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- Title
Synergistic metabolic benefits of an exenatide analogue and cholecystokinin in diet-induced obese and leptin-deficient rodents.
- Authors
Trevaskis, J. L.; Sun, C.; Athanacio, J.; D'Souza, L.; Samant, M.; Tatarkiewicz, K.; Griffin, P. S.; Wittmer, C.; Wang, Y.; Teng, C.‐H.; Forood, B.; Parkes, D. G.; Roth, J. D.
- 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
CHOLECYSTOKININ; LEPTIN; GLUCAGON-like peptide 1; EXPERIMENTAL pharmacology; WEIGHT loss; HYPOGLYCEMIC agents
- Publication
Diabetes, Obesity & Metabolism, 2015, Vol 17, Issue 1, p61
- ISSN
1462-8902
- Publication type
Article
- DOI
10.1111/dom.12390