Uncoupling Insulin Sensitivity From Longevity: A Sex-Dependent Effect of Hepatic Glucagon Signaling.

ABSTRACT: Glucagon, a key hormone in maintaining euglycemia during fasting, also exerts broad metabolic effects, including regulation of lipid oxidation, adiposity, insulin sensitivity, and metabolic rate. However, its role in aging and longevity remains largely unexplored, a significant omission given the extensive research on dietary restriction and insulin signaling in lifespan modulation. Here, we investigated the impact of hepatic glucagon receptor (GCGR) signaling on lifespan using a liver-specific GCGR knockout (LKO) mouse model. While male LKO mice exhibited normal lifespan, female LKO mice displayed a significant reduction in survival. Strikingly, and in contrast to prevailing expectations based on metabolic improvements, this shortened lifespan in females occurred despite marked enhancemen

SUBMITTER: Lasher AT 

PROVIDER: S-EPMC12759044 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature