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.

Keywords: Endotoxin detection; Inflammation; Metabolic endotoxemia; Obesity; Substrate metabolism.

Figure 1

A) Glucose oxidation, B) fatty acid oxidation (Total= total palmitate oxidation (CO₂ + ASM); CO₂=complete palmitate oxidation; ASM= acid soluble metabolites and represents incomplete palmiate oxidation), C) lactate production, and D) neutral lipid synthesis in C2C12 cells following 2 hour treatment with lipopolysaccharide (500 ng/mL). *P<0.05 compared to control. Data are presented as mean± SE. Figure redrawn from Frisard et al..

Figure 2

A) FCCP-stimulated maximal respiration with and without 20 mmol/L NAC, B) FCCP-stimulated maximal respiration with and without 25 U/mL of catalase, C) glucose oxidation with and without 20 mmol/L NAC, and D) fatty acid oxidation with and without 20 mmol/L NAC in C2C12 cells following 2-hour LPS treatment (50 pg/mL). a, significantly different from control without NAC/Catalase co-treatment, P<0.05. b, significantly different from LPS treatment without NAC/Catalase co-treatment, P<0.05. Data are presented as mean± SE. FCCP= Carbonyl cyanide-p-trifluoromethoxyphenylhydrazone; NAC=N-acetyl cysteine. Figure redrawn from Frisard et al..

Figure 3

A) Fasting serum endotoxin, B) postprandial serum endotoxin, C) fasting and postprandial (4 hour post high fat [63%] meal) glucose oxidation, DE) fasting and postprandial p38 MAPK total and phosphorylated protein, and F) fasting and postprandial phospho- to total-p-38 ratio before and after a 5 day, eucaloric high fat (55%) diet in healthy, non-obese males (n=6). *P<0.05. Data are presented as mean± SE. Figure redrawn from Anderson et al..