Modulation of Taste-Related Behavior by Molecular Mediators of Appetite & Satiety

描述（由申请人提供）：近年来味觉研究中的两个范式转变发现重新调整了我们对味觉感知如何与食欲和饱腹感机制相关的思考。首先，肠道中的许多细胞表达与味觉细胞相同的营养检测所需的分子机制。我们现在知道，肠道中的这些受体检测摄入的营养物质，并介导胃激素的分泌。最近，人们了解到这些“胃”激素及其同源受体也表达在外周味觉系统的味觉细胞中。这一最新发现对该领域提出了根本性的挑战，以了解这些外周“胃”激素如何影响味觉功能和摄食行为。鉴于全球糖尿病、肥胖症和相关代谢紊乱的发病率不断上升，我们正在提出研究，以解决我们缺乏关于化学感觉感知的激素调节以及味觉系统中激素信号传导的中断如何影响食物摄入和能量稳态的知识。 我们最近报道，肠道激素，胰高血糖素样肽1（GLP-1），可以调节甜味敏感性。我们还报道了另一种GI肽胰高血糖素，它在葡萄糖稳态调节中起主要作用，也可以调节对甜味剂的味觉敏感性。这些结果，当放置在我们对激素肽YY（PYY）的初步研究结果的背景下，表明味觉系统确实是通过激素作用动态调制。 神经肽Y（NPY）家族肽NPY和PYY在由肠细胞和/或CNS组织表达时在饱腹感的调节中起主要作用。目前，PYY被视为肥胖症的候选治疗方法，并已通过临床试验，因为它能够减少食物摄入量。然而，在这方面， 不幸的是，全身给予高剂量的PYY也引起条件性味觉厌恶（CTA）。我们的数据表明，将PYY引入口腔，虽然在动物模型中导致显著的体重减轻，但不会诱导CTA，重新引入PYY作为肥胖的假定治疗。这些NPY家族肽在口腔中的存在，沿着它们的同源受体在味觉组织中的表达，表明它们可能通过影响外周味觉系统的功能来影响摄食行为。使用遗传和药理学模型的组合，拟议的研究集中在调查的一般假设，味觉相关的行为可以通过代谢激素，如PYY和/或NPY调制。

DESCRIPTION (provided by applicant): Two paradigm-shifting discoveries in taste research in recent years have realigned our thinking as to how taste perception is linked to mechanisms of appetite and satiety. The first was that many cells in the gut express the same molecular machinery required for nutrient detection as that found in taste cells. We now know these receptors in the gut detect ingested nutrients and mediate the secretion of gastric hormones. More recently, it was learned that these 'gastric' hormones together with their cognate receptors are also expressed in taste cells in the peripheral gustatory system. This latest discovery has raised a fundamental challenge to the field to understand how these peripheral 'gastric' hormones affect taste function and ingestive behavior. Given the worldwide rising incidence of diabetes, obesity and related metabolic disorders, we are proposing research that addresses our dearth of knowledge regarding the hormonal modulation of chemosensory perception and how disruption of hormonal signaling in the taste system can impact upon food intake and energy homeostasis. We have recently reported that the gut hormone, glucagon-like peptide 1 (GLP-1), can modulate sweet taste sensitivity. We have also reported that another GI peptide, glucagon, which plays a major role in the regulation of glucose homeostasis, can also act to modulate taste sensitivity to sweeteners. These results, when placed in the context of our preliminary findings on the hormone peptide YY (PYY) suggest that the gustatory system is indeed being dynamically modulated through hormonal action. The neuropeptide Y (NPY) family peptides, NPY and PYY, play a major role in the regulation of satiety when expressed by gut cells and/or in CNS tissues. Currently, PYY is being viewed as a candidate treatment for obesity and has been through clinical trials because of its ability to reduce food intake. However, unfortunately, high doses of PYY given systemically also cause conditioned taste aversion (CTA). Our data suggesting that PYY introduced into the oral cavity, while leading to significant weight loss in animal models, does not induce CTA, reintroduces PYY as a putative treatment for obesity. The presence of these NPY family peptides in the oral cavity, along with the expression of their cognate receptor(s) in gustatory tissues suggests that they may be influencing ingestive behavior by affecting the functioning of the peripheral gustatory system. Using a combination of genetic and pharmacological models, the proposed studies focus on investigating the general hypothesis that taste-related behavior can be modulated by metabolic hormones such as PYY and/or NPY.