Characterizing Brainstem GLP-1 Control of Sensory-Specific Satiety in Male and Female Rats Across the Estrous Cycle

Jan 24, 2025Biological psychiatry

Brainstem GLP-1’s role in feeling full from specific foods in male and female rats during the reproductive cycle

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Abstract

In male rats, brainstem GLP-1 receptors are necessary for the decrease in intake of the same food during sensory-specific satiety.

Sensory-specific satiety is linked to the consumption of different foods, leading to greater caloric intake when food variety is present.
Agonizing brainstem GLP-1 receptors in males reduces overconsumption of different foods, suggesting a role in satiety signaling.
Female rats exhibit sensory-specific satiety that varies according to their estrous cycle, impacting their food consumption patterns.
Blockade of brainstem GLP-1 receptors in female rats can restore overconsumption of different foods during certain phases of the estrous cycle.
Estradiol appears to influence GLP-1 receptor and precursor expression, affecting sensory-specific satiety in both male and female rats.

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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 that underlie SSS are largely unknown.

METHODS: Here, we developed a preclinical model of SSS wherein rats consume more of a different food compared with 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-1Rs 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.

CONCLUSIONS: 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.

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Characterizing Brainstem GLP-1 Control of Sensory-Specific Satiety in Male and Female Rats Across the Estrous Cycle

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