MECHANISMS OF PERIPHERAL FAT DETECTION

在美国和世界范围内，肥胖的发病率持续上升，与此同时，心血管疾病、糖尿病和其他相关疾病的相关问题也相应增加。大部分肥胖是由饮食引起的，与西方平均饮食中的高脂肪含量有关。虽然脂肪摄入和肥胖之间的联系已被广泛研究，但相对而言，人们对身体识别膳食脂肪的机制知之甚少，更不知道这些机制如何相互关联并促进膳食脂肪摄入的调节。我们最近证明，必需脂肪酸为味觉系统提供了显著的线索，这与第一次详细描述它们是“脂肪的味道”是一致的。此外，我们已经在初步实验中表明，这种脂肪酸介导的延迟纠正K+通道的抑制可能是人体识别膳食脂肪的普遍系统。本项目结合电生理学、分子生物学和行为分析的总体目标是识别和表征味觉系统的反应性及其在帮助塑造偏好脂肪和避免脂肪的大鼠的饮食偏好中的作用。为了实现这些目标，我们将在这两种大鼠品系中解决以下3个具体目标：目的1：确定味觉受体细胞对脂肪偏好和避免率的反应性，它们的作用机制以及这种反应性如何与饮食脂肪偏好相关。这将验证这两种菌株的脂肪响应性差异是由于K+通道表达的差异造成的一般假设，并确定脂肪响应元件。目的2：确定脂肪酸作为味觉刺激的有效性。我们将使用一系列的行为分析来验证必需脂肪酸被味觉系统识别的假设，并且它们可能会增强对其他味觉物质的反应。我们还将确定不同饮食脂肪偏好的大鼠在味觉细胞水平上的差异是如何与行为相关的。目的3：确定味觉系统在帮助形成营养（脂肪）摄入方面可能发挥的作用。我们将分析不同饮食下的饮食行为，以验证脂肪酸介导的味觉细胞激活有助于控制脂肪摄入的假设。这些研究将促进我们对脂肪信号传导机制及其与饮食偏好之间关系的理解。此外，它可能提供新的治疗靶点，可用于调节脂肪摄入，并最终控制饮食引起的肥胖及其相关疾病。

The incidence of obesity in the United States and worldwide continues to escalate and with it there is a corresponding increase in the associated problems of cardiovascular disease, diabetes, and other related disorders. Much of the obesity is dietary induced and is correlated with high-fat content in the average Western diet. Though the link between fat intake and obesity has been extensively studied, there is comparatively little known about the mechanisms by which the body recognizes dietary fat and even less known about how these mechanisms correlate and contribute to the regulation of dietary fat intake. We have recently demonstrated that the essential fatty acids provide salient cues to the gustatory system, consistent with this representing the first detailed description of their being a "taste of fat". Moreover, we have shown in preliminary experiments that this fatty acid-mediated inhibition of delayed rectifying K+channels may be a universal system by which the body recognizes dietary fat. The overall aim of this project combining electrophysiology, molecular biology and behavioral assays is to identify and characterize the responsiveness of taste system and its role in helping to shape the dietary preferences of strains of fat-preferring and fat-avoiding rats. To accomplish these goals we will address the following 3 specific aims in these two rat strains: AIM 1: To determine the responsiveness of taste receptor cells from fat-preferring and avoiding rate to fatty acids, their mechanism of action and how this responsiveness correlates with dietary fat preference. This will test the general hypothesis that the differential fat responsiveness in these two strains is due to difference in K+ channel expression and identify the fat responsive elements. AIM 2: To determine the effectiveness of fatty acids as gustatory stimuli. We will use a series of behavioral assays to test the hypotheses that essential fatty acids are recognized by the taste system and that they may enhance the response to other tastants. We will also determine how the differences seen at the taste cell level between rats with different dietary fat preferences is correlated with behavior. AIM 3: To determine the role the taste system may play in helping to shape nutrient (fat) intake. We will analyze eating behavior in the presence of various diets to test the hypothesis that the fatty acid mediated taste cell activation contributes to the control of fat intake. These studies will advance our understanding the mechanisms of fat signaling and their relationship to dietary preferences. Moreover, it may provide insights into a novel therapeutic targets that can be used in the regulation of fat intake and, ultimately, in the control of dietary-induced obesity and its related disorders.