Adipocyte-derived PGE2 is required for intermittent fasting-induced Treg proliferation and improvement of insulin sensitivity.
Adipocyte-derived PGE2 is required for intermittent fasting-induced Treg proliferation and improvement of insulin sensitivity.
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DOI：
10.1172/jci.insight.153755
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发表时间：
2022-03-08
期刊：
影响因子：
8
通讯作者：
Liu M
中科院分区：
文献类型：
--
作者：
Wang C;Zhang X;Luo L;Luo Y;Yang X;Ding X;Wang L;Le H;Feldman LER;Men X;Yan C;Huang W;Feng Y;Liu F;Yang XO;Liu M
间歇性禁食（IF）饮食对糖尿病的预防有深远的好处。然而，IF的有益作用的确切机制仍然不清楚。在这里，我们发现环氧化酶-2 (COX-2)，一种产生前列腺素的酶，在肥胖人群的白色脂肪组织（WAT）中表达水平受到抑制。此外，IF可显著上调肥胖小鼠WAT中COX-2的表达。脂肪细胞特异性消耗COX-2导致CD4+Foxp3+ Tregs的含量降低，CD206+巨噬细胞的频率大幅下降，正常饮食条件下WAT中γδT细胞丰度增加，if诱导的抗炎和胰岛素增敏作用减弱，尽管在肥胖小鼠中具有类似的抗肥胖作用。机制上，脂肪细胞源性前列腺素E2 （PGE2）在体外通过CaMKII途径促进Treg增殖，并挽救cox -2缺陷小鼠脂肪组织中的Treg种群。最终，通过中和抗cd25使Tregs失活，降低了IF引起的抗炎和胰岛素增敏作用，而PGE2恢复了IF在COX-2-KO小鼠中的有益作用。总之，我们的研究表明，脂肪细胞COX-2是Treg增殖的关键调节因子，脂肪细胞衍生的PGE2对于if引发的2型免疫应答和代谢益处至关重要。
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.
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影响因子：
29
作者：
Deng T;Lyon CJ;Minze LJ;Lin J;Zou J;Liu JZ;Ren Y;Yin Z;Hamilton DJ;Reardon PR;Sherman V;Wang HY;Phillips KJ;Webb P;Wong ST;Wang RF;Hsueh WA
通讯作者：
Hsueh WA
DOI：
10.1124/jpet.103.063099
发表时间：
2004-03-01
影响因子：
3.5
作者：
Davis, TW;Zweifel, BS;Masferrer, JL
通讯作者：
Masferrer, JL
影响因子：
32.4
作者：
Delacher, Michael;Imbusch, Charles D.;Feuerer, Markus
通讯作者：
Feuerer, Markus
影响因子：
30.5
作者：
Fallarino, F;Grohmann, U;Puccetti, P
通讯作者：
Puccetti, P
影响因子：
4.6
作者：
Danneskiold-Samsoe, Niels Banhos;Sonne, Si Brask;Kristiansen, Karsten
通讯作者：
Kristiansen, Karsten