Selenoprotein F Deficiency Drives Diet-Induced Metabolic Dysfunction in Female Mice by Aggravating Hypothalamic Endoplasmic Reticulum Stress

Obesity exhibits pronounced sex-dependent differences in susceptibility and progression; however, the molecular mechanisms coordinating central energy sensing with peripheral thermogenic responses remain incompletely defined. Selenoprotein F (SELENOF), an endoplasmic reticulum (ER)-resident member of the selenoprotein family involved in protein quality control and redox-sensitive metabolic regulation, has not previously been investigated in the context of diet-induced obesity. In the present study, WT and SELENOF-deficient mice subjected to a 16-week high-fat diet (HFD) were combined with primary brown adipocyte experiments to determine the role of SELENOF in systemic metabolic homeostasis. SELENOF deficiency markedly aggravated HFD-induced weight gain, adipose tissue expansion, dyslipidemia, and hyperleptinemia selectively in female mice, whereas no genotype-dependent effects were observed in males. Mechanistically, SELENOF deficiency intensified hypothalamic ER stress and leptin resistance, as reflected by increased GRP78, p-IRE1α, and p-PERK expression together with SOCS3 upregulation, reduced STAT3 phosphorylation, and activation of the IKK/NF-κB inflammatory pathway. In parallel, SELENOF deficiency reduced circulating free triiodothyronine (FT3) levels and the ratio of free triiodothyronine to free thyroxine (FT3/FT4 ratio), and suppressed DIO2 and UCP1 expression in brown adipose tissue (BAT). Experiments in primary brown adipocytes further showed that SELENOF deficiency did not disrupt proximal β3-adrenergic signaling but attenuated the downstream induction of DIO2 and UCP1. Collectively, these findings provide preliminary evidence that SELENOF is associated with sex-dependent metabolic adaptation during HFD-induced stress by linking hypothalamic proteostasis with the thyroid hormone-related thermogenic signaling program in BAT.