SOSTDC1 downregulation in CD4+ T cells confers protection against obesity-induced insulin resistance
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<sup>+</sup> 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.
Authors
- Guodong Sun (ORCID: https://orcid.org/0000-0001-5336-368X)
- Jie Wu (ORCID: https://orcid.org/0000-0001-6326-9582)
- Zonghua Liu (ORCID: https://orcid.org/0000-0002-2036-4640)
- Qiping Shi (ORCID: https://orcid.org/0000-0002-2866-3266)
- Dehai Li (ORCID: https://orcid.org/0000-0002-7191-2002)
- Daming Zhang (ORCID: https://orcid.org/0000-0002-5651-8699)
- Hongyun Lu (ORCID: https://orcid.org/0000-0001-8794-0887)
- Hengwen Yang (ORCID: https://orcid.org/0000-0002-6418-1985)
- Guangchao Cao (ORCID: https://orcid.org/0000-0003-2069-3396)
- Zhinan Yin (ORCID: https://orcid.org/0000-0001-6524-8777)
- Hua Zhang (ORCID: https://orcid.org/0000-0002-6767-4750)
- Qiong Wen (ORCID: https://orcid.org/0000-0002-0517-8460)
- Xindong Liu (ORCID: https://orcid.org/0000-0002-2465-0337)
- Qian Wang (ORCID: https://orcid.org/0000-0003-4755-7001)
- Mingyue Zhang (ORCID: https://orcid.org/0000-0002-2293-8847)
- Pei Zheng (ORCID: https://orcid.org/0000-0002-5170-3123)
- Guangqiang Li (ORCID: https://orcid.org/0000-0002-4471-7439)
- Jing Zhu
- Rong Guo
- Jingyi Tan (ORCID: https://orcid.org/0009-0001-8597-6998)
Institutions
- Army Medical University (CN)
- Shandong University (CN)
- Jinan University (CN)
- Zhuhai People's Hospital (CN)
- Southwest Hospital (CN)
- First Affiliated Hospital of Gannan Medical University (CN)
- First Affiliated Hospital of Jinan University (CN)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-04-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.115496
- Citations
- 6
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 4.78