title: IGFBP-3 inhibits cytokine-induced insulin resistance and early manifestations of atherosclerosis.
abstract: Metabolic syndrome is associated with visceral obesity, insulin resistance and an increased risk of cardiovascular diseases. Visceral fat tissue primarily consists of adipocytes that secrete cytokines leading to a state of systemic inflammation in obese conditions. One of the IGF-independent functions of IGFBP-3 is its role as an anti-inflammatory molecule. Our study in obese adolescents show a decrease in total IGFBP-3 levels and increase in proteolyzed IGFBP-3 in circulation when compared to their normal counterparts and establishes a positive correlation between IGFBP-3 proteolysis and adiposity parameters as well as insulin resistance. In human adipocytes, we show that IGFBP-3 inhibits TNF-α-induced NF-κB activity in an IGF-independent manner, thereby restoring the deregulated insulin signaling and negating TNF-α-induced inhibition of glucose uptake. IGFBP-3 further inhibits TNF-α, CRP and high glucose-induced NF-κB activity in human aortic endothelial cells (HAECs) and subsequently suppresses monocyte adhesion to HAEC through the IGFBP-3 receptor. In conclusion, these findings suggest that reduced levels of IGFBP-3 in circulation and reduced expression of IGFBP-3 in macrophages in obesity may result in suppression of its anti-inflammatory functions and therefore IGFBP-3 may present itself as a therapeutic for obesity-induced insulin resistance and for events occurring in the early stages of atherosclerosis.
authors: Department of Pathology, Virginia Commonwealth University, Richmond, VA, USA.
authors: Lathika
authors: L
authors: Mohanraj
authors: Ho-Seong
authors: HS
authors: Kim
authors: Wei
authors: W
authors: Li
authors: Qing
authors: Q
authors: Cai
authors: Ki Eun
authors: KE
authors: Kim
authors: Hye-Jung
authors: HJ
authors: Shin
authors: Yong-Jae
authors: YJ
authors: Lee
authors: Woo Jung
authors: WJ
authors: Lee
authors: Jung Hyun
authors: JH
authors: Kim
authors: Youngman
authors: Y
authors: Oh
mesh_terms: D017667:Adipocytes / Q000378:metabolism / Q000473:pathology; D050154:Adiposity; D000293:Adolescent; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D001692:Biological Transport; D002097:C-Reactive Protein / Q000378:metabolism; D002448:Cell Adhesion; D018932:Chemokine CCL2 / Q000378:metabolism; D002648:Child; D016207:Cytokines / Q000378:metabolism*; D018450:Disease Progression; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D059748:Proteolysis; D012307:Risk Factors; D015398:Signal Transduction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D016207:Cytokines; D007328:Insulin; D018972:Insulin-Like Growth Factor Binding Protein 3; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein; D005947:Glucose
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