plays a crucial role in energy balance by converting chemical energy into heat through the cost of ATP production. In this study, it was demonstrated that Trib3 is a critical determinant of BAT-mediated energy expenditure and whole-body energy homeostasis. Under 60% high-fat diet conditions, Trib3 expression in BAT was elevated. Mice deficient in Trib3 are resistant to diet-induced obesity and exhibit improved glucose homeostasis due to enhanced BAT activity. Furthermore, brown adipocyte progenitor cells (APCs) lacking Trib3 exhibited increased proliferation and promoted brown adipocyte differentiation and mitochondrial biogenesis, contributing to the increase in the maximal thermogenic capacity of BAT in Trib3-deficient mice. Mechanistically, it was discovered that Trib3 expression is upregulated by free fatty acids at the transcriptional level and synergistically upregulated by DAG-PKC at the posttranslational level. This occurs through the modulation of COP1-mediated Trib3 protein turnover. Interestingly, the level of Trib3 expression in BAT increased with age. Trib3 knockout mice were protected from aging-related weight gain and impaired glucose homeostasis. These results suggest that Trib3 acts as an obesity- and aging-associated factor that negatively regulates BAT activity and that the loss of Trib3 may provide a beneficial approach to prevent obesity and aging-associated metabolic syndrome by increasing the thermogenic capacity of BAT. The study investigates how the Trib3 gene influences energy balance and obesity. Researchers discovered that Trib3 knockout mice, which lack the Trib3 gene, are resistant to diet and aging-induced obesity. This study fills a gap in understanding Trib3’s role in brown adipose tissue, a type of fat that generates heat. Researchers conducted experiments on Trib3 KO mice to examine their resistance to obesity using methods like glucose tolerance tests, indirect calorimetry, and PET imaging to analyze the mice. Results showed that Trib3 KO mice had lower body weight and better glucose metabolism compared to control mice. They concluded that Trib3 KO mice have increased energy expenditure due to enhanced BAT activity. This suggests that targeting Trib3 could help treat obesity and related metabolic disorders. Future research could explore Trib3’s role in other tissues and its potential as a therapeutic target. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.