Vascular inflammation, insulin resistance, and reduced nitric oxide production precede the onset of peripheral insulin resistance.
Vascular inflammation, insulin resistance, and reduced nitric oxide production precede the onset of peripheral insulin resistance.
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DOI：
10.1161/atvbaha.108.169722
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发表时间：
2008-11
期刊：
影响因子：
--
通讯作者：
Schwartz MW
中科院分区：
文献类型：
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作者：
Kim F;Pham M;Maloney E;Rizzo NO;Morton GJ;Wisse BE;Kirk EA;Chait A;Schwartz MW
肥胖引起脉管系统以及参与葡萄糖代谢的组织如肝脏、肌肉和脂肪组织中的炎症和胰岛素抵抗。为了研究血管组织对这些效应的相对易感性，我们确定了饮食诱导肥胖（DIO）小鼠各种组织中炎症和胰岛素抵抗发展的时间过程，并将这些基于组织的反应与循环炎症标志物的变化进行了比较。成年雄性C57 BL/6小鼠喂食对照低脂肪饮食（LF; 10%饱和脂肪）或高脂肪饮食（HF，60%饱和脂肪），持续时间范围为1-14周。分别通过测量胸主动脉、肝脏、骨骼肌和内脏脂肪提取物中磷酸化I κBα和胰岛素诱导的Akt磷酸化来评估细胞炎症和胰岛素抵抗。正如预期的那样，与对照组相比，HF喂养诱导体重、脂肪量和空腹胰岛素水平快速增加，其中每一项在4周内均达到统计学显著性。而炎症的血浆标志物在DIO过程中相对较晚地升高（例如，血清淀粉样蛋白A（SAA），第14周），主动脉裂解物中磷酸化I κBα水平在第1周内升高2倍。血管炎症的早期发作伴有内皮功能障碍（一氧化氮产生减少;诱导细胞内粘附分子-1（ICAM-1）和血管细胞粘附分子-1（VCAM-1））和胰岛素抵抗（胰岛素诱导的Akt和eNOS磷酸化受损）的生化证据。虽然炎症和胰岛素抵抗也检测到骨骼肌和肝脏的HF喂养的动物，这些反应观察到更晚（4和8周之间的HF喂养），他们没有检测到内脏脂肪组织，直到14周。在HF喂养诱导的肥胖期间，炎症和胰岛素抵抗在血管系统中发展，而这些反应在肌肉、肝脏或脂肪组织中检测到。这一观察结果表明，脉管系统比其他组织更容易受到营养过载的有害影响。
Obesity causes inflammation and insulin resistance in the vasculature as well as in tissues involved in glucose metabolism such as liver, muscle, and adipose tissue. To investigate the relative susceptibility of vascular tissue to these effects, we determined the time course over which inflammation and insulin resistance develops in various tissues of mice with diet-induced obesity (DIO) and compared these tissue-based responses to changes in circulating inflammatory markers. Adult male C57BL/6 mice were fed either a control low-fat diet (LF; 10% saturated fat) or a high-fat diet (HF, 60% saturated fat) for durations ranging between 1-14 wk. Cellular inflammation and insulin resistance were assessed by measuring phospho-IκBα and insulin-induced phosphorylation of Akt, respectively, in extracts of thoracic aorta, liver, skeletal muscle and visceral fat. As expected, HF feeding induced rapid increases of body weight, fat mass, and fasting insulin levels compared to controls, each of which achieved statistical significance within 4 weeks. Whereas plasma markers of inflammation became elevated relatively late in the course of DIO (e.g., serum amyloid A (SAA), by Week 14), levels of phospho-IκBα in aortic lysates were elevated by 2-fold within the first week. The early onset of vascular inflammation was accompanied by biochemical evidence of both endothelial dysfunction (reduced nitric oxide production; induction of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1)) and insulin resistance (impaired insulin-induced phosphorylation of Akt and eNOS). Although inflammation and insulin resistance were also detected in skeletal muscle and liver of HF-fed animals, these responses were observed much later (between 4 and 8 wk of HF feeding), and they were not detected in visceral adipose tissue until 14 wk. During obesity induced by HF feeding, inflammation and insulin resistance develop in the vasculature well before these responses are detected in muscle, liver or adipose tissue. This observation suggests that the vasculature is more susceptible than other tissues to the deleterious effects of nutrient overload.