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Douros, J.D.* ; Capozzi, M.* ; Novikoff, A. ; Mokrosinski, J.* ; DuBois, B.* ; Stock, J.* ; Rohlfs, R.* ; Anderson, M.* ; Jedrzejcyk, D.J.* ; Poulsen, S.* ; Blenke, E.O.* ; Dago, T.* ; Huus, K.* ; Nørby, P.L.* ; Kobberup, S.* ; Rivir, M.* ; Sorrell, J.* ; Mowery, S.A.* ; Drucker, D.J.* ; D'Alessio, D.A.* ; Campbell, J.E.* ; Müller, T.D. ; Perez-Tilve, D.* ; Finan, B.* ; Knerr, P.J.*

Ectopic, hepatic GLP-1R agonism enhances the weight loss efficacy of GLP-1 analogues.

Mol. Metab. 105:102327 (2026)
Publ. Version/Full Text DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
OBJECTIVE: Unimolecular triagonists drive substantial weight loss in patients with obesity by engaging the glucagon-like peptide 1 receptor (GLP-1R) and glucose dependent insulinotropic polypeptide receptor (GIPR) to reduce food intake (FI) and the hepatic glucagon receptor (GcgR) to enhance energy expenditure (EE). However, their development has been challenged by deleterious cardiovascular (CV) effects including increased heart rate (HR), elongated QTc, and arrhythmia mediated by GcgR agonism. GLP-1R mono-agonists on the other hand improve both obesity and CV outcomes with negligible effects on EE. We sought to imbue peptide GLP-1R agonists with an EE enhancing effect by combining them with ectopic GLP-1R expression and agonism in hepatocytes. METHODS: We used an adeno-associated virus (AAV) to induce the expression of a functional, liver-specific GLP-1R combined with traditional peptide agonist treatment to drive greater body weight loss via reduced energy intake and increased energy expenditure. RESULTS: Agonism of the ectopic GLP-1R with either semaglutide, a cAMP biased GLP-1R analogue (NNC5840), or a dual GLP-1R/GIPR agonist in wild-type (WT) diet induced obese (DIO) mice led to enhanced EE and improved weight loss compared to peptide agonist treatment alone. CONCLUSIONS: This represents a novel mechanism for achieving poly-pharmacology to treat obesity.
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Publication type Article: Journal article
Document type Scientific Article
Keywords GLP-1; Obesity; Pharmacology; Energy expenditure; Glucagon; Glucagon Receptor Agonist; Double-blind; Gip; Ly3437943; Placebo; People
ISSN (print) / ISBN 2212-8778
e-ISSN 2212-8778
Journal Molecular Metabolism
Quellenangaben Volume: 105, Issue: , Pages: , Article Number: 102327 Supplement: ,
Publisher Elsevier
Publishing Place Amsterdam
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Obesity (IDO)