Palmitic acid coordinates impaired visceral adipose ICOShi Treg-mediated immunosuppression and systemic metabolic disturbance during obesity
Weitong Su, Yuxiao Liu, Xi Yan, Mengyao Huang, Linghao Xu, Jing Lin, Xufeng Chen, Puyuan Hu, Chenlin Gao, Jian Wen, Hongdong Wang, Dong Ding, Zengpeng Zheng, Wenjing Li, Lianjia Li, Zhan Liu, Keyu Qian, Jing Gao, Tingting Zhang, Xiaobing Mao, Haibing Zhang, Wei Lu, Bin Li, Hong Li, Aoyuan Cui, Yan Bi, Chunxiang Zhang, Yu Li
Weitong Su, Yuxiao Liu, Xi Yan, Mengyao Huang, Linghao Xu, Jing Lin, Xufeng Chen, Puyuan Hu, Chenlin Gao, Jian Wen, Hongdong Wang, Dong Ding, Zengpeng Zheng, Wenjing Li, Lianjia Li, Zhan Liu, Keyu Qian, Jing Gao, Tingting Zhang, Xiaobing Mao, Haibing Zhang, Wei Lu, Bin Li, Hong Li, Aoyuan Cui, Yan Bi, Chunxiang Zhang, Yu Li
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Research Article Inflammation Metabolism

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

Abstract

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.

Authors

Weitong Su, Yuxiao Liu, Xi Yan, Mengyao Huang, Linghao Xu, Jing Lin, Xufeng Chen, Puyuan Hu, Chenlin Gao, Jian Wen, Hongdong Wang, Dong Ding, Zengpeng Zheng, Wenjing Li, Lianjia Li, Zhan Liu, Keyu Qian, Jing Gao, Tingting Zhang, Xiaobing Mao, Haibing Zhang, Wei Lu, Bin Li, Hong Li, Aoyuan Cui, Yan Bi, Chunxiang Zhang, Yu Li

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Figure 6

Crebzf-deficient ICOShi Tregs suppress eWAT inflammation.

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Crebzf-deficient ICOShi Tregs suppress eWAT inflammation. In an adoptiv...
In an adoptive transfer model, Crebzf-sufficient or -deficient ICOShi or KLRG1hi Tregs were transferred into Rag1–/– recipients, followed by subsequent HFHS diet feeding for 12 weeks. n = 3–5. (A) Schematic diagram of the animal experiment. (B) Fasting blood glucose levels. (C) GTT results and AUC. (D) ITT results and AUC. (E) eWAT weights. (F) Representative H&E staining of eWAT from Rag1–/– mice transferred with Tregs followed by HFHS diet feeding. Scale bars: 50 μm. (G) Relative mRNA levels of inflammatory genes in eWAT. (H and I) Representative flow cytometric plots (H) and frequencies (I) of CD11c+Ly6G+ neutrophils and F4/80+ CD11b+ macrophages in eWAT from Rag1–/– mice transferred with Tregs followed by HFHS diet feeding. Data are presented as the mean ± SEM. n = 3–5. One-way ANOVA for multiple comparison. *P < 0.05 versus no Tregs; #P < 0.05 versus Crebzf +/+ ICOShi; &P < 0.05 versus Crebzf –/– ICOShi.