AQP1: a regulatory factor associated with brown adipose tissue-silencing to combat obesity and metabolic disease

The activation of nonshivering thermogenesis (NST) in brown adipose tissue (BAT) by environmental cold challenge yields strong metabolic benefit in the face of diet-induced obesity (DIO). Yet, a critical barrier to leveraging brown fat NST for therapeutic use against metabolic disease is that BAT is silenced and inactive at physiological ambient temperature conditions in humans. The mechanisms that govern this silencing process remain poorly understood. Here, we identified a putative BAT-silencing factor, aquaporin-1 (AQP1), in brown fat from wild-type (WT) mice via proteomics analysis. We generated the first BAT-specific AQP1 knockout mice (AQP1-KO) and revealed that AQP1-KO could activate NST under BAT-silencing environmental conditions and that the AQP1-KO mice were significantly protected against DIO and metabolic dysfunction compared with Flox controls. We found that AQP1-KO mice on a high-fat diet (HFD) had reduced weight gain through reductions in fat mass, improved glucose tolerance, and increased whole body energy expenditure compared with Flox control mice. Mechanistically, we show that AQP1 ablation in mice had upregulated gene expression related to the electron transport chain (ETC) and mitochondrial translation contributing to the activation of NST under BAT environmental silenced conditions.<b>NEW & NOTEWORTHY</b> BAT activation is strongly associated with improved metabolic health such as enhanced cardiometabolic profiles. However, the mechanisms that restrict BAT in this state are unknown. We have identified a putative BAT silencer called AQP1 and through the creation of the first BAT-specific AQP1-KO mouse model, demonstrated that these mice have increased energy expenditure and protection against DIO. Thus, AQP1 is a promising therapeutic target for metabolic dysfunction.