Abstract
OBJECTIVE: Thermogenic beige adipocytes emerge in white adipose tissue (WAT) under certain physiological and pathological conditions, leading to increased energy expenditure, insulin sensitivity, and glucose tolerance. The induction of beige adipocyte formation represents a promising therapeutic approach for obesity and associated chronic diseases; however, the mechanisms controlling WAT beiging remain incompletely understood. METHODS: We conducted a genome-wide knockout screening in the white adipose progenitors of mice to identify lineage repressors of beige adipocyte formation. We further investigated the metabolic effects and gene expression alterations upon Brd9 antagonism in obesity mouse models. RESULTS: An unbiased genetic screen identified the following four lineage repressors of beige adipocytes: Brd9; Ankib1; Cacng1; and Cfap20. Knockout of each gene individually promoted beige adipocyte differentiation in vitro and WAT beiging in vivo. In diet-induced obesity mouse models, oral administration of Brd9 inhibitors induced beige adipocytes within subcutaneous and visceral WAT, enhanced thermogenic gene expression in brown adipose tissue, and suppressed gluconeogenic gene expression in the liver. These beneficial effects were concomitant with augmented whole-body energy expenditure, reduced body weight/adiposity, and improved endurance and glucose metabolism. CONCLUSIONS: Antagonism of Brd9 and other beige lineage repressors may have significant implications for therapeutic induction of WAT beiging and thermogenesis to treat obesity and its associated chronic diseases.