Palmitic acid coordinates impaired visceral adipose ICOShi Treg-mediated immunosuppression and systemic metabolic disturbance during obesity

Tregs in visceral adipose tissue (VAT) play essential roles in systemic metabolic homeostasis under distinct physiological and pathological conditions. However, the metabolic cues that drive Treg subset specialization in the obese VAT niche remain elusive. Here, we demonstrated that palmitic acid (PA) instigated chronic VAT inflammation and systemic metabolic disturbance by compromising the immunosuppressive function of the ICOShi Treg subset. PA, but not oleic acid, activated CREB/ATF bZIP transcription factor (Crebzf) expression in VAT Tregs from high-fat, high-sucrose diet-induced (HFHS diet-induced) obese and ob/ob mice. Crebzf deficiency significantly attenuated diet-induced obesity and inflammation by upregulating the suppressive function of VAT ICOShi Tregs. Moreover, adoptive transfer of Crebzf-deficient ICOShi Tregs into Rag1-/- mice alleviated HFHS diet-induced inflammation and metabolic disorders more effectively than transfer of Crebzf-sufficient ICOShi Tregs. Mechanistically, CREBZF interacted with c-JUN to inhibit Foxp3 activity, thereby impairing the stability and inhibitory cytokine production of ICOShi Tregs. In humans, CREBZF levels in VAT Tregs were elevated and negatively correlated with FOXP3 activity. Collectively, these findings uncover a specific ICOShi Treg subset that responds to PA, thereby coupling obesogenic signals to VAT remodeling and systemic metabolic homeostasis.