C2orf74 orchestrates germ-Leydig crosstalk to inhibit white adipose tissue browning in male mice

Sex differences in obesity are well recognized; however, the identification of sex-specific obesity genes and the mechanisms through which they affect obesity development remain elusive. Here, we identify a germ-cell-specific gene C2orf74, whose expression is responsive to high-fat diet (HFD) and promotes HFD-induced obesity in male mice by restraining lipolysis and limiting the browning of white adipocytes through suppression of androgen receptor signaling, but not in females. Additionally, C2orf74's expression increases with aging, contributing to aging-related obesity and metabolic comorbidities in chow-fed male mice. We demonstrate that C2orf74 is an ER-residing transmembrane protein that anchors and stabilizes dolichol phosphate mannose synthase 1 (Dpm1) on the ER membrane, facilitating Dpm1-mediated glycosylation and secretion of Bpifa3 from germ cells. As a paracrine regulator, Bpifa3 transcriptionally suppresses the expression of testosterone biosynthesis enzymes in Leydig cells. Therapeutically, we demonstrate that antisense oligonucleotide (ASO) targeting C2orf74 protects male mice from HFD-induced obesity. Thus, our study defines a role for germ-Leydig cell crosstalk, mediated by C2orf74, in the white adipocytes browning in both age-associated and diet-induced obesity.