The estrous cycle moderates the food and body weight suppressive effects of glucagon-like peptide-1 receptor agonism.

Aims: Emerging data suggest more young women than men are prescribed weight loss pharmacotherapies targeting the glucagon-like peptide-1 receptor (GLP-1R). However, preclinical literature has largely used male animals to characterize the neural mechanisms underlying the weight loss abilities of GLP-1R agonists (GLP-1RAs), highlighting a need for female-specific investigations. Recently, we described data pointing to the female estrous cycle as a possible moderator of GLP-1RA's effects in rats. Expression of brainstem Glp1r and the GLP-1 precursor gene, Gcg, increased during two estrous phases, proestrus and estrus (P/E), compared to males and compared to other phases, metestrus and diestrus (M/D). On this basis, we hypothesized that the weight-reducing effects of GLP-1RAs may be potentiated during P/E.

Materials and methods: In separate experiments, we determined whether timing administration of acute liraglutide or chronic semaglutide to either P/E or M/D would moderate food intake and weight loss in female rats maintained on a high fat diet. We also used qPCR to explore estrous cycle-dependent variation in Glp1r within widely distributed nuclei relevant to energy balance control.

Results: GLP-1RA administration during P/E, compared to M/D, enhanced the intake-suppressive effects of liraglutide and semaglutide. Moreover, semaglutide administered only during P/E led to greater body weight loss compared to M/D-administered semaglutide. We also observed greater Glp1r expression in P/E compared to M/D in multiple nuclei.

Conclusions: GLP-1RAs administered in P/E lead to significantly greater body weight loss via reduction in food intake. Collectively, these data may have translational implications for the timing of GLP-1RA administration across the menstrual cycle.