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Adipocyte-derived PGE(2) is required for intermittent fasting–induced Treg proliferation and improvement of insulin sensitivity

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...

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Autores principales: Wang, Chunqing, Zhang, Xing, Luo, Liping, Luo, Yan, Yang, Xin, Ding, Xiaofeng, Wang, Lu, Le, Huyen, Feldman, Lily Elizabeth R., Men, Xuebo, Yan, Cen, Huang, Wendong, Feng, Yingmei, Liu, Feng, Yang, Xuexian O., Liu, Meilian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8983131/
https://www.ncbi.nlm.nih.gov/pubmed/35260536
http://dx.doi.org/10.1172/jci.insight.153755
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author Wang, Chunqing
Zhang, Xing
Luo, Liping
Luo, Yan
Yang, Xin
Ding, Xiaofeng
Wang, Lu
Le, Huyen
Feldman, Lily Elizabeth R.
Men, Xuebo
Yan, Cen
Huang, Wendong
Feng, Yingmei
Liu, Feng
Yang, Xuexian O.
Liu, Meilian
author_facet Wang, Chunqing
Zhang, Xing
Luo, Liping
Luo, Yan
Yang, Xin
Ding, Xiaofeng
Wang, Lu
Le, Huyen
Feldman, Lily Elizabeth R.
Men, Xuebo
Yan, Cen
Huang, Wendong
Feng, Yingmei
Liu, Feng
Yang, Xuexian O.
Liu, Meilian
author_sort Wang, Chunqing
collection PubMed
description 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 E(2) (PGE(2)) 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 PGE(2) 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 PGE(2) is essential for IF-elicited type 2 immune response and metabolic benefits.
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spelling pubmed-89831312022-04-07 Adipocyte-derived PGE(2) is required for intermittent fasting–induced Treg proliferation and improvement of insulin sensitivity Wang, Chunqing Zhang, Xing Luo, Liping Luo, Yan Yang, Xin Ding, Xiaofeng Wang, Lu Le, Huyen Feldman, Lily Elizabeth R. Men, Xuebo Yan, Cen Huang, Wendong Feng, Yingmei Liu, Feng Yang, Xuexian O. Liu, Meilian JCI Insight Research Article 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 E(2) (PGE(2)) 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 PGE(2) 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 PGE(2) is essential for IF-elicited type 2 immune response and metabolic benefits. American Society for Clinical Investigation 2022-03-08 /pmc/articles/PMC8983131/ /pubmed/35260536 http://dx.doi.org/10.1172/jci.insight.153755 Text en © 2022 Wang et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Wang, Chunqing
Zhang, Xing
Luo, Liping
Luo, Yan
Yang, Xin
Ding, Xiaofeng
Wang, Lu
Le, Huyen
Feldman, Lily Elizabeth R.
Men, Xuebo
Yan, Cen
Huang, Wendong
Feng, Yingmei
Liu, Feng
Yang, Xuexian O.
Liu, Meilian
Adipocyte-derived PGE(2) is required for intermittent fasting–induced Treg proliferation and improvement of insulin sensitivity
title Adipocyte-derived PGE(2) is required for intermittent fasting–induced Treg proliferation and improvement of insulin sensitivity
title_full Adipocyte-derived PGE(2) is required for intermittent fasting–induced Treg proliferation and improvement of insulin sensitivity
title_fullStr Adipocyte-derived PGE(2) is required for intermittent fasting–induced Treg proliferation and improvement of insulin sensitivity
title_full_unstemmed Adipocyte-derived PGE(2) is required for intermittent fasting–induced Treg proliferation and improvement of insulin sensitivity
title_short Adipocyte-derived PGE(2) is required for intermittent fasting–induced Treg proliferation and improvement of insulin sensitivity
title_sort adipocyte-derived pge(2) is required for intermittent fasting–induced treg proliferation and improvement of insulin sensitivity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8983131/
https://www.ncbi.nlm.nih.gov/pubmed/35260536
http://dx.doi.org/10.1172/jci.insight.153755
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