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Metabolic endotoxemia initiates obesity and insulin resistance

¹ Institute of Molecular Medicine, I²MR U858, IFR 31, Toulouse, France
² INSERM 558, Toulouse, France
³ INSERM U 626, Marseille, France
⁴ Unité PMNT-73/69, Université catholique de Louvain, Brussels, Belgium
⁵ UMR 5241, CNRS, UPS, Toulouse, France
⁶ Physiogenex S.A.S., Labège innopole, France
⁷ INSERM U 568, Nice, France
⁸ Food microbial sciences unit, Department of Food Biosciences, The University of Reading, Reading, UK

Correspondence: burcelin{at}toulouse.inserm.fr

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 four-week high-fat feeding (HF) chronically increased plasma LPS concentration by 2-3 times, a threshold that we have defined as "metabolic endotoxemia". Importantly, HF increased the proportion of a LPS-containing microbiota in the gut. When metabolic endotoxemia was induced for four weeks in mice through continuous subcutaneous infusion of LPS, fasted glycemia, insulinemia, whole body, liver, and adipose tissue weight gain were increased to a similar extent as in HF 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 HF-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.

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