Introduction and Objective: Regulatory T (Treg) cells serve essential roles in immune tolerance and systemic tissue homeostasis remodeling under distinct physiological and pathological conditions. Visceral adipose tissue (VAT) Treg cells constitute a heterogeneous population capable of responding to diverse microenvironmental signals, however, the precise mechanisms by which VAT Treg cells regulate adipose tissue metabolic homeostasis in obesity remain largely unknown.Methods: Single-cell RNA sequencing (scRNA-seq) was performed to identify ICOShi Treg cell subset is distinct from previously characterized visceral adipose Treg cell populations and exhibited superior immunosuppressive function. The adoptive transfer approach using Rag1-/- mice fed a high-fat, high-sucrose (HFHS) diet as recipients was performed to assess the suppressive function of ICOShi Treg on obesity-induced inflammation and metabolic disturbance.Results: We identified a previously uncharacterized population of ICOShi Treg cells in visceral adipose tissue (VAT) that are primary producers of IL-10. Specifically, the transcription factor CREBZF is induced by palmitic acid and is enriched in ICOShi Treg cells. Treg cell-specific CREBZF deficiency significantly enhanced the abundance and immunosuppressive capacity of visceral adipose ICOShi Tregs, thereby mitigating HFHS diet-induced inflammation and metabolic disorders. Mechanistically, CREBZF impairs ICOShi Treg cell stability and IL-10 production to inhibit Foxp3 transcriptional activity. In human subjects, the CREBZF levels of in visceral adipose Treg cells are elevated and negatively correlated with Foxp3 activity.Conclusion: Collectively, our findings uncover a specific ICOShi Treg subset that acts as a sensor for palmitic acid, thereby regulating visceral adipose tissue remodeling and systemic metabolic homeostasis.
W. Su: None. Y. Liu: None. M. Huang: None. L. Xu: None. J. Lin: None. W. Li: None. S. Wei: None. J. Shen: None. B. Xing: None. P. Hu: None. Z. Zheng: None. D. Ding: None. L. Zhang: None. L. Li: None. M. Wu: None. A. Cui: None. Y. Li: None.
Noncommunicable Chronic Diseases-National Science and Technology Major Project (2024ZD0531300), Strategic Priority Research Program of the Chinese Academy of Science (XDB1150000), National Key R&D Program of China (2023YFA1801100), National Natural Science Foundation of China (32130047), Shanghai Municipal Science and Technology Major Project, Postdoctoral Fellowship Program of CPSF (GZC20251002), Natural Science Foundation of Shanghai (24ZR1478200)
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