{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:47:02Z","timestamp":1785422822454,"version":"3.56.0"},"reference-count":64,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22377028 and 22077040"],"award-info":[{"award-number":["22377028 and 22077040"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["22377028 and 22077040"],"award-info":[{"award-number":["22377028 and 22077040"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Hubei Provincial Central Government Guiding Local Science and Technology Development Fund Project","award":["2025CSA096"],"award-info":[{"award-number":["2025CSA096"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>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-IRE1\u03b1, and p-PERK expression together with SOCS3 upregulation, reduced STAT3 phosphorylation, and activation of the IKK\/NF-\u03baB 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 \u03b23-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.<\/jats:p>","DOI":"10.3390\/biology15131017","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:54:42Z","timestamp":1782694482000},"page":"1017","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Selenoprotein F Deficiency Drives Diet-Induced Metabolic Dysfunction in Female Mice by Aggravating Hypothalamic Endoplasmic Reticulum Stress"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-6682-907X","authenticated-orcid":false,"given":"Zimeng","family":"Li","sequence":"first","affiliation":[{"name":"Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan 430074, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanru","family":"Yang","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan 430074, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5118-9793","authenticated-orcid":false,"given":"Hongmei","family":"Liu","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan 430074, China"},{"name":"Hubei Engineering Research Center for Biomaterials and Medical Protective Materials, Wuhan 430074, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1842","DOI":"10.1016\/j.mayocp.2023.05.026","article-title":"Obesity: A review of pathophysiology and classification","volume":"98","author":"Busebee","year":"2023","journal-title":"Mayo Clin. 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