OR10-02 Effect Of Phosphodiesterase 4 Inhibitors On Weight Loss And Energy Homeostasis In Mice With Obesity Induced By A High-fat-diet

Disclosure: M.A. de Andrade: None. H. da Silva: None. A.A. Jesus: None. F.J. de Paula: None. L. Elias: None. INTRODUCTION: Obesity is a worldwide health problem and the incidence of associated diseases such as type 2 diabetes is increasing. Leptin (Lep) resistance arises from obesity-related inflammation, enhancing the appetite. The expression of phosphodiesterase 4 enzymes (PDE4) is increased in inflammatory conditions. Rolipram (Rol) acts to inhibit PDE4 reducing adiposity and peripheral inflammation. Notwithstanding, the effects of Rol on Lep sensitivity and energy balance are still unknown. Objective: To evaluate the effect of PDE4 inhibition on energy homeostasis and Lep sensitivity and glucose tolerance in mice with obesity induced by a high-fat diet (HFD). Methodology: Four-week-old male C57BL6 mice were fed a HFD (60%, Research Diets) or chow diet (C) for 10 weeks. In the 8th week, they received daily subcutaneous Rol injections (2mg/kg) or vehicle (V) and food intake and body weight were daily measured. Energy expenditure (EE) was measured on the 8th day of treatment using a metabolic cage (Oxymax). After treatment, mice underwent 6h fasting and subsequent intraperitoneal (i.p.) glucose injection (2g/kg). Fasting blood glucose (FG) and 120 minutes after glucose (GTT) were measured. On the last day of treatment, 90 minutes after the Rol or V injection, i.p. Lep (5mg/kg in 100ul) or saline (S) was injected, and weight and food intake were measured 14 and 24h later. Results: 5-10 mice were analyzed in each group (chow + V, CV; chow + Rol, CR; HFD + V, HV; HFD + Rol, HR). There was a significant difference in body weight between HR and HV: absolute weight (HR 35+-4.18; HV 38.8+-3.88g; p 0.038) and weight variation (HR -2.26+-0.99; HV -0.19+-1.25g; p 0.002), but no difference between CR and CV (27.98+-2.25; 26.8 +- 2.22g, p 0.97). Rol effectively reduced ingestion in both diets (CR 42.85+-2.7; CV 48.13+-4.51g; p 0.03) (HR 24.75+-2.44; HV 28.31 +-2.81g; p 0.01). In the HFD groups, compared to V, Rol increased VO2 (p 0.04) and energy expenditure (p 0.049) as well as the heat (p 0.03). There was no difference in VCO2 nor motor activity. Lep sensitivity was evaluated in the HFD group and there was a significant reduction in food intake 24h after the Lep application compared to S (Lep 2.18+-0.2; S 2.47+-0.18g, p 0.04). There was no difference in food intake 14h after Lep or weight after injection at either time point (14/24h). Rol was ineffective to improve FG/GTT in the HFD group. Conclusion: Rolipram, a PDE4 inhibitor, effectively reduces the body weight of diet-induced obesity by reducing food intake, increasing basal energy expenditure and improving leptin sensitivity. PDE4 appears as a potential target to treat obesity. Presentation: Friday, June 16, 2023