Metabolic Endotoxemia Initiates Obesity and Insulin Resistance

University of Reading, Reading, England, United Kingdom
Diabetes (Impact Factor: 8.1). 08/2007; 56(7):1761-72. DOI: 10.2337/db06-1491
Source: PubMed


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.

Download full-text


Available from: Patrice D Cani, Sep 14, 2015
  • Source
    • "Increased intestinal microbiota-derived lipopolysaccharide (LPS) load from the colon lumen was shown to be associated with various metabolic abnormalities including induction of adipose inflammation and insulin resistance (Cani et al. 2007). Bacterial LPS could be delivered from the gut to the circulation through chylomicron-associated transport and via tight junctions in the epithelial lining (Caesar et al. 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Inflammation and metabolic abnormalities are linked to each other. At present, pathogenic inflammatory response was recognized as a major player in metabolic diseases. In humans, intestinal microflora could significantly influence the development of metabolic diseases including atherosclerosis. Commensal bacteria were shown to activate inflammatory pathways through altering lipid metabolism in adipocytes, macrophages, and vascular cells, inducing insulin resistance, and producing trimethylamine-N-oxide. However, gut microbiota could also play the atheroprotective role associated with anthocyanin metabolism and administration of probiotics and their components. Here, we review the mechanisms by which the gut microbiota may influence atherogenesis.
    Full-text · Article · Jun 2015 · Frontiers in Microbiology
  • Source
    • "CD14KO mice were found to be hypersensitive to insulin even when they were fed a normal diet and show delayed occurrence of obesity, diabetes and insulin resistance. Therefore, these fi ndings support the hypothesis that the LPS/CD14 system sets the tone of insulin sensitivity and regulates the onset of obesity and diabetes (Cani et al. 2007). In a subsequent study byCani et al. (2008), antibiotic was used to treat the mice which were fed with high-fat diet and ob/ob mice. "

    Full-text · Article · Jun 2015
  • Source
    • "The gut microbiota may have a vital role in obesity development (Backhed et al., 2004; Collins et al., 2013; Le Chatelier et al., 2013; Zhao, 2013). For example, endotoxin produced by an opportunistic pathogen in the gut, such as Escherichia coli, induced obesity and insulin resistance when a purified form was subcutaneously infused into mice (Cani et al., 2007a). A greater abundance of opportunistic pathogens, such as Betaproteobacteria , was found in the gut of diabetic patients compared with healthy controls (Larsen et al., 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The gut microbiota is hypothesized to have a critical role in metabolic diseases, including type 2 diabetes (T2D). A traditional Chinese herbal formula, Gegen Qinlian Decoction (GQD), can alleviate T2D. To find out whether GQD modulates the composition of the gut microbiota during T2D treatment, 187 T2D patients were randomly allocated to receive high (HD, n=44), moderate (MD, n=52), low dose GQD (LD, n=50) or the placebo (n=41) for 12 weeks in a double-blinded trial. Patients who received the HD or MD demonstrated significant reductions in adjusted mean changes from baseline of fasting blood glucose (FBG) and glycated hemoglobin (HbA1c) compared with the placebo and LD groups. Pyrosequencing of the V3 regions of 16S rRNA genes revealed a dose-dependent deviation of gut microbiota in response to GQD treatment. This deviation occurred before significant improvement of T2D symptoms was observed. Redundancy analysis identified 47 GQD-enriched species level phylotypes, 17 of which were negatively correlated with FBG and 9 with HbA1c. Real-time quantitative PCR confirmed that GQD significantly enriched Faecalibacterium prausnitzii, which was negatively correlated with FBG, HbA1c and 2-h postprandial blood glucose levels and positively correlated with homeostasis model assessment of β-cell function. Therefore, these data indicate that structural changes of gut microbiota are induced by Chinese herbal formula GQD. Specifically, GQD treatment may enrich the amounts of beneficial bacteria, such as Faecalibacterium spp. In conclusion, changes in the gut microbiota are associated with the anti-diabetic effects of GQD.
    Full-text · Article · Oct 2014 · The ISME Journal
Show more