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 3

CREBZF in Tregs links eWAT inflammation to systemic metabolic dysfunction during obesity.

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CREBZF in Tregs links eWAT inflammation to systemic metabolic dysfunctio...
Male Foxp3-Cre Crebzffl/fl and control Foxp3-Cre mice at 8 weeks were fed a chow or HFHS diet for 16 weeks. (A) Representative appearance of mice and tissues of Foxp3-Cre and Foxp3-Cre Crebzffl/fl mice fed a chow or HFHS diet. (B) Body weight, fasting blood glucose levels, plasma insulin levels, and HOMA-IR. (C) GTT results and AUC. (D) ITT results and AUC. (E) Plasma triglyceride and cholesterol levels. (B–E) Data are presented as the mean ± SEM. Chow group, n = 4–9; HFHS group, n = 6–13. Two-way ANOVA for multiple comparison. *P < 0.05 versus Foxp3-Cre and chow; #P < 0.05 versus Foxp3-Cre and HFHS. (F) Representative H&E staining of eWAT from Foxp3-Cre and Foxp3-Cre Crebzffl/fl mice fed a chow or HFHS diet. Scale bars: 50 μm. (G) Quantification of diameters of adipocytes from mice. n = 4–5. (H and I) Relative mRNA levels of inflammatory (H), lipid metabolism–, and mitochondria-related (I) genes in eWAT of mice fed a HFHS diet. (G–I) Data are presented as the mean ± SEM. n = 4–11. Two-tailed, unpaired Student’s t test. *P < 0.05 versus Foxp3-Cre. (J and K) Representative flow cytometric plots (J) and quantification of frequencies and numbers (K) of Tregs in eWAT of mice. (L and M) Representative flow cytometric plots (L) and quantification of frequencies and numbers (M) of IL-10+ Tregs in eWAT of mice. (N and O) Representative flow cytometric plots (N) and quantification of frequencies and numbers (O) of TGF-β+ Tregs in eWAT of mice. Data are presented as the mean ± SEM. Chow group, n = 3–10; HFHS group, n = 4–16. Two-way ANOVA for multiple comparison. *P < 0.05 versus Foxp3-Cre and chow; #P < 0.05 versus Foxp3-Cre and HFHS.