Cyclooxygenase-2 in adipose tissue macrophages limits adipose tissue dysfunction in obese mice
Yu Pan, … , Ming-Zhi Zhang, Raymond C. Harris
Yu Pan, … , Ming-Zhi Zhang, Raymond C. Harris
Published May 2, 2022
Citation Information: J Clin Invest. 2022;132(9):e152391. https://doi.org/10.1172/JCI152391.
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Research Article Inflammation Metabolism

Cyclooxygenase-2 in adipose tissue macrophages limits adipose tissue dysfunction in obese mice

Abstract

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.

Authors

Yu Pan, Shirong Cao, Jiaqi Tang, Juan P. Arroyo, Andrew S. Terker, Yinqiu Wang, Aolei Niu, Xiaofeng Fan, Suwan Wang, Yahua Zhang, Ming Jiang, David H. Wasserman, Ming-Zhi Zhang, Raymond C. Harris

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Figure 9

An EP4 agonist ameliorated HFD-induced metabolic syndrome in myeloid COX-2–/– mice but not in myeloid EP4–/– mice.

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An EP4 agonist ameliorated HFD-induced metabolic syndrome in myeloid COX...
Myeloid COX-2–/– mice and myeloid EP4–/– mice were treated with the HFD for 10 weeks with or without the selective EP4 agonist (EP4a). (A) The EP4a attenuated the HFD-induced gain of body weight in myeloid COX-2–/– mice but not in myeloid EP4–/– mice (n = 8–9). (B and C) The EP4a improved glucose and insulin tolerance in myeloid COX-2–/– mice (B) but not in myeloid EP4–/– mice (C) (n = 8). (D) The EP4a decreased SAT, VAT, and liver mass in the HFD-treated myeloid COX-2–/– mice (n = 9). (E and F) Flow cytometry demonstrated that the EP4a decreased EF ATM number (E) and proinflammatory polarization (CD45+CD11b+F4/80+CD1c+) (F) in myeloid COX-2–/– mice (n = 4 and 5). (G) Immunoblotting showed increased EF insulin-stimulated p-AKT in the EP4a-treated myeloid COX-2–/– mice (n = 4 and 5). (H) Graphical summary of the current studies. Data are mean ± SEM. *P < 0.05, **P < 0.01, analyzed using 2-tailed Student’s t test for A and D–G, and 2-tailed Student’s t test and 2-way ANOVA followed by Tukey’s post hoc test for B and C. EF, epididymal fat; subcutaneous and visceral adipose tissue (SAT and VAT).