Metabolic endotoxemia initiates obesity and insulin resistance
Cani, PD and Amar, J and Iglesias, MA and Poggi, M and Knauf, C and Bastelica, D and Neyrinck, AM and Fava, F and Tuohy, KM and Chabo, C and Waget, A and Delmee, E and Cousin, B and Sulpice, T and Chamontin, B and Ferrieres J, J and Tanti, JF and Gibson, GR and Casteilla, L and Delzenne, NM and Alessi, MC and Burcelin, R, Metabolic endotoxemia initiates obesity and insulin resistance, Diabetes, 56, (7) pp. 1761-72. ISSN 0012-1797 (2007) [Refereed Article]
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.