Endocrine Abstracts

Obesity is associated with peripheral and central low grade inflammation characterized by the increase in pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF). Phosphodiesterase 4 (PDE4) modulates the inflammatory responses and its inhibitor can strongly reduce TNF 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 central and peripheral effects of PDE4 in DIO. To attain this purpose, mice treated were treated with rolipram, a PDE4 inhibitor capable of crossing the blood brain barrier, or YM-976, a brain-impermeable 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 10 weeks and in the 8th week they received daily subcutaneous injections vehicle (VEH), rolipram (2mg/kg) or YM-976 (2mg/kg). During the experimental period, 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 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, rolipram was able to decrease energy intake and energy efficiency, as well as increase energy expenditure in the HFD-treated animals. Consistent with these results, histological analysis showed that rolipram decreased the adipocyte size of inguinal adipose tissue and reduced the whitening of brown adipose tissue in the HFD group. In contrast to rolipram, YM-976 inhibitor was unable to ameliorate the metabolic changes in DIO. These results indicated that mechanisms in the brain are required to the beneficial metabolic effects of PDE4 inhibitors on DIO and reinforce PDE4 as a potential target for the treatment of obesity.