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 7

The PGE2/Treg axis is indispensable for the antiinflammatory and insulin-sensitizing effects of IF.

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The PGE2/Treg axis is indispensable for the antiinflammatory and insulin...
HFD-fed COX-2–KO mice were fed on an IF schedule or Ad for 4 weeks. Two weeks after IF, mice were injected with PGE2 or vehicle (Veh) for 2 weeks. (A) PGE2 administration resulted in significantly decreased body mass of COX-2–KO mice under both IF and Ad conditions. n = 5–8/group. Treatment with PGE2 restored the AT Treg population (B) and the proportion of Tregs in CD4+ cells (C) in COX-2–KO mice under both IF and Ad conditions. n = 4/group. PGE2 administration improved glucose (D) and insulin (E) tolerance in COX-2–KO mice under both IF and Ad conditions. *P < 0.05 and **P < 0.01 for Veh vs. PGE2 with Ad diet; #P < 0.05 for Ad vs. IF with Veh treatment; $P < 0.05 and $$P < 0.01 for IF Veh vs. IF PGE2. HFD-fed C57BL/6 mice were administered CD25 neutralizing antibody for 2 days, followed by PGE2 injection. (F) Blocking the Treg pathway had no significant effect on the antiobesity effect of PGE2, as indicated by the body mass. n = 5–8/group. (G and H) Neutralization of CD25 diminished the inducing effects of PGE2 on the AT Treg population. n = 5/group. Blocking the Treg pathway impaired basal and PGE2-increased glucose (I) and insulin (J) tolerance. *P < 0.05 and **P < 0.01 for Veh vs. PGE2; #P < 0.05 and ##P < 0.01 for Ctrl vs. anti-CD25 (aCD25); $P < 0.05 and $$P < 0.01 for aCD25 vs. PGE2 aCD25. (K) Working model. ANOVA was used to analyze the data in this figure. All data are reported as mean ± SEM. LN, lymph node.