Metabolic endotoxemia initiates obesity and insulin resistance

PD Cani, J Amar, MA Iglesias, M Poggi, C Knauf… - Diabetes, 2007 - Am Diabetes Assoc
PD Cani, J Amar, MA Iglesias, M Poggi, C Knauf, D Bastelica, AM Neyrinck, F Fava…
Diabetes, 2007Am Diabetes Assoc
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 …
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.
Am Diabetes Assoc