PuSH - Publikationsserver des Helmholtz Zentrums München

Export: TXT Text RIS Endnote (RIS) BIB BibTeX
Douros, J.D.* ; Novikoff, A. ; Dubois, B.* ; Rohlfs, R.* ; Mokrosiński, J.* ; Hogendorf, W.F.J.* ; Augustin, R.* ; Merkestein, M.* ; Egaa Martini, L.B.* ; Linderoth, L.* ; Gerrard, E.* ; Kodra, J.T.* ; Norlin, J.* ; Roed, N.K.* ; Oldenburger, A.* ; Mowery, S.A.* ; Waldhoer, M.* ; Perez-Tilve, D.* ; Finan, B.* ; Reedtz-Runge, S.* ; Müller, T.D. ; Knerr, P.J.*

A GLP-1 analogue optimized for cAMP-biased signaling improves weight loss in obese mice.

Mol. Metab. 100:102124 (2025)
Postprint DOI PMC
Open Access Gold
OBJECTIVE: Glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonism is foundational to modern obesity pharmacotherapies. These compounds were engineered for maximal G protein alpha(s) (Gsα) signaling potency and downstream cAMP production. However, this strategy requires reconsideration as partial, biased GLP-1R agonists characterized by decreased Gsα signaling and disproportionate reductions in β-arrestin recruitment relative to the native ligand provide greater weight loss than full, balanced agonists in preclinical models. METHODS: We tested the hypothesis that in vitro signaling bias, which considers both cAMP signaling and β-arrestin recruitment, better predicts weight loss efficacy in diet induced obese (DIO) rodents than cAMP potency alone. RESULTS: Our data demonstrate that signaling bias significantly correlates to GLP-1R agonist mediated weight loss in diet-induced obese mice. We further characterized a protracted GLP-1 analogue (NNC5840) which exhibits a partial-Gsα, cAMP-biased GLP-1R signaling profile in vitro and demonstrates superior maximal body weight reduction compared to semaglutide in DIO mice. The NNC5840 weight loss profile is characterized by reduced in vivo potency but increased maximal efficacy. CONCLUSION: The data demonstrate that biased agonism is a strong predictor of in vivo efficacy for GLP-1R agonists independent of factors like intrinsic cAMP potency or pharmacokinetics. These data suggest that drug discovery screening strategies which take a holistic approach to target receptor signaling may provide more efficacious candidate molecules. The interpretations of these studies are limited by unknowns including how structural modifications to the biased GLP-1R agonist effect physiochemical properties of the molecules.
Impact Factor
Scopus SNIP
Web of Science
Times Cited
Altmetric
6.600
0.000
2
Tags
Anmerkungen
Besondere Publikation
Auf Hompepage verbergern

Zusatzinfos bearbeiten
Eigene Tags bearbeiten
Privat
Eigene Anmerkung bearbeiten
Privat
Auf Publikationslisten für
Homepage nicht anzeigen
Als besondere Publikation
markieren
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Glp-1 ; Biased Agonism ; Obesity ; Semaglutide; Glucagon-like Peptide-1; Receptor Agonist; Gip; Discovery
Sprache englisch
Veröffentlichungsjahr 2025
HGF-Berichtsjahr 2025
ISSN (print) / ISBN 2212-8778
e-ISSN 2212-8778
Zeitschrift Molecular Metabolism
Quellenangaben Band: 100, Heft: , Seiten: , Artikelnummer: 102124 Supplement: ,
Verlag Elsevier
Verlagsort Amsterdam
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Obesity (IDO)
POF Topic(s) 90000 - German Center for Diabetes Research
30201 - Metabolic Health
Forschungsfeld(er) Helmholtz Diabetes Center
PSP-Element(e) G-501900-221
G-502200-001
Förderungen Novo Nordisk
German Center for Diabetes Research
German Research Foundation
European Research Council ERC-CoG
DOI 10.1016/j.molmet.2025.102124
WOS ID 001561396100001
PubMed ID 40157531
Erfassungsdatum 2025-05-09
[➜Korrektur melden]