Selenoprotein F gates diet-induced female-specific obesity via adipose IRE1α-mediated endoplasmic reticulum stress.

Obesity has become a global epidemic and a major public health challenge. Endoplasmic reticulum (ER) stress links nutrient overload to obesity, but whether ER-resident selenoprotein F (SELENOF) regulates this process remains unknown. Here we show that whole-body SELENOF knockout (KO) specifically exacerbated high-fat diet (HFD)-induced obesity, hyperlipidemia, and hepatic steatosis exclusively in female mice, with no significant effect in male mice. The obesity phenotype in SELENOF KO female mice was driven by adipocyte hypertrophy resulting from a coordinated lipid metabolic shift-marked by increased lipogenesis, impaired lipolysis, and suppressed fatty acid oxidation. These lipid metabolism disorders were coupled with ER stress, especially the hyperactivation of IRE1α in adipose tissue. Moreover, in primary adipocytes derived from female mice, SELENOF loss further exacerbated free fatty acids (FFA)-induced lipid metabolism disorder, ER stress and mitochondrial dysfunction, which were significantly reversed by 4μ8C, an IRE1α-specific inhibitor. Collectively, SELENOF KO aggravated HFD-induced obesity and lipid metabolism disorder by promoting adipose IRE1α-mediated ER stress in a female-specific manner. This finding suggests that SELENOF is a female-specific guardian of lipid homeostasis, potentially contributing to the protection against obesity and metabolic disorders.