['We aimed to study circulating pigment epithelium-derived factor (PEDF) in vivo in association with insulin resistance and in vitro in human adipocytes.', 'Circulating PEDF (ELISA) and metabolic profile were assessed in 125 Caucasian men. PEDF levels were also assessed in an independent cohort of subjects (n = 33) to study the effects of changing insulin action. PEDF gene expression and secretion were measured during differentiation of human preadipocytes.', 'In all subjects, PEDF was positively associated with body mass index (r = 0.326; P < 0.0001), waist-to-hip ratio (r = 0.380; P < 0.0001), HbA(1c), and fasting triglycerides and negatively with insulin sensitivity (r = -0.320; P < 0.0001). PEDF levels were significantly increased in subjects with altered glucose tolerance and type 2 diabetes. Of the inflammatory markers measured, PEDF levels were positively associated with serum soluble TNF-α receptor 1 and IL-10 in obese subjects. Interestingly, weight loss led to significantly decreased PEDF concentration from 34.8 ± 19.3 to 22.5 ± 14.2 μg/ml (P < 0.0001). Multiple linear regression analyses revealed that insulin sensitivity contributed independently to explain 14% of the variance in PEDF levels after controlling for the effects of body mass index, age, and log fasting triglycerides. Differences in PEDF observed after weight loss were related to changes in obesity, insulin resistance, and blood pressure measures. PEDF gene expression and secretion increased during differentiation of human preadipocytes.'] Are circulating pigment epithelium-derived factor levels associated with insulin resistance and decrease after weight loss?