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

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.