硒蛋白F通过脂肪组织IRE1α介导的内质网应激调控饮食诱导的雌性特异性肥胖
Selenoprotein F gates diet-induced female-specific obesity via adipose IRE1α-mediated endoplasmic reticulum stress.
摘要(中文译文)
肥胖已成为全球性流行病和重大公共卫生挑战。内质网应激将营养过剩与肥胖联系起来，但内质网驻留硒蛋白F（SELENOF）是否调控这一过程仍不清楚。本研究发现，全身性SELENOF敲除（KO）仅特异性加剧了雌性小鼠高脂饮食（HFD）诱导的肥胖、高脂血症和肝脂肪变性，而对雄性小鼠无显著影响。SELENOF KO雌性小鼠的肥胖表型由脂肪细胞肥大驱动，其源于协调性脂质代谢转变——以脂肪生成增加、脂解受损和脂肪酸氧化受抑制为特征。这些脂质代谢紊乱与内质网应激相耦合，尤其是脂肪组织中IRE1α的过度激活。此外，在来源于雌性小鼠的原代脂肪细胞中，SELENOF缺失进一步加剧了游离脂肪酸（FFA）诱导的脂质代谢紊乱、内质网应激和线粒体功能障碍，而IRE1α特异性抑制剂4μ8C可显著逆转上述效应。总之，SELENOF KO通过以雌性特异性方式促进脂肪组织IRE1α介导的内质网应激，加重了HFD诱导的肥胖和脂质代谢紊乱。这一发现提示，SELENOF是雌性特异性的脂质稳态守护者，可能有助于抵御肥胖和代谢紊乱。
Abstract
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.
如何引用
AMA
Zimeng Li, Pengyu Zhao, Wanru Yang, Jun Zhou, Hongmei Liu. Selenoprotein F gates diet-induced female-specific obesity via adipose IRE1α-mediated endoplasmic reticulum stress.. Biochimica et biophysica acta. Molecular basis of disease. 2027; doi:10.1016/j.bbadis.2026.168411.
APA
Zimeng Li, Pengyu Zhao, Wanru Yang, Jun Zhou, Hongmei Liu (2027). Selenoprotein F gates diet-induced female-specific obesity via adipose IRE1α-mediated endoplasmic reticulum stress.. Biochimica et biophysica acta. Molecular basis of disease. https://doi.org/10.1016/j.bbadis.2026.168411
GB/T 7714
Zimeng Li, Pengyu Zhao, Wanru Yang, Jun Zhou, Hongmei Liu. Selenoprotein F gates diet-induced female-specific obesity via adipose IRE1α-mediated endoplasmic reticulum stress.[J]. Biochimica et biophysica acta. Molecular basis of disease, 2027 doi:10.1016/j.bbadis.2026.168411.
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