Metabolic endotoxemia initiates obesity and 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.
Cani
Patrice D
PD
Institute of Molecular Medicine, I2MR Toulouse, France.
Amar
Jacques
J
Iglesias
Miguel Angel
MA
Poggi
Marjorie
M
Knauf
Claude
C
Bastelica
Delphine
D
Neyrinck
Audrey M
AM
Fava
Francesca
F
Tuohy
Kieran M
KM
Chabo
Chantal
C
Waget
Aurélie
A
Delmée
Evelyne
E
Cousin
Béatrice
B
Sulpice
Thierry
T
Chamontin
Bernard
B
Ferrières
Jean
J
Tanti
Jean-François
JF
Gibson
Glenn R
GR
Casteilla
Louis
L
Delzenne
Nathalie M
NM
Alessi
Marie Christine
MC
Burcelin
Rémy
R
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*
D004041:Dietary Fats; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides