Adipocyte-derived PGE2 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 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 gamma delta T 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.

Automated summary

The intermittent fasting (IF) diet has been found to have significant benefits for diabetes prevention, but the specific mechanisms underlying its effects are not well understood. This study shows that COX-2 expression is suppressed in the white adipose tissue (WAT) of obese humans and is upregulated in the WAT of obese mice when subjected to IF. Depletion of COX-2 in adipocytes leads to a decrease in the fractions of Tregs and a decrease in the frequency of macrophages in WAT, along with an increase in the abundance of gamma delta T cells. Adipocyte-derived PGE2 promotes Treg proliferation and is essential for the immune and metabolic benefits of IF.