Conjugated GLP-1 and Estradiol as a Novel Treatment for Age-related Cognitive Decline in Males and Females

Middle age represents a critical window for metabolic and cognitive health, particularly in the context of rising obesity and diabetes rates. Glucagon-like peptide-1 (GLP-1)-based therapies, which regulate blood glucose and body weight, show sex-specific effects, with estradiol potentiating their metabolic benefits. However, research on GLP-1’s cognitive and neuroprotective roles has largely been conducted in males. Here, we investigated the effects of GLP-1 conjugated to estradiol (GE2) on metabolism, cognition, inflammation and neurogenesis in the hippocampus of middle-aged male and female rats fed a standard (SD) or Western (WD) diet. In both sexes, WD increased body weight, and plasma leptin levels. Furthermore, GE2 treatment led to weight loss, enhanced cued and contextual fear memory, reduced inflammation in the hippocampus in SD rats and increased neurogenesis in the dorsal hippocampus. Sex-specific differences were observed in fat distribution, glucose regulation, central inflammation and neuroplasticity after WD and GE2 treatment. In females only, GE2 reduced visceral (gonadal) fat, reduced inflammation in the dorsal hippocampus and improved basal blood glucose in response to a WD. In males only, GE2 normalised reduced hippocampal neurogenesis after a WD and reduced inflammation in the amygdala. These findings suggest that although WD increased body weight and GE2 improved associative learning in both sexes, both WD and GE2 had differential affects on metabolic hormones, insulin regulation, inflammation and neuroplasticity. Our findings underscore the importance of sex-specific approaches in metabolic and neuroprotective therapeutics in middle-age.