LAUSR

Obesity and related metabolic disorders are epidemic diseases. Promoting thermogenesis and a functional increase in the browning of white adipocytes may counteract obesity. On the other hand, the molecular mechanism that regulates brown and beige fat‐mediated thermogenesis is unclear. This article reports a molecular network led by cytoplasmic FMR1‐interacting protein 2 (CYFIP2) that negatively regulates adipocyte browning in white adipocytes. Although the function of CYFIP2 in Fragile X Syndrome (FXS) and autism have been reported, its physiological roles in adipocytes remain elusive. Therefore, this study examined the physiological consequences of its deprivation in cultured 3T3‐L1 white adipocytes using loss‐of‐function studies. Combined real‐time quantitative reverse‐transcription polymerase chain reaction and immunoblot analysis showed that the loss of CYFIP2 induces fat browning, as evidenced by the gene and protein expression levels of the brown fat‐associated markers. A deficiency of CYFIP2 promoted mitochondrial biogenesis and significantly enhanced the expression of the core set beige fat‐specific genes (Cd137, Cidea, Cited1, Tbx1, and Tmem26) and proteins (PGC‐1α, PRDM16, and UCP1). In addition, a CYFIP2 deficiency promoted lipid catabolism and suppressed adipogenesis, lipogenesis, and autophagy. A mechanistic study showed that the loss of CYFIP2 induces browning in white adipocytes, independently via the activation of mTORC1 and suppression of the GABA‐BR signaling pathway. The present data revealed a previously unidentified mechanism of CYFIP2 in the browning of white adipocytes and emphasized the potential of CYFIP2 as a pharmacotherapeutic target for treating obesity and other metabolic disorders.