Metabolic endotoxemia with obesity: Is it real and is it relevant?

Abstract

Obesity is associated with metabolic derangements in multiple tissues, which contribute to the progression of insulin resistance and the metabolic syndrome. The underlying stimulus for these metabolic derangements in obesity are not fully elucidated, however recent evidence in rodents and humans suggests that systemic, low level elevations of gut derived endotoxin (lipopolysaccharide, LPS) may play an important role in obesity related, whole-body and tissue specific metabolic perturbations. LPS initiates a well-characterized signaling cascade that elicits many pro-and anti-inflammatory pathways when bound to its receptor, Toll-Like Receptor 4 (TLR4). Low-grade elevation in plasma LPS has been termed “metabolic endotoxemia” and this state is associated with a heightened pro-inflammatory and oxidant environment often observed in obesity. Given the role of inflammatory and oxidative stress in the etiology of obesity related cardio-metabolic disease risk, it has been suggested that metabolic endotoxemia may serve a key mediator of metabolic derangements observed in obesity. This review provides supporting evidence of mechanistic associations with cell and animal models, and provides complimentary evidence of the clinical relevance of metabolic endotoxemia in obesity as it relates to inflammation and metabolic derangements in humans. Discrepancies with endotoxin detection are considered, and an alternate method of reporting metabolic endotoxemia is recommended until a standardized measurement protocol is set forth.

The initiation of metabolic inflammation in childhood obesity

“…In adipose tissue, experimental endotoxin infusion in humans rapidly induces chemokine and T cell activation genes and therefore may potentiate leukocyte crosstalk and amplify initial inflammatory responses (105). This concept still remains somewhat controversial, as limitations in endotoxin measurement methods prevent the wide use of endotoxin as a true biomarker for metainflammation (106). However, the observation that treatment of obese adolescents leads to both improvements in insulin resistance and decreased endotoxin levels suggests that early interventions may limit metabolic endotoxemia (107).…”

Modulation of microglia polarization dynamics during diabetic retinopathy in db / db mice

“…LPS-treated Bv.2 cells induced a pro-inflammatory response that was reduced by co-treatment with M2 cytokines or the sp 2 -iminosugar derivative R-DS-ONJ We stimulated Bv.2 cells, a mouse microglia cell line, with LPS (M1 stimulus) in the absence or presence of M2 cytokines (IL4/IL13). LPS was used as a pro-inflammatory stimulus since it induces an environment similar to that found in the obesity-related diabetic context [29]. Based on that, Bv.2 cells were cultured in the presence of LPS, IL4/IL13 (M2) and the combination of both (LPS + M2).…”

Involvement of JNK/NFκB Signaling Pathways in the Lipopolysaccharide-Induced Modulation of Aquaglyceroporin Expression in 3T3-L1 Cells Differentiated into Adipocytes

“…Low level elevations of gut derived endotoxin (lipopolysaccharide (LPS)) have been shown to play an important role in obesity [35], similarly to the consequential production of proinflammatory cytokines (such as interleukin-6 and tumor necrosis α (TNFα)) [36], resulting from LPS-induced TLR4 activation. Previous studies have shown that LPS, mimicking inflammation occurring during obesity, can affect the expression of several aquaglyceroporins.…”