Combined Deletion of miR-27a and miR-27b Enhances Protection Against Diet-Induced Obesity

Obesity impairs adipose tissue thermogenesis, contributing to metabolic dysfunction. Here, we identify miR-27a and miR-27b as cooperative regulators of adipose tissue thermogenesis and adipogenic programming in the context of diet-induced obesity (DIO). Intervention of high-fat diet (HFD) to mice suppressed the expression of Ucp1, Ppary , and Pgc1a in inguinal white adipose tissue (WAT), which correlated with the increased expression of miR-27a/b. Using global knockout models for miR-27a and miR-27b, we identified that combined deletion of both miRNAs (double knockout, DKO) synergistically enhances Ucp1 expression, mitochondrial heat production and browning of WAT. DKO mice displayed improved glucose, insulin sensitivity and reduced adiposity under HFD conditions and outperformed single knockouts. In-vitro and ex-vivo analysis confirmed an increase in thermogenic gene expression and reduced lipid accumulation in DKO adipocytes. Collectively, our findings reveal that miR-27a/b cooperatively suppresses adipose thermogenesis and promotes metabolic dysfunction under obesogenic conditions. Targeting the miR-27a/b axis may offer a novel therapeutic approach to enhance energy expenditure and combat obesity-related metabolic diseases.