LINC00278 and BRG1: A key regulatory axis in male obesity and preadipocyte adipogenesis

Obesity is a significant public health concern directly associated with adipogenesis. Long non-coding RNAs (lncRNAs) have emerged as critical regulators of adipogenesis. However, the roles of sex-specific lncRNAs in adipose tissue are not well comprehended. In this study, we used lncRNA microarrays to profile lncRNAs expression in visceral adipose tissues from obese and lean individuals, identifying LINC00278 as significantly and exclusively expressed in males. Elevated levels of LINC00278 were associated with higher body mass index (BMI) and non-remission after bariatric surgery in individuals with obesity. Mechanistic studies further revealed that METTL14 regulates the m⁶A methylation of LINC00278, which in turn binds with BRG1, activating the PPAR-γ2 pathway and promoting adipogenesis. Additionally, adipose-specific LINC00278 knock-in in C57BL/6 J mice resulted in adipocyte enlargement, increased body weight, higher body fat percentage, and impaired glucose metabolism. Treatment with the BRG1 inhibitor, BRM/BRG1 ATP Inhibitor-1, significantly alleviated the obesity phenotype in these mice. Our findings highlight the critical role of LINC00278 in male adipogenesis, suggesting that targeting the LINC00278-BRG1 axis could be a potential therapeutic strategy for managing obesity and related metabolic disorders in males.