A GLP-1:CCK fusion peptide harnesses the synergistic effects on metabolism of CCK-1 and GLP-1 receptor agonism in mice.

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D C HornigoldJames L Trevaskis

Abstract

Combination approaches for the treatment of metabolic diseases such as obesity and diabetes are becoming increasingly relevant. Co-administration of a glucagon-like peptide-1 receptor (GLP-1R) agonist with a cholecystokinin receptor-1 (CCKR1) agonist exert synergistic effects on weight loss in obese rodents. Here, we report on the effects of a novel fusion peptide (C2816) comprised of a stabilized GLP-1R agonist, AC3174, and a CCKR1-selective agonist, AC170222. C2816 was constructed such that AC3174 was linked to the N-terminus of AC170222, thus preserving the C-terminal amide of the CCK moiety. In functional in vitro assays C2816 retained full agonism at GLP-1R and CCKR1 at lower potency compared to parent molecules, whereas a previously reported fusion peptide in the opposite orientation, (pGlu-Gln)-CCK-8/exendin-4, exhibited no activity at either receptor. Acutely, in vivo, C2816 increased cFos in key central nuclei relevant to feeding behavior, and reduced food intake in wildtype (WT), but less so in GLP-1R-deficient (GLP-1RKO), mice. In sub-chronic studies in diet-induced obese (DIO) mice, C2816 exerted superior reduction in body weight compared to co-administration of AC3174 and AC170222 albeit at a higher molar dose. The...Continue Reading

Citations

Jul 4, 2020·Current Opinion in Clinical Nutrition and Metabolic Care·Rachel H Freire, Jacqueline I Alvarez-Leite
Aug 6, 2019·The Journal of Clinical Investigation·Kerstin StemmerMatthias H Tschöp
Feb 29, 2020·Clinical Medicine Insights. Endocrinology and Diabetes·Annie Hasib
Sep 20, 2018·Journal of Internal Medicine·S J BrandtK Stemmer
Nov 27, 2019·Molecular Metabolism·T D MüllerM H Tschöp
Mar 19, 2020·Cell Metabolism·Ruth E GimenoRandy J Seeley
May 15, 2021·Physiology & Behavior·Kimberly R Smith, Timothy H Moran
Jun 8, 2021·Frontiers in Endocrinology·Ryan A LaffertyPeter R Flatt
Oct 27, 2021·Endocrine Reviews·Angeliki M AngelidiChristos S Mantzoros
Oct 19, 2021·Diabetes, Obesity & Metabolism·Vasiliki VanaHarald S Hansen

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