MECHANISMS OF PERIPHERAL FAT DETECTION

随着西方饮食的普及，全世界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有关的疾病也相应增加。在所有导致肥胖的原因中，最主要的原因似乎是选择--选择吃得更多，运动更少。与肥胖有关的选择之一是选择高脂肪、高热量的饮食。尽管对脂肪摄入和肥胖之间的联系进行了大量研究，但对脂肪味道背后的化学感受机制以及这些机制如何有助于膳食脂肪摄入的了解相对较少。我们之前的研究已经确定了肥胖倾向和抵抗啮齿动物的味觉系统如何对脂肪酸（膳食脂肪的提示）做出反应的差异，以及这与基因表达和受体功能差异的相关性。此外，我们已经证明，这些化学感受机制是由饮食和肥胖的发展。修订后的建议侧重于追求一个更集中的，单一的剩余具体目标，寻求探索如何味觉反应脂肪是由饮食经验调制。有新的和新兴的数据，认为可塑性的周边味觉系统，但我们的理解如何系统的变化与经验是穷人在最好的。具体而言，我们将使用包括多学科方法在内的方法来回答以下问题： 1.脂肪酸转导途径是否受饮食调节？我们通过行为分析基因的多学科方法将被用来测试这一假设，即在高脂肪喂养过程中，味觉细胞中脂肪受体的表达会发生改变，从而导致对脂肪酸的反应性增加。在高脂饮食方案后，将进行分子、细胞和行为测定，以测量脂肪酸信号传导途径中四种主要受体元件的变化，包括CD 36、GPR 120、GPR 84和脂肪酸敏感性DRK通道。我们在前一时期产生的大量初步数据表明，这些是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.