C2orf74 Orchestrates Germ-Leydig Crosstalk to Reprogram White Adipocyte Identity II

Gender differences in obesity is widely reported, however, identification of gender specific obese gene and characterization of its role in obesity remain elusive. Here, we identify a germ cell specifically expressed gene C2orf74 and demonstrate that C2ORF74 promotes high-fat diet (HFD) induced obesity in male but not female male. Loss of C2ORF74 protects male mice from obesity by boosting testosterone levels and enhancing energy expenditure and browning of white adipose tissues (WAT). We demonstrate that spermatogenic C2ORF74 suppresses testosterone biogenesis in Leydig cells through germ-cell secreted BPIFA3, whose maturation and secretion is dependent on DPM1-mediated glycosylation. Collectively, these findings define a role of spermatogenic C2ORF74 in energy expenditure and adipose browning in a gender specific manner.