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 7

Mice with myeloid EP4 deletion recapitulated the phenotype of macrophage COX-2–/– mice in DIO.

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Mice with myeloid EP4 deletion recapitulated the phenotype of macrophage...
WT (EP4fl/fl) and myeloid EP4–/– (CD11b-Cre EP4fl/fl) mice were fed the HFD for 12 weeks. (A) Ptger4 mRNA expression was more than 5 times lower in EF than IF in WT mice, and its expression was markedly decreased in both EF and IF in myeloid EP4–/– mice (n = 6). (B) In situ hybridization indicated that Ptger4 mRNA was colocalized with Cd68 mRNA in ATMs in WT mice (arrows) but was not detectable in myeloid EP4–/– mice. Scale bars: 50 μm. (C–E) Myeloid EP4–/– mice had greater increases in body weight (n = 15) (C), liver steatosis (D), and SAT, VAT, and liver masses (n = 7) (E). Scale bar: 100 μm. (F and G) Myeloid EP4–/– mice had greater increases in fasting blood glucose (n = 15) (F) and HbA1c (n = 8) (G). (H and J) Myeloid EP4–/– mice had decreased glucose tolerance (n = 9) (H) and insulin sensitivity (n = 9) (I), and decreased Adipoq expression in both EF and IF (n = 6) (J). (K–M) Flow cytometry analysis showed more EF ATMs (n = 3) (K) with more proinflammatory phenotype (n = 3) (L) and higher number of crown-like structures (n = 8) (M) in myeloid EP4–/– 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 A and J; 2-tailed Student’s t test for C, E–G, K–M; 2-way ANOVA followed by Tukey’s post hoc test for I; and 2-tailed Student’s t test and 2-way ANOVA followed by Tukey’s post hoc test for H. EF, epididymal fat; IF inguinal fat; subcutaneous and visceral adipose tissue (SAT and VAT).