Nonalcoholic fatty liver disease (NAFLD) is closely associated with obesity. An adipocyte-derived hormone, adiponectin, may play a role in the pathophysiology of NAFLD through insulin-sensitizing and antifibrotic effects. We found that hepatic expression of adiponectin receptor AdipoR2, but not AdipoR1, was down-regulated in 14 patients with NAFLD compared with 7 patients with a normal liver (P < .05). To investigate the significance of the adiponectin system in obesity and NAFLD, we examined the regulation of AdipoR2 expression in a nonmalignant human hepatocyte cell line, the THLE-5b cells. Insulin down-regulated the levels of AdipoR2 messenger RNA (mRNA) and protein, whereas an adipocytokine, tumor necrosis factor alpha, up-regulated them. A thiazolidinedione, pioglitazone, up-regulated the expression of AdipoR2 mRNA and protein in THLE-5b cells. The AdipoR2 mRNA level was decreased in fatty THLE-5b cells induced by coincubating with fatty acids. These findings suggest that down-regulation of AdipoR2 in the liver caused by hyperinsulinemia and steatosis may play a role in the development of NAFLD.