da-8159 and Insulin-Resistance

Nonalcoholic fatty liver disease (NAFLD) refers to a series of diseases, including simple steatosis, caused by the excessive accumulation of fat in hepatocytes, nonalcoholic steatohepatitis with inflammation and fibrosis, and more advanced forms of cirrhosis. The pathogenic mechanisms underlying fatty liver and the progression from simple fatty liver to hepatitis and cirrhosis remain unclear. One potentially unifying mechanism may be a dysregulation of free fatty acid oxidation. The oversupply of fatty acids to the liver can result in mitochondrial dysfunction leading to the accumulation of lipids in the liver. Interestingly, there have been several reports showing that inhibitors of phosphodiesterase 5 (PDE5) can increase mitochondrial biogenesis, preserve mitochondrial function in vitro. And, we have recently demonstrated that the phosphodiesterase type 5 inhibitor udenafil improves insulin sensitivity by increasing mitochondrial function in adipocytes. In this study, we aimed to examine the effects of the PDE5 inhibitor udenafil on NAFLD in the ob/ob mouse model. Treatment of ob/ob mice for 6 weeks with udenafil reduced fat mass and fasting glucose. Importantly, udenafil caused a reduction in lipid accumulation in the liver of these mice, including hepatic triglyceride (TG) and cholesterol levels. Mechanistically, udenafil decreased the proinflammatory cytokines in the liver. Also, udenafil increased the levels in the liver of the important lipolytic enzymes and the levels of several mitochondrial β-oxidation related genes. Similar effects were seen in udenafil treated primary hepatocytes. We believe that our study makes a significant contribution to the literature because the results from our study suggest that udenafil may be an effective treatment for NAFLD by improving mitochondrial function.

Topics: Animals; Cells, Cultured; Cytokines; Disease Models, Animal; Fatty Acids; Hepatocytes; Inflammation Mediators; Insulin Resistance; Lipid Metabolism; Lipolysis; Liver; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Mitochondria, Liver; Non-alcoholic Fatty Liver Disease; Oxidative Phosphorylation; Oxygen Consumption; Phosphodiesterase 5 Inhibitors; Pyrimidines; Sulfonamides

Adipocytes are involved in many metabolic disorders. It was recently reported that phosphodiesterase type 5 (PDE5) is expressed in human adipose tissue. In addition, PDE5 inhibitors have been shown to improve insulin sensitivity in humans. However, the mechanism underlying the role of PDE5 inhibitors as an insulin sensitizer remains largely unknown. The present study was undertaken to investigate the role of the PDE5 inhibitor udenafil in insulin signaling in adipocytes and whether this is mediated through the regulation of mitochondrial function. To study the mechanism underlying the insulin sensitizing action of PDE5 inhibitors, we evaluated quantitative changes in protein or mRNA levels of mitochondrial oxidative phosphorylation (OxPhos) complex, oxygen consumption rate (OCR), and fatty acid oxidation with varying udenafil concentrations in 3T3-L1 cells. Our cell study suggested that udenafil enhanced the insulin signaling pathway in 3T3-L1 cells. Following udenafil treatment, basal mitochondrial OCR, maximal OxPhos capacity, and OxPhos gene expression significantly increased. Finally, we examined whether udenafil can affect the fatty acid oxidation process. Treatment of 3T3-L1 cells with udenafil (10 and 20 μM) significantly increased fatty acid oxidation rate in a dose-dependent manner. In addition, the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) significantly increased. We demonstrated that the PDE5 inhibitor udenafil enhances insulin sensitivity by improving mitochondrial function in 3T3-L1 cells. This might be the mechanism underlying the PDE5 inhibitor-enhanced insulin signaling in adipocytes. This also suggests that udenafil may provide benefit in the treatment of type 2 diabetes and other related cardiovascular diseases.

Topics: 3T3-L1 Cells; Adipocytes; Animals; Dose-Response Relationship, Drug; Fatty Acids; Insulin; Insulin Resistance; Mice; Mitochondria; Oxygen Consumption; Phosphodiesterase 5 Inhibitors; Pyrimidines; Sulfonamides