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Thrombospondin-1 (TSP1) is an adipokine associated with obesity, adipose inflammation and insulin resistance

¹The Central Arkansas Veterans Healthcare System, and the Department of Medicine, Division of Endocrinology
²Department of Pediatrics
³Department of Biostatistics, and Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205
⁴Department of Medicine, University of Maryland, Baltimore, MD 21201
⁵College of Health Sciences, University of Kentucky, Lexington, KY 40502

Objectives: We examined the relationship between the expression of thrombospondin-1 (TSP1), an anti-angiogenic factor and regulator of TGF-β activity, with obesity, adipose inflammation and insulin resistance.

Research Design and Methods: TSP1 gene expression was quantified in subcutaneous adipose tissue (SAT) of 86 non-diabetic 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 co-culture with macrophages on TSP1 gene expression.

Results: TSP1 mRNA was significantly associated with obesity (BMI) and insulin resistance (low S_I). Relatively strong positive associations were seen with markers of inflammation, including CD68, MCP1 and PAI-1 mRNA (r0.46, p=0.001 for each), that remained significant after controlling for BMI and S_I. However, TSP1 mRNA was preferentially expressed in the adipocyte fraction, whereas inflammatory markers predominated in the stromal vascular fraction. Co-culture of adipocytes and macrophages augmented TSP1 gene expression and secretion from both cell types. Pioglitazone (not metformin) treatment resulted in a 54% decrease (p<0.04) in adipose TSP gene expression, as did in vitro pioglitazone treatment of adipocytes.

Conclusion: TSP1 is a true adipokine that is highly expressed in obese, insulin resistant subjects, highly correlated with adipose inflammation, and decreased by pioglitazone. TSP1 is an important link between adipocytes and macrophage-driven adipose tissue inflammation and may mediate the elevation of PAI-1 that promotes a pro-thrombotic state.

Key Words: TSP1 • insulin sensitivity • obesity • subcutaneous adipose tissue • inflammation

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