A Hamster Model of Diet-Induced Obesity for Preclinical Evaluation of Anti-Obesity, Anti-Diabetic and Lipid Modulating Agents

Abstract

Aim: Unlike rats and mice, hamsters develop hypercholesterolemia, and hypertriglyceridemia when fed a cholesterol-rich diet. Because hyperlipidemia is a hallmark of human obesity, we aimed to develop and characterize a novel diet-induced obesity (DIO) and hypercholesterolemia Golden Syrian hamster model.

Methods and results: Hamsters fed a highly palatable fat- and sugar-rich diet (HPFS) for 12 weeks showed significant body weight gain, body fat accumulation and impaired glucose tolerance. Cholesterol supplementation to the diet evoked additional hypercholesterolemia. Chronic treatment with the GLP-1 analogue, liraglutide (0.2 mg/kg, SC, BID, 27 days), normalized body weight and glucose tolerance, and lowered blood lipids in the DIO-hamster. The dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin (3.0 mg/kg, PO, QD) also improved glucose tolerance. Treatment with peptide YY3-36 (PYY3-36, 1.0 mg/kg/day) or neuromedin U (NMU, 1.5 mg/kg/day), continuously infused via a subcutaneous osmotic minipump for 14 days, reduced body weight and energy intake and changed food preference from HPFS diet towards chow. Co-treatment with liraglutide and PYY3-36 evoked a pronounced synergistic decrease in body weight and food intake with no lower plateau established. Treatment with the cholesterol uptake inhibitor ezetimibe (10 mg/kg, PO, QD) for 14 days lowered plasma total cholesterol with a more marked reduction of LDL levels, as compared to HDL, indicating additional sensitivity to cholesterol modulating drugs in the hyperlipidemic DIO-hamster. In conclusion, the features of combined obesity, impaired glucose tolerance and hypercholesterolemia in the DIO-hamster make this animal model useful for preclinical evaluation of novel anti-obesity, anti-diabetic and lipid modulating agents.

Fig 1. Hamsters fed a palatable diet become more obese than hamsters fed commercial purified high-fat diets.

(A) Body weight (g), (B) whole-body fat mass (g), and (C) blood glucose and (D) plasma insulin levels were measured during an OGTT of hamsters fed chow, highly palatable fat- and sugar-rich (HPFS) diet, 31.8E % and 60.0E % purified HF diets for 12 weeks. Values are means ± SEM (n = 10 per group; ^aP<0.05 for HPFS vs. chow-fed group and ^cP<0.05 for 60.0E % HF diet vs. chow fed-group, (*** indicates P<0.001).

Fig 2. Body weight of hamsters fed highly palatable fat- and sugar-rich diet with 0.5% cholesterol supplementation.

Body weight (g) of hamsters fed the highly palatable fat- and sugar-rich (HPFS) diet with 0.5% cholesterol supplementation for 12 weeks. Values are means ± SEM (n = 6 per group; ^aP<0.05 for HPFS vs. chow-fed, ^bP<0.05 for HPFS + 0.5% cholesterol vs. chow-fed group).

Fig 3. Effect of treatment with liraglutide and linagliptin on body weight and glycaemic control in DIO hamsters.

(A) Body weight change (% of day 0) of obese hyperlipidemic hamsters treated for 26 days with vehicle (PO, QD), liraglutide (0.2 mg/kg, SC, BID) or linagliptin (3.0 mg/kg, PO, QD). Mean weight on day 0 was 185.6 ± 18.29 g. Absolute weight loss for the liraglutide group was 31.8 ± 14.6 g. (B, C) blood glucose and (D, E) plasma insulin responses to an OGTT following 26 days of treatment with vehicle (PO, QD), liraglutide (0.2 mg/kg, SC, BID) or linagliptin (3.0 mg/kg, PO, QD). Hamsters were semi-fasted 16 h before the OGTT. Drugs were administered 45 min prior to the oral glucose load (2g/kg). Hamsters included in the study were fed a HPFS diet with 0.5% cholesterol supplemented for 12 weeks before initiation of the study. Values are means ± SEM (n = 6 per group; ^aP<0.05 for liraglutide vs. vehicle group, ^bP<0.05 for linagliptin vs. vehicle group, (** indicates P<0.01).

Fig 4. Effect of NMU, PYY_3-36, liraglutide or co-treatment with liraglutide and PYY_3-36 on body weight and cumulative energy intake.

(A) Body weight change (% of day 0), (B) Cumulative total energy intake (kJ), (C) cumulative intake of the HPFS diet with 0.5% cholesterol supplement (kJ), and (D) cumulative intake of regular chow (kJ) after 14 days treatment of obese hyperlipidemic hamsters with vehicle (SC, BID) + vehicle (osmotic pump), liraglutide (0.1 mg/kg, SC, BID) + vehicle (osmotic pump), vehicle (SC, BID) + PYY_3-36 (1.0 mg/kg/day, osmotic pump), the co-treatment group liraglutide (0.1 mg/kg, SC, BID) + PYY_3-36 (1.0 mg/kg/day, osmotic pump), or vehicle (SC, BID) + NMU (1.5 mg/kg/day, osmotic pump). Hamsters included in the study were fed a HPFS diet with 0.5% cholesterol supplemented for 12 weeks before initiation of the study. Data are given as mean ± SEM with n = 8/group. Statistical analysis: two-way ANOVA with Bonferronis post hoc test; ^a P<0.05 for liraglutide vs. vehicle group, ^b P<0.05 for PYY_3-36 vs. vehicle group, ^c P<0.05 for PYY_3-36 + liraglutide vs. vehicle group, and ^d P<0.05 for NMU vs. vehicle group.