Gut Microbiome, Obesity-Related Comorbidities, and Low-Grade Chronic Inflammation

Extract

Obesity is a complex disease appearing as a polygenic condition affected by environmental factors (mainly, but not only, diet and physical activity). The combination of genotype and epigenetic modifications explains the association of susceptibility to obesity with dietary patterns and sedentary lifestyle. The rising incidence of obesity (in the form of total and/or visceral adiposity) in Western countries is associated with various obesity-related health complications, including—beyond the most prominent conditions of coronary artery disease and cancer, type 2 diabetes mellitus, obstructive sleep apnea syndrome (OSAS), chronic kidney disease, osteoarthritis, and cognitive impairment—the well-recognized nonalcoholic fatty liver disease (NAFLD). Recent evidence suggests that adipose tissue is an endocrine/metabolic organ secreting the so-called adipocytokines, among which the most important are TNF-α, IL-6, adiponectin, and leptin. The imbalanced production of pro- and anti-inflammatory adipokines secreted from fat contributes to the pathogenesis of obesity-related NAFLD. Modulation of those interactions may provide exciting pharmacological targets for the treatment of NAFLD. For example, in patients with obesity-related NAFLD, serum levels of leptin are increased, and the liver becomes refractory to the “antisteatotic” effects of leptin (1). Consequently, the external administration of leptin is of scarce therapeutic value in patients with NAFLD. TNF-α, a proinflammatory adipokine, interferes with insulin signaling by inducing serine phosphorylation of insulin receptor substrate-1 and inducing insulin resistance and consequently favors NAFLD progression. Neutralization of TNF-α activity might improve NAFLD in human beings. IL-6 is a polyvalent cytokine with proinflammatory and pro-oncogenic activity that is a predictor marker of insulin resistance and coronary artery disease (2). Initially, this cytokine was considered hepatoprotective because it reduces oxidative stress and prevents mitochondrial dysfunction in animal models (3). IL-6, contextually with TNF-α, suppresses adiponectin levels (4). Adiponectin is an adipocytokine with anti-inflammatory properties, and it decreases in subjects with increased liver fat concentration (5). Treatment of cells with proinflammatory cytokines such as TNF-α and IL-1 or with bacterial products such as lipopolysaccharide (LPS) leads to the activation of a specific-IKK complex that phosphorylates IκB and thereby tags it for ubiquitination and degradation by the proteasome (6). The degradation of IκB thus allows nuclear factor-κB (NF-κB) to translocate into the nucleus where it can act as a transcription factor that up-regulates IL-6 production and secretion. IL-6 works locally through paracrine and/or endocrine mechanisms to activate IL-6 signaling in the liver. IL-6 is known to induce insulin resistance in hepatocytes (7). Hepatic production of IL-6 also provides a further pathogenic link to extrahepatic organs such as muscle. NF-κB target genes are not up-regulated in transgenic mouse muscle, but IL-6 target genes are, including suppressor of cytokine signaling and signal transducer and activator of transcription proteins. These genes are reversed during IL-6 neutralization, which is consistent with the pathogenic involvement of IL-6. Activation of NF-κB leads to a severe syndrome of muscle wasting, surprisingly without insulin resistance (8). Fat mass in overweight/obese subjects has a primary role in determining low-grade chronic inflammation and, in turn, insulin resistance and ectopic lipid storage within the liver. The confounding effect of visceral obesity colors the findings of much of the published data investigating IL-6 in OSAS. A number of case control studies favor an independent effect of OSAS on IL-6 levels (9), whereas other researchers show some criticism of this interpretation (10). Clearly, inflammation is an adaptive and energy-consuming process, in response to rich fat-calorie content of diet, with adiponectin being one of the most critical signals to reducing an inflammatory response. Adiponectin levels in NAFLD patients were generally low. Its expression is lower by one-third in NAFLD patients, lending credence to the hypothesis that adiponectin deficiency is a cornerstone mechanism in determining the more severe form of NAFLD, ie, nonalcoholic steatohepatitis. Some animal-based studies have demonstrated that exogenous adiponectin lessens hepatic inflammation by decreasing hepatic expression of TNF-α and depletes lipid accumulation. Inflammatory mediators that are biosynthesized in the liver and increased in NAFLD patients include C- reactive protein, IL-6, fibrinogen, and plasminogen activator inhibitor-1. Furthermore, fat in the liver represents a site beyond adipose tissue that independently contributes to synthesis of inflammatory mediators.