Sestrin2 ablation attenuates the exercise‐induced browning of white adipose tissue in C57BL/6J mice

Abstract Aim With exercise, white adipose tissues (WAT) are readily convertible to a “brown‐like” state, altering from lipid‐storing to energy‐catabolizing function, which counteracts obesity and increases insulin sensitivity. Sestrin2 (SESN2) is a stress‐inducible protein that can regulate the cold‐induced increase of uncoupling protein 1 (UCP1), which is paramount for the thermogenic capacity of brown‐like WAT. This study aimed to elucidate the necessity of SESN2 in mediating exercise‐induced browning of WAT. Methods We used 8‐week, male wild‐type and SESN2 knockout C57BL/6J mice to explore the potential role of SESN2 in the exercise‐induced WAT browning process. Over a 3‐week intervention (sedentary versus treadmill exercise, normal chow versus 60% high‐fat diet), we examined the exercise‐induced alterations of the browning phenotype in different depots of white fat. In vitro, 3T3‐L1 pre‐adipocytes and primary adipocytes were used to determine the potential mechanism. Results Our data revealed that SESN2 was required for the exercise‐induced subcutaneous WAT (scWAT) browning. This may be mediated by higher fibronectin type III domain containing 5 (FNDC5) contents in scWAT locally, rather than skeletal muscle FNDC5 expression and circulating serum irisin levels. SESN2 ablation significantly impaired the exercise‐improved glucose metabolism, where browning of scWAT may serve as an essential pathway. Moreover, SESN2 ablation significantly attenuated the exercise‐promoted respiratory exchange ratio and indexes of energy metabolism (oxygen uptake and energy expenditure). Conclusion Taken together, our results provided evidence that SESN2 is a key integrating factor in driving the diverse metabolic benefits conferred by aerobic exercise.