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 8

Mice with myeloid EP4 deletion had similar ATM dysfunction as myeloid COX-2–/– mice.

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Mice with myeloid EP4 deletion had similar ATM dysfunction as myeloid CO...
WT mice and myeloid EP4–/– mice were fed with the HFD for 12 weeks. (A and B) Myeloid EP4–/– mice had higher EF mRNA levels of proinflammatory cytokines (Tnf, Il6, and Il1b) (A) and higher EF TNF-α protein levels (B) (n = 5 and 6). (C) CD31 immunofluorescent staining showed less vascular density in myeloid EP4–/– mice. Scale bars: 100 μm (left) and 50 μm (right). (D and E) Myeloid EP4–/– mice had decreased EF Vegfa mRNA expression (D) and decreased EF ATM VEGF-A expression (E) (n = 4 and 6). Scale bar: 50 μm. (F and G) Myeloid EP4–/– mice had decreased adipose tissue perilipin 1 (Plin1) mRNA (F) and protein (G) expression (n = 6). Scale bar: 100 μm. (H) Myeloid EP4–/– mice had increased EF mRNA expression of Acta2, Tgfb1, and Col1a1 (n = 6). (I) Myeloid EP4–/– mice had significantly increased fibrosis in both EF and IF, with more than 4-fold higher level of fibrosis in EF compared with IF (n = 8). Scale bar: 100 μm. (J) Myeloid EP4–/– mice had decreased EF ATM expression of LAMP2A, a marker of ATM MMe polarization. Scale bar: 100 μm. Data are mean ± SEM. *P < 0.05, **P < 0.01, by 2-tailed Student’s t test for A, B, D, E, and H, and 2-way ANOVA followed by Bonferroni’s post hoc test for F and I. EF, epididymal fat; IF inguinal fat.