title: Synergistic metabolic benefits of an exenatide analogue and cholecystokinin in diet-induced obese and leptin-deficient rodents.
abstract: OBJECTIVE
  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.
authors.affiliation: Amylin Pharmaceuticals, LLC, San Diego, CA, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Trevaskis
authors.forename: C
authors.initials: C
authors.lastname: Sun
authors.forename: J
authors.initials: J
authors.lastname: Athanacio
authors.forename: L
authors.initials: L
authors.lastname: D'Souza
authors.forename: M
authors.initials: M
authors.lastname: Samant
authors.forename: K
authors.initials: K
authors.lastname: Tatarkiewicz
authors.forename: P S
authors.initials: PS
authors.lastname: Griffin
authors.forename: C
authors.initials: C
authors.lastname: Wittmer
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: C-H
authors.initials: CH
authors.lastname: Teng
authors.forename: B
authors.initials: B
authors.lastname: Forood
authors.forename: D G
authors.initials: DG
authors.lastname: Parkes
authors.forename: J D
authors.initials: JD
authors.lastname: Roth
mesh_terms: D000107:Acetylation; D000818:Animals; D019440:Anti-Obesity Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002766:Cholecystokinin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000009:adverse effects; D002149:Energy Intake / Q000187:drug effects; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D055104:Infusions, Subcutaneous; D058228:Islet Amyloid Polypeptide / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008817:Mice, Mutant Strains; D009765:Obesity / Q000150:complications / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D043886:Receptor, Cholecystokinin A / Q000819:agonists / Q000378:metabolism; D043887:Receptor, Cholecystokinin B / Q000819:agonists / Q000378:metabolism; D018027:Receptors, Glucagon / Q000819:agonists / Q000378:metabolism; D015431:Weight Loss / Q000187:drug effects
chemical_list: C553564:AC3174; D019440:Anti-Obesity Agents; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D058228:Islet Amyloid Polypeptide; D010455:Peptides; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D018027:Receptors, Glucagon; D002766:Cholecystokinin
keywords: GLP-1 analogue; antidiabetic drug; experimental pharmacology; weight loss therapy