Thrombospondin-1 Is an Adipokine Associated With Obesity, Adipose Inflammation, and Insulin Resistance

Abstract

OBJECTIVE-We examined the relationship between the expression of thrombospondin (TSP)1, an antiangiogenic factor and regulator of transforming growth factor-␤ activity, obesity, adipose inflammation, and insulin resistance.RESEARCH DESIGN AND METHODS-TSP1 gene expression was quantified in subcutaneous adipose tissue (SAT) of 86 nondiabetic subjects covering a wide range of BMI and insulin sensitivity, from visceral adipose (VAT) and SAT from 14 surgical patients and from 38 subjects with impaired glucose tolerance randomized to receive either pioglitazone or metformin for 10 weeks. An adipocyte culture system was also used to assess the effects of pioglitazone and coculture with macrophages on TSP1 gene expression. RESULTS-TSP1mRNA was significantly associated with obesity (BMI) and insulin resistance (low insulin sensitivity index). Relatively strong positive associations were seen with markers of inflammation, including CD68, macrophage chemoattractant protein-1, and plasminogen activator inhibitor (PAI)-1 mRNA (r Ն 0.46, P ϭ 0.001 for each), that remained significant after controlling for BMI and S i . However, TSP1 mRNA was preferentially expressed in adipocyte fraction, whereas inflammatory markers predominated in stromal vascular fraction. Coculture of adipocytes and macrophages augmented TSP1 gene expression and secretion from both cell types. Pioglitazone (not metformin) treatment resulted in a 54% decrease (P Ͻ 0.04) in adipose TSP gene expression, as did in vitro pioglitazone treatment of adipocytes.CONCLUSIONS-TSP1 is a true adipokine that is highly expressed in obese, insulin-resistant subjects; is highly correlated with adipose inflammation; and is decreased by pioglitazone. TSP1 is an important link between adipocytes and macrophagedriven adipose tissue inflammation and may mediate the elevation of PAI-1 that promotes a prothrombotic state. Diabetes 57: 432-439, 2008

Glucose and insulin modify thrombospondin 1 expression and secretion in primary adipocytes from diet-induced obese rats

“…The HFD-fed rats utilized in this work showed an obesity state [4] that correlated positively with the TSP-1 levels in blood, and with the mRNA expression of this protein in adipocytes from epididymal WAT, which is consistent with a previous report [41]. Interestingly, when the adipocytes were subjected to culture treatments, cells from HFD rats showed lower TSP-1 gene expression than controls, except when the adipocytes where cultured under…”

“…This observation is consistent with the fact that in the present results: 1) insulin significantly inhibited TSP-1 gene expression, lowering the secretion levels of this proatherogenic agent, and 2) TSP-1 expression and secretion were augmented in adipocytes from obese animals. Finally, it is worth to mention that it has been reported that TPS-1 exerts antiangiogenic activities in the adipose tissue and modulates the activity of TGF-β and PAI-1, both proteins closely related with insulinresistance and metabolic syndrome [41].…”

“…Recently, this protein has been included among the group of adipokines, since its expression is increased in WAT of obese and insulin-resistant subjects, presenting positive correlations with the level of adiposity [35,41]. Furthermore, it has been reported as an important factor in the adipocyte-and macrophage-driven inflammation in the adipose tissue, and that could mediate the elevation of PAI-1, promoting a prothrombotic state [41].…”

“…Furthermore, it has been reported as an important factor in the adipocyte-and macrophage-driven inflammation in the adipose tissue, and that could mediate the elevation of PAI-1, promoting a prothrombotic state [41]. Also, TSP-1 has been described as a major regulator of the transforming growth factor (TGF)-β activity [11,31], which, together with the increased 3 PAI-1 levels, are correlated with different features of obesity, insulin-resistance, and metabolic syndrome [1,29,37].…”

Thrombospondin-1 is a glucocorticoid responsive protein in humans

“…TSP1 has multiple actions. It regulates cellular events involved in tissue repair, activation of transforming growth factor beta-1 (TGFb1) (27), attenuates vasodilatation via an effect on nitric oxide synthase (28) and is positively correlated with BMI and negatively with insulin sensitivity (29). As all of these actions of TSP1 are also effects of glucocorticoids (8), we hypothesize that TSP1 may be an effector of glucocorticoid activity.…”