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TSP1 is an endogenous anti-angiogenic factor and regulator of TGF-β activity and is implicated in the biology of tumor progression, atherosclerosis and arthritis. Major sources of TSP1 are platelets, megakaryocytes, endothelial cells, and macrophages. TSP1 expression has been noted in adipose tissue and a few studies have observed increased TSP1 expression in obese rodents. We examined TSP1 gene expression in the adipose tissue of non-diabetic subjects, and examined the relationship to obesity and insulin resistance. From subcutaneous adipose tissue biopsies, adipocyte and stromal vascular fractions were obtained, and TSP1 mRNA measured. TSP1 mRNA was significantly higher in the adipocyte fraction, suggesting that TSP1 is a true adipokine. We further examined TSP1 expression from whole adipose tissue in 86 subjects, with normal (NGT) or impaired glucose tolerance (IGT), covering a wide range of BMI (19-55 Kg/m[sup 2]) and S[sub 1] (1.02-26.77 x 10[sup -5] x min[sup -1]/pM). TSP1 mRNA demonstrated a significant positive association with BMI (r=0.29, p=0.008, n=82), and a significant negative association with S[sub 1] (r=-0.32, p= 0.006, n=71). TSP1 correlated positively with markers of inflammation, including CD68 and MCP1 (r=0.46, p=0.001, n=81 and r=0.53, p=0.001, n=81), respectively. The relationship with inflammatory markers remained significant on controlling for BMI and S[sub 1]. Thirty eight of the IGT subjects were randomized to receive either pioglitazone or metformin for 10 weeks. Pioglitazone (but not metformin) treatment resulted in a significant 54% decrease (p<0.04) in adipose TSP1 gene expression. Thus, TSP1 is an adipokine that is highly expressed in obese, insulin resistant subjects which is associated with markers of adipose inflammation, and is decreased by pioglitazone. TSP1 may be an important link between macrophage-driven inflammation and altered adipocyte function in metabolic syndrome. [ABSTRACT FROM AUTHOR]