Ectopic, hepatic GLP-1R agonism enhances the weight loss efficacy of GLP-1 analogues
Year: 2026
Type: article
Abstract: Objective Unimolecular triagonists drive substantial weight loss in patients with obesity (PwO) by engaging the glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) receptors to reduce food intake (FI) and the hepatic glucagon (Gcg) receptor 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 monoagonists 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 attenuated adenovirus (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 low internalization GLP-1R agonist (Sema584), 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 agonist treatment alone. Conclusions This represents a novel mechanism for achieving polypharmacy to treat obesity. Highlights A Glp1r encoding AAV induces expression of a functional receptor mouse livers. Endogenous GLP-1R does not mediate semaglutide clearance. Ectopic GLP-1R mediates semaglutide clearance. Ectopic, hepatic Glp1r plus semaglutide enhances weight loss in mice. Ectopic, hepatic Glp1r plus a dual incretin agonist enhances weight loss in mice.
Source: Molecular Metabolism
Authors: Jonathan D. Douros, Megan Capozzi, Aaron Novikoff, Jacek Mokrosinski, Barent DuBois, Joseph Stock, Rebecca Rohlfs, Mikayla Anderson, Dominika J. Jedrzejcyk, Svend Poulsen, Erik Oude Blenke, Tomas Dago, Kasper Huus, Peder L. Nørby, Sune Kobberup, Marita Rivir, Joyce Sorrell, Stephanie A. Mowery, Daniel J. Drucker, David A. D'Alessio, Jonathan E. Campbell, Timo D. Müller, Diego Perez-Tilve, Brian Finan, Patrick J. Knerr
Institutions: Duke University, Helmholtz Munich, German Center for Diabetes Research, Novo Nordisk (United States), Novo Nordisk (Denmark), University of Cincinnati, Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute, Walther-Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München
Language: English
Subfield: Endocrine and Autonomic Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,270
OpenAlex ID: W7127885384