40, 41 In the present study, we induced NAFLD in mice by feeding them an HFHFr diet. ATRA treatment improved their hepatic steatosis and insulin sensitivity and ameliorated liver damage. Expression analysis of genes involved in hepatic lipid metabolism suggested that ATRA enhanced lipolysis and suppressed lipogenesis, possibly contributing to the improvement in hepatic histology. These results are consistent with published observations in transgenic mice expressing liver-specific dominant-negative RARα.24 The slight discrepancy observed in the extent of lipid accumulation as assessed by biochemical or histological Lumacaftor purchase assays of mice fed the HFHFr diet implies

that other lipids such as diacylglycerols and glycerophospholipids may be involved in the formation of lipid droplets in murine steatosis models.42 Further research will be required to investigate the effect of retinoids on hepatic lipid metabolism in more detail, using techniques such as lipid profiling.42 These data suggest that retinoids have potential for use in treating NAFLD by improving hepatic lipid metabolism and ameliorating insulin resistance. learn more In contrast to findings in the liver, ATRA treatment modestly decreased visceral

fat mass. Others have reported that Am80 and ATRA prevent preadipocyte differentiation.20, 21 In particular, ATRA enhances lipolysis in mature adipocytes

by inducing and activating PPARβ, leading to decreased white adipose tissue mass in diet-induced obese mice.21 Moreover, upon the activation of PPARβ, ATRA requires fatty acid binding protein 5, whose expression is undetectable in the liver.21, 43 However, we were unable to detect a difference in the expression of PPARβ between the visceral adipose tissues from the HFHFr and ATRA + HFHFr groups (data not shown). In contrast, because increased expression of PPARβ was observed in the livers of the ATRA + HFHFr group, hepatic PPARβ may be indirectly involved in ATRA-induced improvement of fatty liver. Considering that the RARα/β selective agonist Am80 affected hyperglycemia and hyperinsulinemia with an efficacy similar HSP90 to that of ATRA, RAR-independent mechanisms are unlikely to be involved in the retinoid-induced insulin sensitization, at least under the conditions of present study. In conclusion, to our knowledge, the previously unrecognized actions of retinoids described here provide valuable insight into understanding the physiological function of leptin in the liver. Our results strongly suggest that ligand-dependent RAR activation could benefit insulin-resistant patients. Additional Supporting Information may be found in the online version of this article.