Endocrine Abstracts

Non-alcoholic fatty liver disease (NAFLD) is characterized by the pathological increase of lipid droplets, altered fat metabolism in hepatocytes and increased inflammation. Phosphodiesterase 4 (PDE4) modulates the inflammatory responses and its inhibitor can strongly reduce TNF-α release and inflammation. Additionally, PDE4 knockout mice were shown to be resistant to diet-induced obesity (DIO). The aim of this study was to investigate the role of pharmacological PDE4 inhibition in the NAFLD phenotype in DIO. To attain this purpose, obese mice were treated with rolipram, a PDE4 inhibitor. All experimental protocols were approved by the Ethics Committee for Animal Use of the Ribeirao Preto Medical School. Male C57Bl6 mice were fed with either chow or high-fat diet (HFD; 60% fat) for 12 weeks and in the 10th week they received daily subcutaneous injections of vehicle (VEH) or rolipram (2 mg/kg). Food intake and body weight were monitored and at the end of the study inguinal, retroperitoneal and brown fat pads were collected for analysis. Rolipram decreased the absolute value and change in body weight and energy intake in the HFD group, which was associated with a decrease in epididymal and retroperitoneal fat pad weight, with no effect in the chow group. Remarkably, PDE4 inhibition decreased liver triglycerides in obese animals and this effect was associated with increased noradrenaline content. Consistent with these results, histological analysis showed that rolipram decreased lipid accumulation in hepatocytes. No changes were found in plasma cholesterol, free fatty acids or triglycerides in the rolipram group compared to vehicle. In contrast, PDE4 inhibition increased PGC1-a and PPARa expression while it decreased Elov3 and MCP-1. To verify whether this effect persists regardless of change in the body weight, we fed animals with a HFD for 3 days and assessed the in vivo VLDL secretion by inhibiting the lipoprotein lipase enzyme in animals that received acute rolipram injection. PDE4 inhibition increased VLDL secretion in HFD-treated animals, but not in chow animals. In addition, this was associated with increased CD36 and EPAC content in the liver. These results indicate that PDE4 appears to play a role in the pathogenesis of NAFLD and reinforce PDE4 as a potential target for the treatment of obesity-associated liver disease.