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To examine the role of adipose-resident macrophages in insulin resistance, we examined the gene expression of CD68, a macrophage marker, along with macrophage chemoattractant protein-1 (MCP-1) in human subcutaneous adipose tissue using real-time RT-PCR. Both CD68 and MCP-1 mRNAs were expressed in human adipose tissue, primarily in the stromal vascular fraction. When measured in the adipose tissue from subjects with normal glucose tolerance, covering a wide range of BMI (21-51 kg/m²) and insulin sensitivity (S[sub I]) (0.6-8.0 x 10[sup -4] min[sup -1] ⋅ µU[sup -1] ⋅ ml[sup -1]), CD68 mRNA abundance, which correlated with the number of CD68-positive cells by immunohistochemistry, tended to increase with BMI but was not statistically significant. However, there was a significant inverse relation between CD68 mRNA and S[sub I] (r = -0.55, P = 0.02). In addition, there was a strong positive relationship among adipose tissue CD68 mRNA, tumor necrosis factor-α (TNF-α) secretion in vitro (r = 0.79, P < 0.005), and plasma interleukin-6 (r - 0.67, P < 0.005). To determine whether improving S[sub I] in subjects with impaired glucose tolerance (IGT) was associated with decreased CD68 expression, IGT subjects were treated for 10 weeks with pioglitazone or metformin. Pioglitazone increased S[sub I] by 60% and in the same subjects reduced both CD68 and MCP-1 mRNAs by >50%. Furthermore, pioglitazone resulted in a reduction in the number of CD68-positive cells in adipose tissue and reduced plasma TNF-α. Metformin had no effect on any of these measures. Thus, treatment with pioglitazone reduces expression of CD68 and MCP-1 in adipose tissue, apparently by reducing macrophage numbers, resulting in reduced inflammatory cytokine production and improvement in S[sub I]. Diabetes 54:2305-2313, 2005 [ABSTRACT FROM AUTHOR]

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]