The Hospital for Sick Children, Toronto, Ontario, Canada;
The Hospital for Sick Children, Toronto, Ontario, Canada; University of Toronto, Toronto, Ontario, Canada.
Am J Physiol Endocrinol Metab. 2014 Jun 15;306(12):E1341-53. doi: 10.1152/ajpendo.00089.2014. Epub 2014 Apr 22.
Chronic low-grade inflammation is an important contributor to the development of insulin resistance, a hallmark of type 2 diabetes mellitus (T2DM). Obesity and high-fat feeding lead to infiltration of immune cells into metabolic tissues, promoting inflammation and insulin resistance. We hypothesized that macrophages from mice lacking NOX2 (Cybb), an essential component of the NADPH oxidase complex highly expressed in immune cells and associated with their inflammatory response, would be less inflammatory and that these mice would be protected from the development of high-fat-induced insulin resistance. Bone marrow-derived macrophages from NOX2 knockout (NOX2-KO) mice expressed lower levels of inflammatory markers (Nos2, Il6); however, NOX2-KO mice were hyperphagic and gained more weight than wild-type (WT) mice when fed either a chow or a high-fat (HF) diet. Surprisingly, NOX2-KO mice stored less lipid in epididymal white adipose tissue but more lipid in liver and had higher indexes of liver inflammation and macrophage infiltration than WT mice. Contrary to our hypothesis, HF-fed NOX2-KO mice were hyperinsulinemic and more insulin resistant than HF-fed WT mice, likely as a result of their higher hepatic steatosis and inflammation. In summary, NOX2 depletion promoted hyperphagia, hepatic steatosis, and inflammation with either normal or high-fat feeding, exacerbating insulin resistance. We propose that NOX2 participates in food intake control and lipid distribution in mice.
慢性低度炎症是胰岛素抵抗发展的一个重要因素，而胰岛素抵抗是 2 型糖尿病的一个标志。肥胖和高脂肪饮食会导致免疫细胞浸润代谢组织，促进炎症和胰岛素抵抗。我们假设缺乏 NADPH 氧化酶复合物必需成分 NOX2（Cybb）的小鼠的巨噬细胞炎症反应较低，并且这些小鼠将免受高脂肪诱导的胰岛素抵抗的发展。缺乏 NOX2（NOX2-KO）的小鼠的骨髓来源的巨噬细胞表达较低水平的炎症标志物（Nos2、Il6）；然而，与野生型（WT）小鼠相比，NOX2-KO 小鼠在喂食标准饮食或高脂肪（HF）饮食时表现出更高的食欲和体重增加。令人惊讶的是，NOX2-KO 小鼠在附睾白色脂肪组织中储存的脂质较少，但在肝脏中储存的脂质较多，并且肝脏炎症和巨噬细胞浸润的指标高于 WT 小鼠。与我们的假设相反，高脂肪喂养的 NOX2-KO 小鼠比高脂肪喂养的 WT 小鼠表现出更高的胰岛素血症和胰岛素抵抗，可能是由于其更高的肝脂肪变性和炎症。总之，NOX2 的耗竭促进了高食欲、肝脂肪变性和炎症，无论采用正常饮食还是高脂肪饮食，都会加重胰岛素抵抗。我们提出，NOX2 参与了小鼠的摄食控制和脂质分布。
