69 Adipose tissue contains several different cell types, including adipocytes and macrophages that produce cytokines (such as interleukin-6 [IL-6] and tumor necrosis factor α) and chemokines (such as CCL2 [also known as monocyte chemoattractant

protein 1]), which can cause inflammation and insulin resistance.70 Adipose tissue macrophage content and production of cytokines and chemokines are greater in obese than lean subjects.71 Moreover, macrophage infiltration and inflammatory markers are greater in adipose tissue of subjects with NAFLD than Selleck Gefitinib BMI-matched subjects with normal IHTG content.72 Therefore, the secretion of adipose tissue inflammatory

proteins in obese persons with NAFLD PD98059 purchase is likely involved in the pathogenesis of insulin resistance, but the relative contribution of adipose tissue inflammation in comparison with other potential factors that can cause insulin resistance is not known. Diet-induced and genetically induced obesity in rodent models cause steatosis, insulin resistance, and increased hepatic NF-κB activity.73, 74 In addition, selective activation of hepatocellular NF-κB causes hepatic inflammation without steatosis and results in both hepatic and skeletal muscle insulin resistance.74 These animals have increased hepatocyte expression of IL-6 and plasma IL-6 concentrations. Suppression of IL-6 activity by administering neutralizing IL-6 antibodies resulted in a decrease in both hepatic and peripheral MCE公司 insulin resistance. These data suggest that steatosis can cause

both hepatic and systemic insulin resistance by activating NF-κB, which up-regulates the production of proinflammatory cytokines that affect both local and systemic insulin action. Adipocytes produce a series of peptide hormones that are associated with insulin action (such as resistin, retinol-binding protein 4, adiponectin, leptin). Among these proteins, adiponectin, the most abundant secretory protein produced by adipose tissue, is the most closely related with insulin action. Plasma adiponectin concentrations are inversely associated with hepatic steatosis,22, 75 insulin resistance,76 T2DM,77 and the metabolic syndrome. Delivery of recombinant adiponectin into mice with liver steatosis markedly reduced hepatomegaly and IHTG content.44 The endoplasmic reticulum (ER) is a critical intracellular organelle that coordinates synthesis, folding, and trafficking of proteins. Transmembrane and secreted proteins are folded into the ER and then directed to cellular destinations. Unfolded or misfolded proteins are detected, removed from the ER, and degraded by proteasome system.