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

## TL;DR

Researchers found that adding a liver-specific GLP-1R to existing GLP-1 treatments improves weight loss in mice by boosting energy expenditure.

## Contribution

A novel approach combining ectopic hepatic GLP-1R expression with GLP-1 agonists enhances weight loss efficacy.

## Key findings

- Ectopic GLP-1R in the liver increases energy expenditure and improves weight loss in obese mice.
- Combining AAV-induced GLP-1R with semaglutide or dual agonists leads to greater weight loss.
- Ectopic GLP-1R mediates semaglutide clearance, suggesting a new mechanism for drug action.

## Abstract

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.

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.

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.

This represents a novel mechanism for achieving poly-pharmacology to treat obesity.

Image 1

•A Glp1r encoding AAV induces expression of a functional receptor in 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.

A Glp1r encoding AAV induces expression of a functional receptor in 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.