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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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 1

COX-2 expression in adipose tissue macrophages from epididymal fat increased in the early phase of DIO.

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COX-2 expression in adipose tissue macrophages from epididymal fat incre...
Male FVB mice were fed an HFD for 4 or 12 weeks. (A) Flow cytometry gating on the SVF indicated that the HFD led to increased EF CD45+CD11b+F4/80+ ATMs (n = 4). (B–E) Four weeks of the HFD led to increases in mRNA levels of both EF Cd68 and Emr1 (B), plasma levels of insulin (C), FFA (D), and glycerol (E) (n = 5). (F) Isolated EF ATM Ptgs2 mRNA levels were increased in mice with the HFD for 4 or 12 weeks (n = 6). (G–J) PA stimulated COX-2 expression in isolated mouse peritoneal macrophages (G), in the human macrophage-like THP1 cells (H and I), and in the mouse macrophage-like RAW264.7 cells (J) (n = 3–4 independent repeats). Data are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, analyzed using 2-tailed Student’s t test for A–E and G–J and 2-way ANOVA followed by Bonferroni’s post hoc test for F. EF, epididymal fat; FFA, free fatty acid; PA, palmitic acid; SVF, stromal vascular fraction.