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 (TNF alpha), along with diminished secretion of the "protective" adiponectin. In our view, TNF alpha and adiponectin are antagonistic in stimulating nuclear transcription factor-kappa B (NF-kappa B) activation. Through this activation, TNF alpha 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-kappa B 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-kappa B activation and further downstream modulate specific clinical manifestations of metabolic syndrome.
Department of Medicine, Division of Endocrinology, Metabolism and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. gsonnen@mcw.edu
Gabriele E
GE
Sonnenberg
Glenn R
GR
Krakower
Ahmed H
AH
Kissebah
D052242:Adiponectin; D000273:Adipose Tissue / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D024821:Metabolic Syndrome / Q000209:etiology* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009765:Obesity / Q000150:complications* / Q000378:metabolism; D018384:Oxidative Stress; D011506:Proteins / Q000378:metabolism / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology
D052242:Adiponectin; D015815:Cell Adhesion Molecules; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha