Article

Metabolic Endotoxemia Initiates Obesity and Insulin Resistance

University of Reading, Reading, England, United Kingdom
Diabetes (Impact Factor: 8.47). 08/2007; 56(7):1761-72. DOI: 10.2337/db06-1491
Source: PubMed

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.

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    • "Therefore, it is plausible and likely that lymph-derived LPS contributes to PLAT inflammation. This hypothesis is supported by studies showing that high-fat-diet-induced increases in circulating LPS is an early event preceding metabolic dysregulation (Cani et al., 2007). For example, a short exposure to high-fat diet leading to a " prediabetic " state increases bacterial translocation to mesenteric adipose tissue, suggesting the development of diet-induced metabolic dysregulation (Amar et al., 2011). "
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    ABSTRACT: Background The digestive tract lymphatics transport approximately two-thirds of all lymph produced in the body and have a key role in mucosal immunity through their contribution to antigen transport and immune cell trafficking. Mesenteric lymphatic pumping function integrity is critical for maintaining homeostasis and lipid transport. We previously demonstrated that acute alcohol intoxication (AAI) increases mesenteric lymphatic amplitude of contraction and ejection fraction, enhancing the ability of the lymphatic vessels to pump lymph. AAI has been shown to disrupt intestinal barrier integrity, which would be expected to increase the endotoxin content of mesenteric lymph. In this study, we tested the prediction that AAI increases lymphatic permeability directly affecting perilymphatic adipose tissue (PLAT) milieu.Methods Male Sprague Dawley rats received an intragastric infusion of 2.5 g/kg of alcohol. Isovolumic administration of water (vehicle) served as control. PLAT was isolated for the determination of Evans Blue extravasation (permeability), cytokine content, and immunohistochemistry for inflammatory cell infiltration at 30 minutes and 24 hours after alcohol administration.ResultsPLAT isolated from AAI animals had greater Evans Blue concentrations and cytokine expression (24 hours post-AAI) and mast cell and neutrophil density than that isolated from controls. AAI resulted in significantly higher plasma lipopolysaccharide (endotoxin) levels, lower plasma adiponectin levels (at 30 minutes), and unchanged plasma visfatin levels.Conclusions The data indicate that AAI induces mesenteric lymphatic hyperpermeability, promotes PLAT inflammatory milieu and disrupts the systemic adipokine profile. These findings suggest an association between alcohol-induced lymphatic hyperpermeability and early manifestations of metabolic dysfunction as a result of alcohol abuse. We propose that crosstalk between lymph and PLAT results in adipose inflammation and adipokine dysregulation during AAI.
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    • "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). "
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    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.
    Frontiers in Microbiology 06/2015; 6:671. DOI:10.3389/fmicb.2015.00671 · 3.94 Impact Factor
    • "All these findings confirmed that LPS is directly implicated in the inflammatory cascade and in weight control. Consequently, a strict relation among gut microbiota (through LPS), HFD, body weight and inflammation exists (Cani et al., 2007). This is also true for WD, but since it has a lower fat content, the endotoxaemia is lower. "
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