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 2

Myeloid COX-2–/– mice had more significant metabolic abnormalities in DIO.

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Myeloid COX-2–/– mice had more significant metabolic abnormalities in DI...
WT (COX-2fl/fl) mice and myeloid COX-2–/– (CD11b-Cre COX-2fl/fl) mice were fed the HFD for 12 weeks. (A) Flow cytometry gating on the SVF indicated greater increases in EF ATMs in myeloid COX-2–/– mice (n = 5). (B and C) Myeloid COX-2–/– mice had more EF F4/80-positive ATMs, (B) but lower Ptgs2 mRNA levels (C), compared with WT mice (n = 5–6). Scale bar: 100 μm. (D) Representative images showed that COX-2 was expressed in many ATMs in crown-like structures in the HFD-treated WT mice but was minimally expressed in WT mice on normal chow and was undetectable in the HFD-treated myeloid COX-2–/– mice. Scale bars: 100 μm (left) and 50 μm (right). (E and F) Myeloid COX-2–/– mice had greater increases in body weight (n = 10) (E) and fat and liver masses (n = 6–8) (F). (G–J) Myeloid COX-2–/– mice had greater increases in fasting blood glucose (n = 8) (G) and HbA1c (n = 6) (H) and decreased insulin tolerance (n = 8) (I) and glucose tolerance (n = 8) (J). (K) Representative images showed more severe liver steatosis in myeloid COX-2–/– mice. Scale bar: 100 μm. Data are mean ± SEM. *P < 0.05, **P < 0.01, analyzed using 2-way ANOVA followed by Bonferroni’s post hoc test for F, 2-tailed Student’s t test for A, C, F, and H, 2-way ANOVA followed by Tukey’s post hoc test for E, G, and I, 2-tailed Student’s t test and 2-way ANOVA followed by Tukey’s post hoc test for J. EF, epididymal fat; SVF, stromal vascular fraction.