Role of glucagon-like peptide-1 signaling in mediating sensory-specific satiety

项目摘要/摘要 尽管它在停止进食中起着关键作用，但感官特有的神经内分泌机制 饱腹感(SSS)在很大程度上是未知的。SSS是最近一段时间内动力和愉悦感的短暂下降 吃了很多食物。虽然享乐值的这种选择性下降抑制了相同食物的消费，但在 导致未食用的可口食物的奖励价值相对增加。因此，各种现成的 可用的替代食物可能会导致过度消费。鉴于在世界各地普遍存在的各种高热量食物 在现代环境中，了解SSS调节食物摄入量的机制很重要。对这件事 最后，我们建议使用我们新的SSS大鼠模型来研究一个饱食信号的神经行为， 胰升糖素样肽-1(GLP-1)。事实上，我们的初步数据表明，GLP-1受体(GLP-1Rs)在 后脑是SSS导致的相同食物消耗量下降的关键。此外，后脑GLP- 1R足以防止过度消费可用的替代食物。这些数据显示出后脑勺 GLP-1信号对于减少相同食物的摄入量很重要。相比之下，GLP-1的作用 在相对增加的替代可用食物摄入量期间，信号是静音的。 然而，这些数据揭示了关于SSS的神经基础的其他问题。值得注意的是， 介导这一信号转导的神经元群(S)尚不清楚。外周信号的积分器，核团 尾侧脑干孤束(NTS)是参与SSS的GLP-1信号的宿主。 NTS不仅含有表达GLP-1R的细胞，而且还含有胰高血糖素原(PPG)神经元，这些神经元 合成GLP-1。因此，在目标I中，我们建议研究这两个不同的NTS神经的作用 种群在控制SSS中的作用。 此外，目前还不清楚GLP-1信号的影响是如何减弱的，以使增加的摄入量 一种替代食物。两种皮质下结构，终纹床核(BNST)和中央 杏仁核(CEA)在功能和解剖学上都适合调节GLP-1信号。这两个地区都进行了调解 进食行为和奖赏的各个方面，每个区域都直接投射到PPG NTS神经元。因此，在AIM中 我们将描述BNST/CEAPPG预测在替代食物摄入量增加过程中的作用。 考虑到美国不断增长的肥胖率，了解神经内分泌是如何 信号调节最近的食物体验对消费的影响是发展的重要一步 治疗适应不良进食行为疾病的方法。为此，我们的实验将 研究中枢GLP-1介导的SSS调节食物摄入的机制。

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.