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

Feb 7, 2026Molecular metabolism

Activating liver GLP-1 receptors may improve weight loss with GLP-1 drugs

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Abstract

Agonism of the ectopic GLP-1 receptor resulted in enhanced energy expenditure and improved weight loss in diet-induced obese mice.

Engaging the ectopic GLP-1 receptor in liver cells may increase energy expenditure compared to standard peptide treatments.
Weight loss was greater when combining ectopic GLP-1 receptor activation with traditional GLP-1 receptor agonists.
This approach could offer a new mechanism for treating obesity through poly-pharmacology.
Ectopic expression of GLP-1 receptor may address limitations of existing obesity treatments related to cardiovascular effects.

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

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