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 2

Adipocyte-specific depletion of COX-2 suppressed IF-induced PG production and increased adipocyte development.

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Adipocyte-specific depletion of COX-2 suppressed IF-induced PG productio...
(A–E) Three-month-old male COX-2–KO and control (Ctrl) mice were used. (A) COX-2 was highly enriched in AT compared with other tissue or organs, and adipocyte-specific depletion of COX-2 markedly downregulated COX-2 but not COX-1 protein levels in eWAT, iWAT, and BAT, with little effect on muscle, liver, pancreas, brain, or blood vessels. (B and C) The mRNA levels of Ptgs2 but not Ptgs1 were notably decreased by COX-2 depletion in eWAT and iWAT. The basal and IF secretion levels of PGE2 (D) and PGI2 (E) in eWAT and iWAT were significantly decreased in COX-2–KO mice compared with Ctrls. The tissue samples of eWAT and iWAT were minced and incubated in medium for 8 hours. The medium was collected and the levels of PGE2 and PGI2 were determined by an ELISA kit accordingly. (F–K) Six-month-old male COX-2–KO and Ctrl mice were used for these studies. (F) COX-2 deficiency promoted adipocyte development. The lean mass, fat mass, total mass, and fat percentage were measured using dual-energy X-ray absorptiometry scanning. (G) The mass of epididymal and inguinal fat pads, but not of brown fat, was increased in COX-2–KO mice. The organs were weighed after mice were euthanized. (H) Representative images of eWAT, iWAT, BAT, and liver in COX-2–KO and Ctrl mice. (I) H&E staining of eWAT, iWAT, BAT, and liver in COX-2–KO and Ctrl mice. (J and K) The fat cells’ size was enlarged by COX-2 deficiency in eWAT and iWAT. (B–G, J, and K) Data are presented as the mean ± SEM. (B, C, F, G, J, and K) Data were analyzed via t test. (D and E) ANOVA was used for statistical analysis. *P < 0.05; **P < 0.01.