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Synergistic metabolic benefits of an exenatide analogue and cholecystokinin in diet-induced obese and leptin-deficient rodents
- Source :
- Diabetes, Obesity and Metabolism. 17:61-73
- Publication Year :
- 2014
- Publisher :
- Wiley, 2014.
-
Abstract
- Aim To test the impact of cholecystokinin (CCK) plus either amylin or a glucagon-like peptide-1 receptor (GLP-1R) agonist on metabolic variables in diet-induced obese (DIO) rodents. Methods A stabilized acetylated version of CCK-8 (Ac-Y*-CCK-8), selective CCK1 receptor (CCK1R) or CCK2 receptor (CCK2R) agonists, amylin or the GLP-1R agonist and exenatide analogue AC3174 were administered in select combinations via continuous subcutaneous infusion to DIO rats for 14 days, or Lepob/Lepob mice for 28 days, and metabolic variables were assessed. Results Combined administration of Ac-Y*-CCK-8 with either amylin or AC3174 induced greater than additive weight loss in DIO rats, with the overall magnitude of effect being greater with AC3174 + Ac-Y*-CCK-8 treatment. Co-infusion of AC3174 with a specific CCK1R agonist, but not a CCK2R agonist, recapitulated the weight loss mediated by AC3174 + Ac-Y*-CCK-8 in DIO rats, suggesting that synergy is mediated by CCK1R activation. In a 4 × 4 full-factorial response surface methodology study in DIO rats, a synergistic interaction between AC3174 and the CCK1R-selective agonist on body weight and food intake was noted. Co-administration of AC3174 and the CCK1R-selective agonist to obese diabetic Lepob/Lepob mice elicited a significantly greater reduction in percentage of glycated haemoglobin and food intake relative to the sum effects of monotherapy groups. Conclusions The anti-obesity and antidiabetic potential of combined GLP-1R and CCK1R agonism is an approach that warrants further investigation.
- Subjects :
- Male
Agonist
endocrine system
medicine.medical_specialty
medicine.drug_class
Endocrinology, Diabetes and Metabolism
Amylin
Pharmacology
Diet, High-Fat
Infusions, Subcutaneous
Glucagon-Like Peptide-1 Receptor
Rats, Sprague-Dawley
Random Allocation
Endocrinology
Weight loss
Internal medicine
Weight Loss
Diabetes Mellitus
Receptors, Glucagon
Internal Medicine
medicine
Animals
Hypoglycemic Agents
Obesity
Cholecystokinin
business.industry
Leptin
digestive, oral, and skin physiology
Acetylation
Drug Synergism
Mice, Mutant Strains
Receptor, Cholecystokinin B
Islet Amyloid Polypeptide
Receptor, Cholecystokinin A
Cholecystokinin B receptor
Drug Therapy, Combination
Anti-Obesity Agents
medicine.symptom
Energy Intake
Peptides
business
Exenatide
Diet-induced obese
hormones, hormone substitutes, and hormone antagonists
medicine.drug
Subjects
Details
- ISSN :
- 14628902
- Volume :
- 17
- Database :
- OpenAIRE
- Journal :
- Diabetes, Obesity and Metabolism
- Accession number :
- edsair.doi.dedup.....6794c9e33f58c6d7977b395c3ef2fcbe