Adiponectin, a hormone produced by adipocytes, is involved in glucose metabolism and insulin sensitivity. The production of this adipokine is impaired in obesity and insulin resistance. Eicosapentaenoic acid (EPA) is a dietary n-3 polyunsaturated fatty acid that improves insulin sensitivity in several models of obesity and diabetes, which has been suggested to be related to adiponectin induction. An increase in adiponectin production has been also associated with an up-regulation of the transcriptional factor PPARgamma. The aim of this trial was to evaluate the direct effects of EPA on adiponectin gene expression and protein secretion in isolated rat adipocytes as well as to explore the potential mechanisms involved. A comparative study with troglitazone, a PPARgamma agonist, was also performed. For these purposes, primary rat adipocytes were cultured with EPA (100 and 200 microM) and with troglitazone (10 microM) for 96 hours. Both EPA and troglitazone improved glucose utilization by adipocytes. As expected, troglitazone enhanced adiponectin secretion and increased PPARgamma gene expression. However, EPA significantly decreased adiponectin gene expression and protein secretion and reduced PPARy mRNA levels, suggesting that the inhibition of adiponectin by EPA is likely to be secondary to the down-regulation of this adipogenic transcription factor. Moreover, these results suggest that other mechanisms different from the direct stimulation of adiponectin by the fatty acid are underlying the insulin-sensitizing properties observed after EPA treatment in vivo.