title: Metabolic endotoxemia initiates obesity and insulin resistance.
abstract: 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.
authors: Institute of Molecular Medicine, I2MR Toulouse, France.
authors: Patrice D
authors: PD
authors: Cani
authors: Jacques
authors: J
authors: Amar
authors: Miguel Angel
authors: MA
authors: Iglesias
authors: Marjorie
authors: M
authors: Poggi
authors: Claude
authors: C
authors: Knauf
authors: Delphine
authors: D
authors: Bastelica
authors: Audrey M
authors: AM
authors: Neyrinck
authors: Francesca
authors: F
authors: Fava
authors: Kieran M
authors: KM
authors: Tuohy
authors: Chantal
authors: C
authors: Chabo
authors: Aurélie
authors: A
authors: Waget
authors: Evelyne
authors: E
authors: Delmée
authors: Béatrice
authors: B
authors: Cousin
authors: Thierry
authors: T
authors: Sulpice
authors: Bernard
authors: B
authors: Chamontin
authors: Jean
authors: J
authors: Ferrières
authors: Jean-François
authors: JF
authors: Tanti
authors: Glenn R
authors: GR
authors: Gibson
authors: Louis
authors: L
authors: Casteilla
authors: Nathalie M
authors: NM
authors: Delzenne
authors: Marie Christine
authors: MC
authors: Alessi
authors: Rémy
authors: R
authors: Burcelin
mesh_terms: D000818:Animals; D004041:Dietary Fats / Q000009:adverse effects; D019446:Endotoxemia / Q000150:complications*; D007333:Insulin Resistance / Q000502:physiology*; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D008070:Lipopolysaccharides / Q000009:adverse effects*; D008297:Male; D051379:Mice; D009765:Obesity / Q000276:immunology*
chemical_list: D004041:Dietary Fats; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides