摘要
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.
摘要译文
与肥胖相关的并发症正在导致全球发病率和死亡率增加。肥胖症中脂肪组织的膨胀导致低度慢性炎症和代谢失调的状态，导致胰岛素抵抗和代谢综合征。脂肪组织巨噬细胞（ATM）积聚在肥胖症中，是促炎细胞因子的来源，可进一步加剧脂肪细胞功能障碍。巨噬细胞是环氧酶（COX）的丰富来源，这是前列腺素E2（PGE2）生产的速率限制酶。当小鼠被喂食高脂饮食（HFD）时，ATM会增加COX-2的表达。选择性髓样细胞COX-2缺失导致ATM的单核细胞募集和增殖增加，从而导致促炎性降低的吞噬能力增加促炎ATM。体重增加和肥胖增加，外周胰岛素敏感性和葡萄糖利用率降低，脂肪组织炎症和纤维化增加以及异常的脂肪组织血管生成。 HFD配对喂养导致体重增加类似，但是具有选择性髓样细胞COX-2的小鼠仍然表现出降低的周围胰岛素敏感性和葡萄糖利用率。巨噬细胞PGE2受体亚型EP4的选择性髓细胞缺失产生了类似的表型，并且选择性EP4激动剂改善了用ATM COX-2缺失看到的代谢异常。因此，这些研究表明，ATM COX-2/PGE2/EP4轴在抑制脂肪组织功能障碍中起重要作用。
Yu Pan; Shirong Cao; Jiaqi Tang; Juan P. Arroyo; ;rew S. Terker; Yinqiu Wang; Aolei Niu; Xiaofeng Fan; Suwan Wang; Yahua Zhang; Ming Jiang; David H. Wasserman; Ming-Zhi Zhang; ; Raymond C. Harris. Cyclooxygenase-2 in adipose tissue macrophages limits adipose tissue dysfunction in obese mice[J]. Journal of Clinical Investigation, 2022,132(9)