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


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.
Gubra, Hørsholm, Denmark.
Louise S
LS
Dalbøge
Gubra, Hørsholm, Denmark.
Philip J
PJ
Pedersen
Gubra, Hørsholm, Denmark.
Gitte
G
Hansen
Gubra, Hørsholm, Denmark.
Katrine
K
Fabricius
Gubra, Hørsholm, Denmark.
Henrik B
HB
Hansen
Gubra, Hørsholm, Denmark.
Jacob
J
Jelsing
Gubra, Hørsholm, Denmark.
Niels
N
Vrang
D000818:Animals; D019440:Anti-Obesity Agents / Q000627:therapeutic use*; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D001786:Blood Glucose / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D006224:Cricetinae; D059305:Diet, High-Fat / Q000009:adverse effects*; D004435:Eating / Q000187:drug effects; D000069438:Ezetimibe / Q000627:therapeutic use; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D000069476:Linagliptin / Q000627:therapeutic use; D008297:Male; D008647:Mesocricetus; D009479:Neuropeptides / Q000627:therapeutic use; D009765:Obesity / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D010446:Peptide Fragments / Q000627:therapeutic use; D019894:Peptide YY / Q000627:therapeutic use
D019440:Anti-Obesity Agents; D000924:Anticholesteremic Agents; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D009479:Neuropeptides; D010446:Peptide Fragments; D019894:Peptide YY; C056900:neuromedin U; C061785:peptide YY (3-36); D000069476:Linagliptin; D002784:Cholesterol; D000069438:Ezetimibe