MECHANISMS OF PERIPHERAL FAT DETECTION

随着西方饮食的普及，全球肥胖症的发病率继续上升，心血管疾病、糖尿病、终末期肾病和其他与肥胖相关的疾病也相应增加。在导致肥胖的所有原因中，最主要的似乎是选择--选择吃得更多，锻炼得更少。与肥胖有关的选择之一是选择高脂肪、高热量的饮食。尽管对脂肪摄入量和肥胖之间的联系进行了很多研究，但对脂肪味道背后的化学感觉机制以及这些机制如何有助于饮食脂肪摄入量的了解相对较少。我们之前的研究已经确定了肥胖倾向和抵抗力强的啮齿动物的味觉系统对脂肪酸的反应方式的差异，以及这与基因表达和受体功能的差异是如何关联的。脂肪酸是饮食中脂肪的线索。此外，我们已经证明，这些化学感觉机制受到饮食和肥胖发展的调节。修订后的提案侧重于追求一个更有针对性的、唯一的具体目标，即寻求探索饮食经验如何调节对脂肪的味觉反应。有新的和新兴的数据证明了外围味觉系统的可塑性，但我们对该系统如何变化与体验的理解充其量也是很差的。具体来说，我们将使用一种包括多学科方法的方法来回答以下问题： 1.脂肪酸转导途径受饮食调控吗？我们通过行为分析基因的多学科方法将被用来检验这一假设，即在高脂肪喂养期间，味觉细胞中的脂肪受体表达会发生变化，从而导致对脂肪酸的反应增强。在高脂饮食方案之后，将进行分子、细胞和行为分析，以测量脂肪酸信号通路中四个主要感受元件的变化，包括CD36、GPR 120、GPR 84和脂肪酸敏感的DRK通道。我们在前一个时期产生的广泛的初步数据将争辩说，这些是奠定味觉系统识别和响应游离脂肪酸能力的途径的主要组成部分。

The incidence of obesity worldwide continues to escalate with the spread of the Western diet and with it there has been a corresponding increase in cardiovascular disease, diabetes, end-stage renal disease and other obesity-related disorders. Of all the causes for obesity, the predominant one seems to be choice - the choice to eat more and exercise less. One of the choices that has been linked with obesity has been the selection of a high fat, calorically dense diet. Despite much research on the link between fat intake and obesity, relatively little is known about the chemosensory mechanisms that underlie the taste of fat and how these mechanisms might contribute to dietary fat intake. Our previous research has identified differences in how the taste systems in obesity-prone and –resistant rodents respond to fatty acids, a cue for dietary fat, and how this was correlated to differences in gene expression and receptor function. Moreover, we have demonstrated that these chemosensory mechanisms are modulated by diet and the development of obesity. The revised proposal focuses on pursuing a more focused, single remaining specific aim that seek to explore how the gustatory response to fat is modulated by dietary experience. There is new and emerging data that argues to the plasticity of the peripheral taste system, yet our understanding of how the system changes in relation to experience is poor at best. Specifically, we will use an approach including a multidisciplinary approach to answer the following question: 1. Is the fatty acid transduction pathway modulated by diet? Our multidisciplinary approach analyzing genes through behavior will be used to test the hypothesis that fat receptor expression in taste cells is altered during high fat feeding in a manner that results in an increased responsiveness to fatty acids. Following high fat dietary regimens, molecular, cell-based and behavioral assays will be performed to measure changes in four primary receptive elements in the fatty acid signaling pathway, including CD36, GPR 120, GPR 84 and fatty acid-sensitive DRK channels. Our extensive preliminary data generated in the previous period would argue that these are the primary components of the pathway that underlies the ability of the gustatory system to recognize and respond to free fatty acids.