1: Diabetes. 2007 Jul;56(7):1761-72. Epub 2007 Apr 24.

Metabolic endotoxemia initiates obesity and insulin resistance.

Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F,
Tuohy KM, Chabo C, Waget A, Delmée E, Cousin B, Sulpice T, Chamontin B, Ferrières
J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R.

Institute of Molecular Medicine, I2MR Toulouse, France.

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.

Publication Types: 
    Research Support, Non-U.S. Gov't

PMID: 17456850 [PubMed - in process]

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