A novel pathway to the manifestations of metabolic syndrome

Pathways leading from obesity to the manifestations of metabolic syndrome involve a number of metabolic risk factors, as well as adipokines, mediators of inflammatory response, thrombogenic and thrombolytic parameters, and vascular endothelial reactivity. Increased adipose tissue mass contributes to augmented secretion of proinflammatory adipokines, particularly tumor necrosis factor-alpha (TNFalpha), along with diminished secretion of the "protective" adiponectin. In our view, TNFalpha and adiponectin are antagonistic in stimulating nuclear transcription factor-kappaB (NF-kappaB) activation. Through this activation, TNFa induces oxidative stress, which exacerbates pathological processes leading to oxidized low-density lipoprotein and dyslipidemia, glucose intolerance, insulin resistance, hypertension, endothelial dysfunction, and atherogenesis. NF-kappaB activation further stimulates the formation of additional inflammatory cytokines, along with adhesion molecules which promote endothelial dysfunction. Elevated free fatty acid, glucose, and insulin levels enhance this NF-kappaB activation and further downstream modulate specific clinical manifestations of metabolic syndrome.