1: Diabetes. 2007 Jul;56(7):1761-72. Epub 2007 Apr 24. Metabolic endotoxemia initiates obesity and insulin resistance. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmée E, Cousin B, Sulpice T, Chamontin B, Ferrières J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R. Institute of Molecular Medicine, I2MR Toulouse, France. 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 high-fat-fed mice. In addition, adipose tissue F4/80-positive cells and markers of inflammation, and liver triglyceride content, were increased. Furthermore, liver, but not whole-body, 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. Publication Types: Research Support, Non-U.S. Gov't PMID: 17456850 [PubMed - in process] Related Links Influence of PAI-1 on adipose tissue growth and metabolic parameters in a murine model of diet-induced obesity. [Arterioscler Thromb Vasc Biol. 2000] PMID:10764686 Development of high fat diet-induced obesity and leptin resistance in C57Bl/6J mice. [Int J Obes Relat Metab Disord. 2000] PMID:10849588 Loss-of-function mutation in TLR4 prevents diet-induced obesity and insulin resistance. [Diabetes. 2007] PMID:17519423 Adipose overexpression of phosphoenolpyruvate carboxykinase leads to high susceptibility to diet-induced insulin resistance and obesity. [Diabetes. 2006] PMID:16443757 Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. [Circ Res. 2007] PMID:17478729