Longevity & AgingLiver-Targeted GLP-1 Receptor Gene Delivery Supercharges Semaglutide Weight Loss
Researchers engineered mice to express the GLP-1 receptor (GLP-1R) specifically in liver cells using an adeno-associated virus (AAV), then treated them with semaglutide or other GLP-1 analogues. The ectopic liver GLP-1R activated cAMP signaling in hepatocytes — a mechanism normally reserved for the glucagon receptor — boosting energy expenditure without the dangerous heart rate increases seen with glucagon receptor agonists. Compared to peptide treatment alone, mice with the hepatic GLP-1R showed enhanced fat loss and greater overall weight reduction. The approach worked with semaglutide, a cAMP-biased GLP-1R analogue (NNC5840), and a dual GLP-1R/GIPR agonist, suggesting broad applicability. This proof-of-concept study demonstrates a novel strategy for layering energy expenditure benefits onto existing safe obesity drugs.
