Regulation of adiponectin receptors in hepatocytes by the peroxisome proliferator-activated receptor-γ agonist rosiglitazone

Aims/hypothesis: Adiponectin is an adipocyte-derived hormone that plays a critical role in the development of type 2 diabetes via interaction with adiponectin receptors 1 (ADIPOR1) and 2 (ADIPOR2). Rosiglitazone is a peroxisome proliferator-activated receptor-gamma (PPARG) agonist that is widely used in the treatment of type 2 diabetes. We hypothesised that rosiglitazone regulates lipid and glucose metabolism through modulation of the expression of adiponectin receptors in the liver. Methods: The expression of ADIPOR1 and ADIPOR2 was analysed in HepG2 hepatocytes. The promoters of adiponectin receptors were isolated and used to analyse the transcriptional regulation. The expression of adiponectin receptors in the liver was determined in mice treated with rosiglitazone. Results: Rosiglitazone elevated the mRNA and protein levels of ADIPOR2 and stimulated ADIPOR2 promoter in HepG2 cells. Analysis with the ADIPOR2 promoter revealed a putative rosiglitazone-responsive region that contained a glucocorticoid receptor (GR)-binding element. The GR agonist dexamethasone synergised with rosiglitazone to stimulate the ADIPOR2 promoter wheras the GR antagonist RU486 abolished this stimulation. Treatment of mice with rosiglitazone elevated the expression of ADIPOR2 in the liver. Conclusions/interpretation: This study indicates that rosiglitazone can elevate the expression of ADIPOR2 in hepatocytes. Our data also suggest that the PPARG agonist rosiglitazone can interact functionally with a GR element in the ADIPOR2 promoter to mediate stimulation of transcription. This study thus reveals a new paradigm underlying the therapeutic effect of PPARG activators in the treatment of type 2 diabetes.