Circulating adiponectin levels are increased by the thiazolidinedione (TZD) class of PPAR- agonists in concert with their insulin-sensitizing effects. Two receptors for adiponectin (AdipoR1 and AdipoR2) are widely expressed in many tissues, but their physiological significance to human insulin resistance remains to be fully elucidated. We examined the expression patterns of AdipoR1 and AdipoR2 in fat and skeletal muscle of human subjects, their relationship to insulin action and whether they are regulated by TZD's. Expression patterns of both AdipoR's were similar in subcutaneous and omental fat depots with higher expression in adipocytes than in stromal cells and macrophages. To determine the effects of TZD's on AdipoR expression, subcutaneous fat and quadriceps muscle were biopsied in fourteen insulin resistant subjects with type 2 diabetes mellitus after pioglitazone 45 mg or placebo for 21 days. This duration of pioglitazone improved insulin's suppression of glucose production by 41% and enhanced stimulation of glucose uptake by 27% in concert with increased gene expression and plasma levels of adiponectin. Pioglitazone did not affect AdipoR expression in muscle, whole fat or cellular adipose fractions, and receptor expression did not correlate with baseline or TZD-enhanced insulin action. In summary, both adiponectin receptors are expressed in cellular fractions of human fat, particularly adipocytes. TZD administration for sufficient duration to improve insulin action and increase adiponectin levels did not affect expression of AdipoR1 or AdipoR2. While TZD's probably exert many of their effects via adiponectin, changes in these receptors do not appear to be necessary for their insulin-sensitizing effects.