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Published on: May 19, 2023
Adipocyte-derived PGE2 is required for intermittent fasting-induced Treg proliferation and improvement of insulin
Chunqing Wang1, Xing Zhang1, Liping Luo1
1Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.
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.
Insights
Intermittent fasting (IF) benefits diabetes prevention by regulating cyclooxygenase-2 (COX-2) in white adipose tissue. This pathway influences immune cells, enhancing anti-inflammatory and insulin-sensitizing effects.
Area of Science:
- Immunology
- Metabolic Diseases
- Endocrinology
Background:
- Intermittent fasting (IF) shows promise for diabetes prevention, but its mechanisms are unclear.
- Cyclooxygenase-2 (COX-2) expression is reduced in obese human white adipose tissue (WAT).
Purpose of the Study:
- To elucidate the role of COX-2 in white adipose tissue (WAT) in mediating the metabolic benefits of intermittent fasting (IF).
Main Methods:
- Investigated COX-2 expression in obese human WAT and IF-treated obese mice.
- Utilized adipocyte-specific COX-2 knockout mice to assess immune cell populations and metabolic parameters.
- Examined the effect of prostaglandin E2 (PGE2) on regulatory T cell (Treg) proliferation in vitro and in vivo.
- Assessed the impact of Treg inactivation on IF-induced metabolic improvements.
Main Results:
- IF upregulated COX-2 expression in mouse WAT.
- Adipocyte COX-2 deficiency altered immune cell composition in WAT and attenuated IF's anti-inflammatory and insulin-sensitizing effects.
- Adipocyte-derived PGE2 promoted Treg proliferation and restored IF benefits in COX-2 deficient mice.
- Treg inactivation diminished IF's metabolic advantages, which were rescued by PGE2.
Conclusions:
- Adipocyte COX-2 is crucial for Treg proliferation.
- Adipocyte-derived PGE2 mediates the type 2 immune response and metabolic benefits of IF.
- Targeting the COX-2/PGE2/Treg axis may offer therapeutic strategies for metabolic diseases.
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