Cell Rep. 2025 Apr 1;44(4):115496. doi: 10.1016/j.celrep.2025.115496. Online ahead of print.
ABSTRACT
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.
PMID:40173040 | DOI:10.1016/j.celrep.2025.115496