Role of glucagon-like peptide-1 signaling in mediating sensory-specific satiety
胰高血糖素样肽-1 信号传导在介导感觉特异性饱腹感中的作用
基本信息
- 批准号:10750216
- 负责人:
- 金额:$ 4.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAffectAgonistAmygdaloid structureAnatomyBrainBrain StemCaloriesCell NucleusCellsConsumptionDataDevelopmentDiseaseEatingEnvironmentExposure toFeeding behaviorsFoodGLP-I receptorGastrointestinal tract structureIncentivesInjectionsIntakeMediatingModelingModernizationMotivationMusNeuronsNeurosecretory SystemsObesityPeripheralPlayPopulationPositioning AttributePrevalenceRattusRewardsRoleSatiationSensorySignal TransductionSiteStructureStructure of terminal stria nuclei of preoptic regionTestingTimeUnited StatesVirusantagonistcomparativedesigner receptors exclusively activated by designer drugsexperienceexperimental studyfeedingfood consumptionglucagon-like peptide 1hedonichindbrainmotivated behaviorneuralneuromechanismnovelpreproglucagonspreventreduced food intakesource localization
项目摘要
PROJECT SUMMARY/ABSTRACT
Despite its critical role in meal cessation, the neuroendocrine mechanisms underlying sensory-specific
satiety (SSS) are largely unknown. SSS is the transient reduction in motivation and pleasantness for a recently
consumed food. While this selective decrease in hedonic value suppresses consumption of the same food, in
leads to a comparative increase in the reward value of uneaten palatable foods. As a result, a variety of readily
available alternative foods can drive overconsumption. Given the variety of highly caloric foods pervasive in the
modern environment, it is important to understand the mechanisms by which SSS regulates food intake. To this
end, we propose to use our novel rat model of SSS to investigate the neural action of one satiation signal,
glucagon-like peptide-1 (GLP-1). Indeed, our preliminary data indicate GLP-1 receptors (GLP-1Rs) in the
hindbrain are critical for the SSS-induced decline in consumption of the same food. Moreover, hindbrain GLP-
1Rs are sufficient to prevent the overconsumption of an available alternative food. These data show hindbrain
GLP-1 signaling is important for decreased consumption of the same food. In contrast, the effects of GLP-1
signaling is muted during the comparative increased intake of an alternative available food.
However, these data unearth additional questions regarding the neural underpinnings of SSS. Notably, the
neural population(s) mediating this GLP-1 signaling are unknown. An integrator of peripheral signals, the nucleus
tractus solitarius (NTS) of the caudal brainstem is well-positioned to host the GLP-1 signaling involved in SSS.
Not only does the NTS contain GLP-1R-expressing cells, but it also holds preproglucagon (PPG) neurons that
synthesize GLP-1. Therefore, in Aim I, we propose to investigate the role of these two distinct NTS neural
populations in controlling SSS.
Furthermore, it is unclear how the effects of GLP-1 signaling are muted to enable the increased intake of
an alternative food. Two subcortical structures, the bed nucleus of the stria terminalis (BNST) and the central
amygdala (CeA) are functionally and anatomically suited to modulate GLP-1 signaling. Both regions mediate
aspects of ingestive behavior and reward, and each region projects directly to PPG NTS neurons. Thus, in Aim
II we will characterize the role of BNST/CeA → PPG projections during increased intake of an alternative food.
Considering the ever-growing prevalence of obesity in the United States, understanding how neuroendocrine
signals mediate the impact of recent food experiences on consumption is an important step in the development
of approaches for treating diseases of maladaptive ingestive behavior. To this end, our experiments will
investigate central GLP-1-mediated mechanisms by which SSS modulates food intake.
项目总结/摘要
尽管它在停止进食中起着关键作用,但感觉特异性的神经内分泌机制
satiety(SSS)在很大程度上是未知的。SSS是最近一段时间内,
消耗的食物。虽然这种享乐价值的选择性降低抑制了对同一种食物的消费,
导致未食用的可口食物的奖励价值相对增加。因此,各种容易
可用的替代食品会导致过度消费。考虑到高热量食物的多样性,
在现代环境中,重要的是要了解SSS调节食物摄入的机制。本
最后,我们建议使用我们的新的SSS大鼠模型来研究一个饱足信号的神经作用,
胰高血糖素样肽-1(GLP-1)。事实上,我们的初步数据表明,GLP-1受体(GLP-1 R)在
对于SSS引起的相同食物消耗量的下降至关重要。此外,后脑GLP-
1 Rs足以防止过度消费现有的替代食品。这些数据显示,
GLP-1信号对于减少相同食物的消耗很重要。相反,GLP-1的作用
在可替代的可用食物的相对增加的摄入期间,信号被减弱。
然而,这些数据揭示了关于SSS神经基础的其他问题。特别是
介导这种GLP-1信号传导的神经群是未知的。细胞核是外周信号的整合者
尾侧脑干的孤束(NTS)很好地定位于宿主参与SSS的GLP-1信号传导。
NTS不仅含有GLP-1 R表达细胞,而且还含有前胰高血糖素原(PPG)神经元,
合成GLP-1。因此,在目的I中,我们建议研究这两种不同的NTS神经元的作用。
控制SSS的人群。
此外,尚不清楚GLP-1信号传导的作用是如何减弱的,以使GLP-1的摄入量增加。
一种替代食物。两个皮质下结构,终纹床核(BNST)和中央
杏仁核(CeA)在功能上和解剖学上适合于调节GLP-1信号传导。两个区域都调解
摄食行为和奖励方面,每个区域直接投射到PPG NTS神经元。在Aim
我们将描述BNST/CeA → PPG预测在替代食物摄入量增加期间的作用。
考虑到美国肥胖症的流行率不断上升,了解神经内分泌是如何影响肥胖症的,
信号介导最近的食物经验对消费的影响是发展的重要一步
治疗不良摄食行为疾病的方法。为此,我们的实验将
研究SSS调节食物摄入的中枢GLP-1介导机制。
项目成果
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