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 4

COX-2 deficiency suppressed IF-induced Treg proliferation and improvement of insulin resistance.

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COX-2 deficiency suppressed IF-induced Treg proliferation and improvemen...
A HFD was fed to 6-week-old male COX-2–KO and control (Ctrl) mice for 8 weeks followed by IF (n = 6–8/group) for 30 days. (A) IF led to a 32.6% loss of fat mass and a 18.7% loss of body mass but not lean mass in Ctrl mice, and the antiobesity effect was not significantly affected by COX-2 deficiency. (B) IF-induced mass loss in eWAT and BAT was little affected, whereas the effects on iWAT and liver were suppressed in COX-2–KO mice compared with Ctrl mice. (C) Representative images of eWAT, iWAT, BAT, and liver in HFD-fed COX-2–KO and Ctrl mice before and after IF. COX-2 deficiency alleviated IF-induced increase in the Treg fraction (D) and the proportion of Tregs in CD4+ cells (E); suppressed the inhibitory effects of IF on the γδT cell fraction (F) and the proportion of γδT cells in CD3+ cells (G); and diminished the inducing effect of IF on mRNA levels of Foxp3, GATA3, and TGFβ3 with little effect on IL-10, TGFβ1, and TGFβ2 (H) in eWAT. (I) COX-2 deficiency diminished IF-improved glucose tolerance. (J) COX-2 deficiency diminished IF-improved insulin tolerance. (K and L) Insulin-stimulated phosphorylation of Akt at Thr308 (T308) and Ser473 (S473) in the liver of COX-2–KO and Ctrl mice treated with or without IF. n = 4/group. *P < 0.05 and **P < 0.01 for Ad vs. IF in Ctrl mice; #P < 0.05 for Ctrl vs. KO mice with Ad diet; $P < 0.05 for Ad vs. IF in KO mice. ANOVA was used to analyze all the data in this figure. (A, B, and D–H) Data are presented as mean ± SEM. * P < 0.05; **P < 0.01.