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

Early human evidence such as case series or small samples is exploring possible benefits.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Macrophages are primary immune cells involved in obesity-triggered chronic low-grade inflammation in adipose tissues. Prostaglandin E2 (PGE 2 ), mainly generated from macrophages, can regulate adipose tissue remodeling, yet the underlying mechanisms are not fully understood. Here, we observed that PGE 2 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.

Evidence level

Early human evidence such as case series or small samples is exploring possible benefits.

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