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

Diabetes Obes Metab. 2015 Jan;17(1):61-73. doi: 10.1111/dom.12390. Epub 2014 Oct 14.

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 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.

Keywords: GLP-1 analogue; antidiabetic drug; experimental pharmacology; weight loss therapy.

Publication types

  • Comparative Study

MeSH terms

  • Acetylation
  • Animals
  • Anti-Obesity Agents / administration & dosage
  • Anti-Obesity Agents / adverse effects
  • Anti-Obesity Agents / therapeutic use*
  • Cholecystokinin / administration & dosage
  • Cholecystokinin / adverse effects
  • Cholecystokinin / analogs & derivatives*
  • Cholecystokinin / therapeutic use
  • Diabetes Mellitus / drug therapy*
  • Diabetes Mellitus / 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
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / therapeutic use*
  • Infusions, Subcutaneous
  • Islet Amyloid Polypeptide / administration & dosage
  • Islet Amyloid Polypeptide / adverse effects
  • Islet Amyloid Polypeptide / therapeutic use*
  • Male
  • Mice, Mutant Strains
  • Obesity / complications
  • Obesity / drug therapy*
  • Obesity / etiology
  • Obesity / metabolism
  • Peptides / administration & dosage
  • Peptides / adverse effects
  • Peptides / therapeutic use*
  • Random Allocation
  • Rats, Sprague-Dawley
  • Receptor, Cholecystokinin A / agonists
  • Receptor, Cholecystokinin A / metabolism
  • Receptor, Cholecystokinin B / agonists
  • Receptor, Cholecystokinin B / metabolism
  • Receptors, Glucagon / agonists
  • Receptors, Glucagon / metabolism
  • Weight Loss / drug effects

Substances

  • 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