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.