Cyclooxygenase-2 in adipose tissue macrophages limits adipose tissue dysfunction in obese mice
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
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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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 6

Increased monocyte recruitment and proliferation of ATMs contributed to more ATM accumulation in the HFD-treated myeloid COX-2–/– mice.

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Increased monocyte recruitment and proliferation of ATMs contributed to ...
WT and myeloid COX-2–/– mice were on the HFD for 4 weeks and EF was used for experiments. (A) Schematic of experimental protocol. (B) The percentage of CD45+ live cells and CD45+CD11b+F4/80+ ATMs in EF were markedly higher in myeloid COX-2–/– mice than in WT mice (n = 4). (C) COX-2–/– BMDMs had increased EF infiltration in both WT and myeloid COX-2–/– recipients, and myeloid COX-2–/– recipients had increased WT and COX-2–/– monocyte recruitment (n = 4). (D) Myeloid COX-2–/– mice had increased EF ATM proliferation rates. n = 4. (E) Myeloid COX-2–/– mice had more Ki67-positive EF ATMs (n = 4). Scale bars: 50 μm. (F) Both infiltrating WT and COX-2–/– BMDMs had greater EdU incorporation in myeloid COX-2–/– than WT recipients (n = 4). Data are mean ± SEM. **P < 0.01, analyzed using 2-tailed Student’s t test for B, D, and E, and 2-way ANOVA followed by Bonferroni’s post hoc test for C and F. EF, epididymal fat.