MECHANISMS OF PERIPHERAL FAT DETECTION

随着西方饮食的传播，世界范围内肥胖的发病率不断上升，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，最主要的似乎是选择——选择多吃少运动。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觉机制以及这些机制如何影响饮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抗性啮齿类动物的味觉系统对脂肪酸（饮食脂肪的线索）的反应差异，以及这与基因表达和受体功能的差异之间的关系。此外，我们已经证明，这些化学感觉机制是由饮食和肥胖的发展调节的。修订后的提案侧重于追求一个更有针对性的、单一的、剩余的具体目标，即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表明，外围味觉系统的可塑性，但我们的理解是如何改变系统的经验，充其量是贫乏的。具体来说，我们将使用包括多学科方法在内的方法来回答以下问题：

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.