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

Sep 11, 2014Diabetes, obesity & metabolism

Combined metabolic benefits of an exenatide-like drug and a digestion hormone in obese and leptin-lacking rodents

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Abstract

Combined administration of *Ac-Y-CCK-8** with either amylin or AC3174 induced greater than additive weight loss in diet-induced obese rats.

The greatest weight loss effect was observed with the combination of AC3174 and Ac-Y*-CCK-8.
Activation of the CCK1 receptor appears to mediate the observed weight loss synergy.
A synergistic interaction between AC3174 and a CCK1R-selective agonist was noted in a study involving DIO rats.
Co-administration of AC3174 and a CCK1R-selective agonist resulted in a significant reduction in glycated hemoglobin and food intake in obese diabetic Lep(ob)/Lep(ob) mice.
The findings suggest potential anti-obesity and antidiabetic benefits of combining GLP-1R and CCK1R agonism.

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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.

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

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