Hepatic GCGR is Key for Superior Weight Loss with Survodutide Analog

Dual agonists targeting both Glucagon-like peptide-1 receptor (GLP-1R) and Glucagon receptor (GCGR) are emerging as highly effective treatments for obesity and metabolic dysfunction. While survodutide (BI 456906) has shown promising results in clinical trials, the precise contribution of GCGR activation, especially in the liver, to its superior metabolic benefits remains unclear. This study specifically investigated the necessity of hepatic GCGR for the enhanced weight loss and metabolic improvements observed with a survodutide-like dual agonist.

The study revealed that the survodutide analogue significantly improved metabolic health in wild-type mice. In these mice, the analogue led to superior reductions in body weight and marked improvements in glucose homeostasis. This indicates that the liver's response to GCGR activation is a key driver of the analogue's potent anti-obesity and anti-diabetic actions. Without functional hepatic GCGR, the analogue's efficacy was significantly diminished, highlighting the liver's central role. The most critical finding was that the superior weight loss and metabolic benefits of the analogue were completely abolished in L-GCGR-KO mice, demonstrating that hepatic GCGR is absolutely required for these effects.