Metabolic endotoxemia initiates obesity and insulin resistance
Metabolic endotoxemia initiates obesity and insulin resistance
复制标题
DOI：
10.2337/db06-1491
复制
发表时间：
2007-07-01
期刊：
影响因子：
7.7
通讯作者：
Burcelin, Remy
中科院分区：
文献类型：
--
作者：
Cani, Patrice D.;Amar, Jacques;Burcelin, Remy
糖尿病和肥胖是两种以胰岛素抵抗和低度炎症为特征的代谢性疾病，为了寻找导致胰岛素抵抗、肥胖和糖尿病发病的炎症因子，我们已经确定了细菌脂多糖（LPS）作为触发因子。我们发现，在营养基础上，正常的内毒素血症在喂食或禁食状态下分别增加或减少，而4周的高脂肪饮食长期增加血浆LPS浓度2至3倍，我们将其定义为代谢性内毒素血症。重要的是，高脂肪饮食增加了肠道中含有脂多糖的微生物群的比例。通过持续皮下输注LPS诱导小鼠代谢内毒素血症4周后，空腹血糖和胰岛素血症以及全身、肝脏和脂肪组织增重的增加程度与高脂喂养小鼠相似。脂肪组织f4 /80阳性细胞、炎症标志物和肝脏甘油三酯含量均升高。此外，lps注射小鼠肝脏（而非全身）出现胰岛素抵抗。CD14突变小鼠抵抗了大多数脂多糖和高脂肪饮食诱导的代谢疾病的特征。这一新发现表明，代谢性内毒素血症失调炎症基调，引发体重增加和糖尿病。我们得出结论，LPS/CD14系统设定了胰岛素敏感性和糖尿病和肥胖发病的基调。降低血浆脂多糖浓度可能是控制代谢性疾病的有效策略。
Diabetes and obesity are two metabolic diseases characterized by insulin resistance and a low-grade inflammation Seeking an inflammatory factor causative of the onset of insulin resistance, obesity, and diabetes, we have identified bacterial lipopolysaccharide (LPS) as a triggering factor. We found that normal endotoxemia increased or decreased during the fed or fasted state, respectively, on a nutritional basis and that a 4-week high-fat diet chronically increased plasma LPS concentration two to three times, a threshold that we have defined as metabolic endotoxemia. Importantly, a high-fat diet increased the proportion of an LPS-containing microbiota in the gut. When metabolic endotoxemia was induced for 4 weeks in mice through continuous subcutaneous infusion of LPS, fasted glycemia and insulinemia and whole-body, liver, and adipose tissue weight gain were increased to a similar extent as in highfat-fed mice. In addition, adipose tissue F4/80-positive cells and markers of inflammation, and liver triglyceride content, were increased. Furthermore, liver, but not wholebody, insulin resistance was detected in LPS-infused mice. CD14 mutant mice resisted most of the LPS and high-fat diet-induced features of metabolic diseases. This new finding demonstrates that metabolic endotoxemia dysregulates the inflammatory tone and triggers body weight gain and diabetes. We conclude that the LPS/CD14 system sets the tone of insulin sensitivity and the onset of diabetes and obesity. Lowering plasma LPS concentration could be a potent strategy for the control of metabolic diseases.