Adiponectin Expression from Human Adipose Tissue: Relation to Obesity, Insulin Resistance, and Tumor Necrosis Factor-α Expression

Adiponectin is a 29-kDa adipocyte protein that has been linked to the insulin resistance of obesity and lipodystrophy. To better understand the regulation of adiponectin expression, we measured plasma adiponectin and adipose tissue adiponectin mRNA levels in nondiabetic subjects with varying degrees of obesity and insulin resistance. Plasma adiponectin and adiponectin mRNA levels were highly correlated with each other (r = 0.80, P \u3c 0.001), and obese subjects expressed significantly lower levels of adiponectin. However, a significant sex difference in adiponectin expression was observed, especially in relatively lean subjects. When men and women with a BMI2were compared, women had a twofold higher percent body fat, yet their plasma adiponectin levels were 65% higher (8.6 ± 1.1 and 14.2 ± 1.6 μg/ml in men and women, respectively; P \u3c 0.02). Plasma adiponectin had a strong association with insulin sensitivity index (SI) (r = 0.67, P \u3c 0.0001, n = 51) that was not affected by sex, but no relation with insulin secretion. To separate the effects of obesity (BMI) from SI, subjects who were discordant for SI were matched for BMI, age, and sex. Using this approach, insulin-sensitive subjects demonstrated a twofold higher plasma level of adiponectin (5.6 ± 0.6 and 11.2 ± 1.1 μg/ml in insulin-resistant and insulin-sensitive subjects, respectively; P \u3c 0.0005). Adiponectin expression was not related to plasma levels of leptin or interleukin-6. However, there was a significant inverse correlation between plasma adiponectin and tumor necrosis factor (TNF)-α mRNA expression (r = -0.47, P \u3c 0.005), and subjects with the highest levels of adiponectin mRNA expression secreted the lowest levels of TNF-α from their adipose tissue in vitro. Thus, adiponectin expression from adipose tissue is higher in lean subjects and women, and is associated with higher degrees of insulin sensitivity and lower TNF-α expression

Expression of CD68 and Macrophage Chemoattractant Protein-1 Genes in Human Adipose and Muscle Tissues: Association with Cytokine Expression, Insulin Resistance, and Reduction by Pioglitazone

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 (SI) (0.6-8.0 × 10-4 min-1 · μU-1 · ml-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 SI (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 \u3c 0.005), and plasma interleukin-6 (r = 0.67, P \u3c 0.005). To determine whether improving SI 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 S1 by 60% and in the same subjects reduced both CD68 and MCP-1 mRNAs by \u3e50%. 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 SI