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 3

Myeloid COX-2–/– mice had decreased insulin sensitivity in insulin-sensitive tissues after high-fat feeding.

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Myeloid COX-2–/– mice had decreased insulin sensitivity in insulin-sensi...
WT and myeloid COX-2–/– mice were on the HFD for 11 weeks. (A) Hyperinsulinemic-euglycemic clamps determined more severe insulin resistance in myeloid COX-2–/– mice, as less glucose infusion was needed to maintain a constant blood glucose (n = 4). (B–D) Myeloid COX-2–/– mice had increased plasma insulin levels at baseline and during clamp periods (B), decreased rates of glucose disappearance (RD) (C), and increased endogenous glucose production (EGP) (D) (n = 4 and 5). (E) Myeloid COX-2–/– mice had decreased glucose uptake, a marker of insulin resistance in adipose tissues (BAT, SAT, VAT), SM (gastrocnemius and soleus), and heart and brain (n = 4 and 5). (F) Picrosirius red staining indicated more fibrosis in EF and IF in myeloid COX-2–/– mice than WT mice (n = 8). Scale bars: 100 μm. (G) Myeloid COX-2–/– mice had decreased insulin-stimulated p-Akt in EF, SM, and liver, an indication of increased insulin resistance (n = 4–6). (H) Quantitative p-Akt immunofluorescent staining showed insulin insensitivity in SM in myeloid COX-2–/– mice (n = 6). Scale bars: 100 μm. (I) Myeloid COX-2–/– mice had lower Adipoq mRNA levels in EF and IF (n = 6). Data are mean ± SEM. *P < 0.05, **P < 0.01, analyzed using 2-way ANOVA followed by Tukey’s post hoc test for A, 2-way ANOVA followed by Bonferroni’s post hoc test for B–D, F, and I, and 2-tailed Student’s t test for E, G, and H. Brown, subcutaneous, and visceral adipose tissue (BAT, SAT, and VAT); EF, epididymal fat; IF inguinal fat; SM, skeletal muscle.