Obesity-associated complications are causing increasing morbidity and mortality worldwide. Expansion of adipose tissue in
obesity leads to a state of low-grade chronic
inflammation and dysregulated metabolism, resulting in
insulin resistance and
metabolic syndrome. Adipose tissue macrophages (ATMs) accumulate in
obesity and are a source of proinflammatory
cytokines that further aggravate adipocyte dysfunction. Macrophages are rich sources of
cyclooxygenase (COX), the rate limiting
enzyme for
prostaglandin E2 (
PGE2) production. When mice were fed a high-fat diet (HFD), ATMs increased expression of COX-2. Selective myeloid cell COX-2 deletion resulted in increased monocyte recruitment and proliferation of ATMs, leading to increased proinflammatory ATMs with decreased phagocytic ability. There were increased
weight gain and adiposity, decreased peripheral
insulin sensitivity and
glucose utilization, increased adipose tissue
inflammation and
fibrosis, and abnormal adipose tissue angiogenesis. HFD pair-feeding led to similar increases in
body weight, but mice with selective myeloid cell COX-2 still exhibited decreased peripheral
insulin sensitivity and
glucose utilization. Selective myeloid deletion of the macrophage
PGE2 receptor subtype, EP4, produced a similar phenotype, and a selective EP4 agonist ameliorated the metabolic abnormalities seen with ATM COX-2 deletion. Therefore, these studies demonstrated that an ATM COX-2/
PGE2/EP4 axis plays an important role in inhibiting adipose tissue dysfunction.