Chronic inflammation causes visceral white adipose tissue (VAT) dysfunction and systemic metabolic disturbance in obesity. However, how the obese microenvironment reshapes the heterogeneity and functional integrity of tissue-resident Treg cells remains largely unexplored.

In a study published online in The Journal of Clinical Investigation, a team led by Prof. LI Yu from the Shanghai Institute of Nutrition and Health of the Chinese Academy of Sciences and the collaborators identified a novel mechanism by which palmitic acid induces CREBZF overactivation, impairing ICOS^hi Treg-mediated immunosuppression and exacerbating metabolic disturbance in obesity.

Through single‑cell RNA sequencing on VAT from obese mice, researchers identified two functionally distinct Treg subsets: KLRG1^hi and ICOS^hi. The ICOS^hi subset exhibited potent immunosuppressive activity, and its frequency and suppressive function were markedly impaired under obese conditions.

Researchers revealed transcription factor CREBZF as a critical regulator of ICOS^hi Treg function. CREBZF deficiency enhanced both the stability and immunosuppressive activity of these cells, alleviating visceral adipose inflammation. When transferred into Rag1^-/- mice, CREBZF‑deficient ICOS^hi Treg cells suppressed local inflammation and improved systemic metabolic abnormalities more effectively.

Besides, researchers found that elevated palmitic acid in the obese milieu induced CREBZF expression in ICOS^hi Treg cells. CREBZF directly interacted with c‑JUN to inhibit AP‑1 transcriptional activity, suppressing Foxp3 activity and impairing the stability and production of inhibitory cytokines in ICOS^hi Treg cells.

Importantly, CREBZF expression levels were significantly negatively correlated with FOXP3 as well as anti-inflammatory cytokines IL-10 and TGFβ in VAT from obese human subjects.

This study advances the understanding of how palmitic acid–CREBZF signaling impairs ICOS^hi Treg subset function, and demonstrates that targeting this regulatory axis offers therapeutic potential for treating obesity-related metabolic diseases.