Applebey Sarah V, Xiao Allison G, Harris Erin P, Levine Caleb, Belser Drew L, Geisler Caroline E, Parent Marise B, Bangasser Debra A, Crist Richard C, Reiner Benjamin C, Hayes Matthew R
Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Neuroscience Institute, Georgia State University, Atlanta, Georgia; Center for Behavioral Neuroscience, Georgia State University, Atlanta, Georgia.
Biol Psychiatry. 2025 Aug 1;98(3):249-259. doi: 10.1016/j.biopsych.2025.01.012. Epub 2025 Jan 22.
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.
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.
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.
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.
食物种类多样会通过延迟特定感觉饱腹感（SSS）促进过度进食，特定感觉饱腹感是指最近摄入食物的奖励价值的短暂降低。尽管其在进食停止中起作用，但SSS背后的神经内分泌机制在很大程度上尚不清楚。
在此，我们建立了一个SSS的临床前模型，其中与再次呈现相同食物相比，大鼠会更多地食用不同的食物，从而导致热量摄入增加。使用针对脑干的药理学和分子方法，我们研究了饱腹感信号胰高血糖素样肽-1（GLP-1）在介导雄性大鼠（n = 96）和雌性大鼠（n = 85）整个发情周期的SSS中的作用。我们还评估了雌激素调节GLP-1和SSS的充分性。
在雄性中，脑干GLP-1受体（GLP-1Rs）对于SSS诱导的相同食物摄入量减少是必需的，而激活脑干GLP-1Rs足以减轻不同食物的过度进食。雌性大鼠以发情周期依赖性方式表现出SSS，并且在动情后期至发情前期和发情前期至发情期不会更多地食用不同的食物。然而，阻断脑干GLP-1Rs可恢复不同食物的过度进食。此外，在动情后期至发情前期和发情前期至发情期，脑干的孤束核和最后区显示GLP-1前体胰高血糖素（Gcg）的表达增加，而在发情前期至发情期Glp1r表达更高。同样，对雄性大鼠注射17β-雌二醇不仅增加了Glp1r和Gcg的表达，还降低了SSS。
我们确定了脑干GLP-1R信号在调节SSS中的双向作用，其作用依赖于发情周期。此外，我们的数据表明雌激素调节Glp1r和Gcg的表达，并可能影响SSS。
