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.