Deletion of EP3 prostaglandin receptor in murine macrophages aggravates diet-induced obesity by suppressing SPARC.

Abstract

Macrophages are primary immune cells involved in obesity-triggered chronic low-grade inflammation in adipose tissues. Prostaglandin E2 (PGE2), mainly generated from macrophages, can regulate adipose tissue remodeling, yet the underlying mechanisms are not fully understood. Here, we observed that PGE2 receptor subtype 3 (EP3) was remarkably downregulated in adipose tissue macrophages from high-fat diet (HFD)-fed mice and patients with obesity. Notably, macrophage-specific deletion of EP3 exacerbated HFD-induced fat expansion, whereas EP3α isoform overexpression in macrophages alleviated obesity phenotypes. Further, EP3 deficiency suppressed secretion of anti-adipogenic matricellular protein SPARC from macrophages. SPARC deletion in macrophages abrogated the protection of EP3-overexpression against diet-induced obesity. Mechanistically, EP3 activation promoted SPARC expression by suppressing DNA methylation in macrophages through a PKA-Sp1-Dnmt1/3a signaling cascade. Finally, EP3 agonist treatment ameliorated HFD-induced obesity in mice. Thus, EP3 inhibits adipogenesis through promoting release of SPARC from macrophages, suggesting a novel therapeutic target for diet-induced obesity.