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.
View: Text | PDF
Research Article Inflammation Metabolism Article has an altmetric score of 23

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

×

Figure 4

Myeloid COX-2–/– mice had greater adipocyte hypertrophy, fat tissue fibrosis, and vascular rarefaction.

Options: View larger image (or click on image) Download as PowerPoint
Myeloid COX-2–/– mice had greater adipocyte hypertrophy, fat tissue fibr...
WT and myeloid COX-2–/– mice were on the HFD for 12 weeks. (A) Myeloid COX-2–/– mice had larger adipocytes in EF (n = 390, 65 adipocytes measured from each of 6 mice in each group). Scale bars: 200 μm. (B–E) Myeloid COX-2–/– mice had increased EF mRNA expression of profibrotic and fibrotic components, including Acta2, Tgfb1, Col1a1, and Col4a1 (B), and increased α-SMA protein expression (D), but decreased EF expression of Plin1 mRNA (C) and protein (E) (n = 6 and 7). Scale bars: 100 μm. (F) Myeloid COX-2–/– mice had higher plasma FFA levels at 4 weeks but lower FFA levels at 12 weeks after the HFD (n = 5 and 6). (G and H) Myeloid COX-2–/– mice had decreased EF blood vessel density, as indicated by decreased Cd31 mRNA expression (G) and quantitative CD31 immunofluorescent staining for blood vessels (H) (n = 6). Scale bars: 100 μm (left) and 50 μm (right). (I) Myeloid COX-2–/– mice had decreased EF Vegfa (n = 7). (J) VEGF-A was primarily localized to ATMs in EF and its expression was markedly decreased in myeloid COX-2–/– mice (n = 6). Scale bars: 50 μm. 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.