Metabolic Endotoxemia Initiates Obesity and Insulin Resistance

• DOI: 10.2337/db06-1491
• Publication Date: 2007-06-27T16:33:45Z
• Authors: Patrice D. Cani; Jacques Amar; Miguel Angel Igle...; Marjorie Poggi; Claude Knauf; Delphine Bastelica; Audrey M. Neyrinck; Francesca Fava; Kieran M. Tuohy; Chantal Chabo; Aurélie Waget; Evelyne Delmée; Béatrice Cousin; Thierry Sulpice; Bernard Chamontin; Jean Ferrières; Jean-François Tanti; Glenn R. Gibson; Louis Casteilla; Nathalie M. Delzenne; Marie Christine A...; Rémy Burcelin
• Keywords: Lipopolysaccharides; Male; 0301 basic medicine; 2. Zero hunger; Lipopolysaccharide Receptors; Antigens, CD14; Dietary Fats; Endotoxemia; 3. Good health; Mice; 03 medical and health sciences; Animals; Obesity; Insulin Resistance

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.