Abstract
Tribbles homolog 1 (TRIB1) belongs to the Tribbles family of pseudokinases, which plays a key role in tumorigenesis and inflammation. Although genome-wide analysis shows that TRIB1 expression is highly correlated with blood lipid levels, the relationship between TRIB1 and adipose tissue metabolism remains unclear. Accordingly, the aim of the present study was to explore the role of TRIB1 on mitochondrial function in the brown adipose tissue (BAT). Trib1-knockout mice were established using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology. The metabolic function of the BAT was induced by a β3-adrenoceptor agonist and the energy metabolism function of mitochondria in the BAT of mice was evaluated. Trib1-knockout mice exhibited obesity and impaired BAT thermogenesis. In particular, Trib1 knockout reduced the ability of the BAT to maintain body temperature, inhibited β3-adrenoceptor agonist-induced thermogenesis, and accelerated lipid accumulation in the liver and adipose tissues. In addition, Trib1 knockout reduced mitochondrial respiratory chain complex III activity, produced an imbalance between mitochondrial fusion and fission, caused mitochondrial structural damage and dysfunction, and affected heat production and lipid metabolism in the BAT. Conversely, overexpression of Trib1 in 3T3-L1 adipocytes increased the number of mitochondria and improved respiratory function. These findings support the role of Trib1 in regulating the mitochondrial respiratory chain and mitochondrial dynamics by affecting mitochondrial function and thermogenesis in the BAT.
Highlights
Obesity is a global health problem that increases the risk of noncommunicable diseases such as cardiovascular disease, diabetes, and cancer [1]
Since we found that Tribbles homolog 1 (TRIB1) interacts with UQCRC2, we further explored the effects of Trib1 on the mitochondrial respiratory measuring oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), respectively, in a seahorse assay
These findings suggest that the decrease in mitochondrial respiratory mitochondrial respiratory chain activity, resulting in an imbalance in mitochondrial fusion and fission with subsequent mitochondrial structural damage and lipid metabolism dysfunction
Summary
Obesity is a global health problem that increases the risk of noncommunicable diseases such as cardiovascular disease, diabetes, and cancer [1]. Our results suggest that Trib affects mitochondrial function mice showed higher levels of insulin and leptin (Fig. 3d, e), but and BAT heat production through the mitochondrial lower levels of adiponectin (Fig. 3f). These results further respiratory chain and mitochondrial dynamics. Despite its well-known role in leukemia and M2 macrophages calorimetry measurements showed that the metabolic capacity of [21, 25], the physiological role of TRIB1 in the adipose tissue Trib1-knockout mice was lower than that of wild-type mice
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