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

¹ Central Arkansas Veterans Healthcare System and the Department of Medicine, Division of Endocrinology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
² Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas
³ Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, Arkansas
⁴ Department of Medicine, University of Maryland, Baltimore, Maryland
⁵ Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas
⁶ College of Health Sciences, University of Kentucky, Lexington, Kentucky

Address correspondence and reprint requests to Philip A. Kern, MD, Central Arkansas Veterans Healthcare System, 598/151 LR, 4300 West 7th St., Little Rock, AR 72205. E-mail: kernphilipA{at}uams.edu

Key Words: ADHASC, adult-derived human adipocyte stem cell • cDNA, complementary DNA • C_t, cycle threshold • IGT impaired glucose tolerant • MCP, macrophage chemoattractant protein • PAI, plasminogen activator inhibitor • SAT, subcutaneous adipose tissue • SGBS, Simpson-Golabi-Behmel syndrome • SVF, stromal vascular fraction • TGF, transforming growth factor • TSP, thrombospondin • TZD, thiazoladinediones • VAT, visceral adipose tissue

OBJECTIVE—We examined the relationship between the expression of thrombospondin (TSP)1, an antiangiogenic factor and regulator of transforming growth factor-β 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—TSP1 mRNA 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 0.46, P = 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 < 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 macrophage-driven adipose tissue inflammation and may mediate the elevation of PAI-1 that promotes a prothrombotic state.

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