CD4 T细胞中SOSTDC1的下调赋予了对肥胖诱导的胰岛素抵抗的保护作用。
SOSTDC1 downregulation in CD4 T cells confers protection against obesity-induced insulin resistance.
作者信息
Li Dehai, Zhu Jing, Zhang Mingyue, Shi Qiping, Guo Rong, Zhang Daming, Zheng Pei, Zhang Hua, Li Guangqiang, Wu Jie, Sun Guodong, Wen Qiong, Tan Jingyi, Liu Zonghua, Liu Xindong, Yang Hengwen, Lu Hongyun, Cao Guangchao, Yin Zhinan, Wang Qian
机构信息
Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University), Jinan University, Zhuhai 519000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China; Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China.
Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University), Jinan University, Zhuhai 519000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, The Biomedical Translational Research Institute, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China; Key Laboratory of Viral Pathogenesis & Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou 510632, China.
出版信息
Cell Rep. 2025 Apr 22;44(4):115496. doi: 10.1016/j.celrep.2025.115496. Epub 2025 Apr 1.
Adipose-resident T cells play a crucial role in the development of obesity-induced insulin resistance. However, the specific mechanisms, particularly those involving non-immune cytokines, remain unclear. Here, we report significantly elevated levels of sclerostin domain-containing protein 1 (SOSTDC1) in individuals with type 2 diabetes (T2D), showing positive correlations with fasting glucose and HbA1c. T cell-specific Sostdc1-deficient mice exhibit resistance to age-induced adipose lipid accumulation and glucose dysregulation at 12 months and protect against obesity-induced insulin resistance without affecting proinflammatory macrophage infiltration or adipose inflammation. Mechanistically, SOSTDC1 disrupts the lipid balance in adipocytes by promoting lipogenesis and inhibiting lipolysis through the LRP5/6-β-catenin pathway. Furthermore, T cell receptor (TCR) signaling significantly amplifies SOSTDC1 secretion in CD4 T cells. In summary, our study uncovers an additional mechanism by which T cells contribute to obesity and insulin resistance, suggesting that inhibiting SOSTDC1 could be a promising immunotherapeutic strategy for metabolic disorders.
脂肪组织驻留T细胞在肥胖诱导的胰岛素抵抗发展中起关键作用。然而，具体机制，尤其是涉及非免疫细胞因子的机制仍不清楚。在此，我们报告2型糖尿病（T2D）患者中含硬化蛋白结构域蛋白1（SOSTDC1）水平显著升高，且与空腹血糖和糖化血红蛋白（HbA1c）呈正相关。T细胞特异性Sostdc1基因敲除小鼠在12个月时对年龄诱导的脂肪脂质积累和葡萄糖调节异常具有抗性，并能预防肥胖诱导的胰岛素抵抗，且不影响促炎巨噬细胞浸润或脂肪炎症。从机制上讲，SOSTDC1通过促进脂肪生成并通过LRP5/6-β-连环蛋白途径抑制脂肪分解来破坏脂肪细胞中的脂质平衡。此外，T细胞受体（TCR）信号显著增强CD4 T细胞中SOSTDC1的分泌。总之，我们的研究揭示了T细胞导致肥胖和胰岛素抵抗的另一种机制，表明抑制SOSTDC1可能是一种有前景的代谢紊乱免疫治疗策略。
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