Kim Francis, Pham Matilda, Maloney Ezekiel, Rizzo Norma O, Morton Gregory J, Wisse Brent E, Kirk Elizabeth A, Chait Alan, Schwartz Michael W
Department of Medicine, Diabetes and Obesity Center of Excellence, University of Washington, Seattle, WA 98104, USA.
Arterioscler Thromb Vasc Biol. 2008 Nov;28(11):1982-8. doi: 10.1161/ATVBAHA.108.169722. Epub 2008 Sep 4.
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 to 14 weeks. Cellular inflammation and insulin resistance were assessed by measuring phospho-IkappaBalpha 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 (eg, serum amyloid A [SAA], by Week 14), levels of phospho-IkappaBalpha 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 and vascular cell adhesion molecule-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 weeks of HF feeding), and they were not detected in visceral adipose tissue until 14 weeks.
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.
肥胖会导致血管以及参与葡萄糖代谢的组织（如肝脏、肌肉和脂肪组织）发生炎症和胰岛素抵抗。为了研究血管组织对这些影响的相对易感性，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进程，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C57BL/6小鼠分别喂食对照低脂饮食（LF；10%饱和脂肪）或高脂饮食（HF，60%饱和脂肪），持续时间为1至14周。通过分别测量胸主动脉、肝脏、骨骼肌和内脏脂肪提取物中的磷酸化IκBα和胰岛素诱导的Akt磷酸化来评估细胞炎症和胰岛素抵抗。如预期的那样，与对照组相比，高脂喂养导致体重、脂肪量和空腹胰岛素水平迅速增加，在4周内均达到统计学显著差异。虽然炎症的血浆标志物在DIO过程中相对较晚升高（例如，血清淀粉样蛋白A [SAA]，在第14周），但主动脉裂解物中磷酸化IκBα的水平在第一周内升高了2倍。血管炎症的早期发生伴随着内皮功能障碍（一氧化氮产生减少；细胞间粘附分子-1和血管细胞粘附分子-1的诱导）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。虽然在高脂喂养动物的骨骼肌和肝脏中也检测到了炎症和胰岛素抵抗，但这些反应在更晚的时候才观察到（高脂喂养4至8周之间），直到14周才在内脏脂肪组织中检测到。
在高脂喂养诱导的肥胖过程中，血管中的炎症和胰岛素抵抗在肌肉、肝脏或脂肪组织中检测到这些反应之前就已经出现。这一观察结果表明，血管比其他组织更容易受到营养过剩的有害影响。
