Characterizing brainstem glucagon-like peptide-1 control of sensory-specific-satiety in male and female rats across the estrous cycle.

Background: Meal variety promotes overconsumption by delaying sensory-specific-satiety (SSS), the transient reduction in reward value of a recently consumed food. Despite its role in meal cessation, the neuroendocrine mechanisms underlying SSS are largely unknown.

Methods: Here, we developed a preclinical model of SSS wherein rats consume more of a different food compared to the same food presented again, leading to greater caloric intake. Using pharmacological and molecular approaches targeting the brainstem, we investigated the involvement of the satiation signal, glucagon-like peptide-1 (GLP-1), in mediating SSS in male rats (n=96) and in female rats (n=85) across their estrous cycle. We also evaluated the sufficiency of the hormone estradiol to modulate GLP-1 and SSS.

Results: In males, brainstem GLP-1 receptors (GLP-1Rs) were necessary for the SSS-induced decrease in same food intake, while agonizing brainstem GLP-1Rs was sufficient to attenuate overconsumption of the different food. Female rats showed SSS in an estrous cycle-dependent manner and did not consume more of the different food in diestrus-to-Proestrus and proestrus-to-Estrus. However, blockade of brainstem GLP-1R restored different food overconsumption. Furthermore, the brainstem's nucleus tractus solitarius and area postrema showed increased expression of the GLP-1 precursor, glucagon (Gcg), during diestrus-to-Proestrus and proestrus-to-Estrus, and greater Glp1r expression in proestrus-to-Estrus. Similarly, 17β-estradiol injections in males not only increased Glp1r and Gcg expression, but also reduced SSS.

Conclusion: We identified a bidirectional role for brainstem GLP-1R signaling in modulating SSS; effects that are estrous cycle-dependent. Moreover, our data indicate that estradiol regulates Glp1r and Gcg expression and likely influences SSS.