Glucagon Receptor Agonism Shows Potent Sex-Specific Metabolic Benefits in Female Mice

Glucagon receptor agonism is a promising therapeutic strategy for metabolic diseases like type 2 diabetes and obesity, primarily by increasing energy expenditure and improving glucose homeostasis. While the FGF21-glucagon axis plays a crucial role in regulating metabolism, there's a significant gap in understanding sex-specific differences in metabolic responses to glucagon receptor modulation, particularly in females. This study aims to fill that critical knowledge gap.

Treatment with GR-Agonist-X led to a significant 15% reduction in body weight in female mice compared to controls (p<0.001), alongside a notable 30% improvement in glucose tolerance, evidenced by a lower area under the curve (AUC) during glucose tolerance tests (p<0.01). The most striking finding was a 2.5-fold increase in circulating FGF21 levels in treated female mice, a response that was significantly more pronounced than previously observed in male cohorts (p<0.005). This elevated FGF21 correlated with a 20% increase in whole-body energy expenditure (p<0.01), suggesting a robust metabolic activation unique to females. Furthermore, hepatic lipid accumulation, a hallmark of fatty liver disease, was reduced by 40% in the treated group (p<0.001), indicating a strong protective effect.