To evaluate drugs targeting obesity/type 2 diabetes on weight loss and cardiometabolic benefits, and mimic human hyperenergetic nutritional behavior, we set-up a new diet-induced obese (DIO) rat model fed a free choice (FC) diet: control chow (CC) or high fat/cholesterol (HFC) diet, and normal water (NW) or 10% fructose water (FW). After an 8-week FC diet period, rats were treated with vehicle, liraglutide 0.4mg/kg s.c. QD (LIRA, a GLP-1 receptor agonist), lorcaserin 18mg/kg p.o. QD (LORCA, a 5-HT2C receptor agonist) and pioglitazone 10mg/kg p.o. QD (PIO, a PPARgamma agonist) for 5 weeks. FC diet induced high intake of HFC and FW, resulting in significantly higher caloric intake and overweight, as compared with rats fed a CC diet alone. LIRA induced a 12% body weight loss (p<0.01 vs. FC), with marked reduction in HFC and FW intake and lower visceral fat mass (p<0.001). LORCA induced lower body weight gain (p<0.001 vs. FC), while PIO showed higher body weight gain (p<0.01). FC diet raised HOMA-IR index by 66% (p<0.05 vs. CC), which was 50% lower with LIRA and PIO (both p<0.05 vs. FC), but unchanged by LORCA. Glucose intolerance induced by FC diet was significantly improved by LIRA, LORCA and PIO. During an insulin tolerance test, glucose area under the curve was 27% higher in FC rats (p<0.001 vs. CC) and was significantly reduced by LIRA and PIO, but not by LORCA. LIRA reduced liver fatty acids, triglycerides and cholesterol by 68, 71 and 51% (all p<0.001). PIO reduced liver triglycerides and LORCA had no effect on liver steatosis. Using echocardiography, we detected a diastolic dysfunction with reduced E/A ratio under FC diet (p<0.01 vs. CC), which was improved by both LIRA and LORCA (both p<0.01 vs. FC). LIRA also raised fractional shortening (p<0.01 vs. FC).
In conclusion, LIRA showed superior cardiometabolic benefits than LORCA and PIO in our DIO rat fed a FC diet. This novel model mimicking human overfeeding will be useful to evaluate drugs targeting obesity/type 2 diabetes.
F. Briand: Employee; Self; Physiogenex. E. Brousseau: Employee; Self; Physiogenex. T. Sulpice: Employee; Self; Physiogenex.