Adipocyte-derived PGE2 is required for intermittent fasting–induced Treg proliferation and improvement of insulin sensitivity
Chunqing Wang, Xing Zhang, Liping Luo, Yan Luo, Xin Yang, Xiaofeng Ding, Lu Wang, Huyen Le, Lily Elizabeth R. Feldman, Xuebo Men, Cen Yan, Wendong Huang, Yingmei Feng, Feng Liu, Xuexian O. Yang, Meilian Liu
Chunqing Wang, Xing Zhang, Liping Luo, Yan Luo, Xin Yang, Xiaofeng Ding, Lu Wang, Huyen Le, Lily Elizabeth R. Feldman, Xuebo Men, Cen Yan, Wendong Huang, Yingmei Feng, Feng Liu, Xuexian O. Yang, Meilian Liu
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Research Article Metabolism

Adipocyte-derived PGE2 is required for intermittent fasting–induced Treg proliferation and improvement of insulin sensitivity

Abstract

The intermittent fasting (IF) diet has profound benefits for diabetes prevention. However, the precise mechanisms underlying IF’s beneficial effects remain poorly defined. Here, we show that the expression levels of cyclooxygenase-2 (COX-2), an enzyme that produces prostaglandins, are suppressed in white adipose tissue (WAT) of obese humans. In addition, the expression of COX-2 in WAT is markedly upregulated by IF in obese mice. Adipocyte-specific depletion of COX-2 led to reduced fractions of CD4+Foxp3+ Tregs and a substantial decrease in the frequency of CD206+ macrophages, an increase in the abundance of γδT cells in WAT under normal chow diet conditions, and attenuation of IF-induced antiinflammatory and insulin-sensitizing effects, despite a similar antiobesity effect in obese mice. Mechanistically, adipocyte-derived prostaglandin E2 (PGE2) promoted Treg proliferation through the CaMKII pathway in vitro and rescued Treg populations in adipose tissue in COX-2–deficient mice. Ultimately, inactivation of Tregs by neutralizing anti-CD25 diminished IF-elicited antiinflammatory and insulin-sensitizing effects, and PGE2 restored the beneficial effects of IF in COX-2–KO mice. Collectively, our study reveals that adipocyte COX-2 is a key regulator of Treg proliferation and that adipocyte-derived PGE2 is essential for IF-elicited type 2 immune response and metabolic benefits.

Authors

Chunqing Wang, Xing Zhang, Liping Luo, Yan Luo, Xin Yang, Xiaofeng Ding, Lu Wang, Huyen Le, Lily Elizabeth R. Feldman, Xuebo Men, Cen Yan, Wendong Huang, Yingmei Feng, Feng Liu, Xuexian O. Yang, Meilian Liu

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Figure 1

COX-2 expression is suppressed by obesity and is induced by IF in AT.

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COX-2 expression is suppressed by obesity and is induced by IF in AT. Th...
The expression levels of COX-2 but not COX-1 in protein (A and B) and mRNA (C) were suppressed by obesity in visceral fat of human participants, compared with that of lean controls, despite a decrease in mRNA of PTGS2, a gene that encodes human COX-2. PTGS1 is a gene encoding human COX-1. Tubulin was used as the loading control. The expression levels of COX-2 but not COX-1 in protein (D and E) and mRNA (F) were markedly induced by IF in eWAT of mice with diet-induced obesity. The protein (G and H) and mRNA (I) levels of COX-2 in iWAT were also induced by IF despite the suppression of COX-1 in protein in obese mice. The upregulation of COX-2 expression by IF was also observed in eWAT (J–L) and iWAT (M and N) of NCD mice, although no significant effect was observed on the mRNA levels of both Ptgs2, a gene that encodes mouse COX-2, and Ptgs1, a gene that encodes mouse COX-1, in iWAT (O). We fed 6-week-old male mice a 45% HFD or NCD for 8 weeks, which was followed by Ad or IF for 30 days. All data in this figure were analyzed by t test and are presented as the mean ± SEM. *P < 0.05; **P < 0.01.