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.; Kobberup, S.; Rivir, M.; Sorrell, J.; Mowery, S.; Drucker, D. J.; D'Alessio, D. A.; Campbell, J. E.; Muller, T. D.; Perez-Tilve, D.; Knerr, P. J.; Finan, B.

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.