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

摘要

Initially, this cytokine was considered hepatoprotec- tive because it reduces oxidative stress and prevents mi- tochondrial dysfunction in animal models (3). IL-6, con- textually with TNF-a, 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 proinflam- matory cytokines such as TNF-a and IL-1 or with bacterial products such as lipopolysaccharide (LPS) leads to the activation of a specific-IKK complex that phosphorylates IxB and thereby tags it for ubiquitination and degradation by the proteasome (6). The degradation of IkB thus allows nuclear factor-?B (NF-xB) 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 re- sistance in hepatocytes (7). Hepatic production of IL-6 also provides a further pathogenic link to extrahepatic organs such as muscle. NF-?B 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. Ac- tivation of NF-?B 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.