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Synergistic metabolic benefits of an exenatide analogue and cholecystokinin in diet-induced obese and leptin-deficient rodents.

AbstractAIM:
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 Lep(ob) /Lep(ob) 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 Lep(ob) /Lep(ob) 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.
AuthorsJ L Trevaskis, C Sun, J Athanacio, L D'Souza, M Samant, K Tatarkiewicz, P S Griffin, C Wittmer, Y Wang, C-H Teng, B Forood, D G Parkes, J D Roth
JournalDiabetes, obesity & metabolism (Diabetes Obes Metab) Vol. 17 Issue 1 Pg. 61-73 (Jan 2015) ISSN: 1463-1326 [Electronic] England
PMID25204356 (Publication Type: Comparative Study, Journal Article)
Copyright© 2014 John Wiley & Sons Ltd.
Chemical References
  • AC3174
  • Anti-Obesity Agents
  • Glp1r protein, mouse
  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Islet Amyloid Polypeptide
  • Peptides
  • Receptor, Cholecystokinin A
  • Receptor, Cholecystokinin B
  • Receptors, Glucagon
  • Cholecystokinin
Topics
  • Acetylation
  • Animals
  • Anti-Obesity Agents (administration & dosage, adverse effects, therapeutic use)
  • Cholecystokinin (administration & dosage, adverse effects, analogs & derivatives, therapeutic use)
  • Diabetes Mellitus (drug therapy, metabolism)
  • Diet, High-Fat (adverse effects)
  • Drug Synergism
  • Drug Therapy, Combination (adverse effects)
  • Energy Intake (drug effects)
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents (administration & dosage, adverse effects, therapeutic use)
  • Infusions, Subcutaneous
  • Islet Amyloid Polypeptide (administration & dosage, adverse effects, therapeutic use)
  • Male
  • Mice, Mutant Strains
  • Obesity (complications, drug therapy, etiology, metabolism)
  • Peptides (administration & dosage, adverse effects, therapeutic use)
  • Random Allocation
  • Rats, Sprague-Dawley
  • Receptor, Cholecystokinin A (agonists, metabolism)
  • Receptor, Cholecystokinin B (agonists, metabolism)
  • Receptors, Glucagon (agonists, metabolism)
  • Weight Loss (drug effects)

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