Mechanisms of Fatty Acid Control of Feeding Behavior

描述（由申请人提供）：脂肪是一种主要的代谢燃料，是禁食期间和摄入高脂肪饮食期间大多数组织利用的主要燃料。过去二十年的研究集中在来自储存脂肪的信号（特别是瘦素），而循环脂肪可能改变食物摄入的机制却被忽视了。然而，循环脂肪酸有内在的潜力，影响食物摄入和其他稳态功能急性，因此可能是特别重要的控制开始和大小的日常膳食。一种重要的脂肪酸摄食控制被称为减脂控制，这是一种通过阻断脂肪酸氧化的药物（如2-巯基乙酸酯（MA））实验诱发的摄食刺激控制。尽管被广泛接受，这种控制的基本机制知之甚少。虽然已知其依赖于迷走神经感觉神经元，但MA引起食物摄入的作用部位、作用机制和中枢通路尚不清楚。在这个应用程序中，我们研究的机制，潜在的lipoprovic控制喂养。到目前为止，人们一直认为这种摄食控制完全是由减少脂肪酸氧化引起的。然而，我们最近发现，MA，最常用于研究lipoprovic控制的药物，也可能对G蛋白偶联受体（GPR 40和/或GPR 120）具有脂肪酸受体阻断作用，这些受体不依赖于脂肪氧化。具体目标1使用各种组织中的钙成像检查MA的这种潜在机制，包括已知表达这些受体的培养细胞系和GPR 40和GPR 120敲除小鼠。使用体内方法，Specific Aim 2研究了MA通过改变影响饥饿和饱腹感的肠道激素分泌部分刺激进食的可能性，包括MA与GPR 40和GPR 120在这些作用中的可能相互作用。具体目标3解决了MA控制摄食的知之甚少的中枢途径，重点是食欲肽、黑色素浓缩激素（MCH）和甘丙肽，这是迄今为止已知的唯一被MA激活的肽。拟议的实验结果可能是范式转变，就我们的理解lipoprovic控制的食物摄入量和广泛的自由脂肪酸受体参与这种控制。此外，一些结果可能对糖尿病具有转化意义，其中β细胞GPR 40已经是药物开发的靶点。

DESCRIPTION (provided by applicant): Fat is a major metabolic fuel and is the predominant fuel utilized by most tissues during periods of fasting and during intake of high fat diets. Research in the last two decades has focused on signals (notably, the hormone leptin) derived from stored fat, while the mechanisms through which circulating fats may alter food intake have been neglected. Yet circulating fatty acids have the inherent potential to influence food intake and other homeostatic functions acutely and therefore may be of special significance in controlling onset and size of daily meals. One important control of feeding by fatty acids is known as the lipoprivic control, a stimulatory control of feeding evoked experimentally by drugs such as 2-mercaptoacetate (MA) that block fatty acid oxidation. Despite being well accepted, the underlying mechanisms of this control are poorly understood. Although it is known to be dependent on vagal sensory neurons, the sites of action, mechanisms of action and central pathways through which MA evokes food intake are not known. In this application, we examine mechanisms underlying lipoprivic control of feeding. It has been assumed until now that this control of feeding arises entirely from reduced fatty acid oxidation. However, we found recently that MA, the drug most commonly used to study lipoprivic control, may also have fatty acid receptor blocking effects at G-protein coupled receptors (GPR40 and/or GPR120) that are independent of fat oxidation. Specific Aim 1 examines this potential mechanism of MA using calcium imaging in various tissues, including cultured cell lines known to express these receptors and GPR40 and GPR120 knockout mice. Using in vivo approaches, Specific Aim 2 examines the possibility that MA stimulates feeding in part by altering secretion of gut hormones that influence hunger and satiety, including MA's possible interaction with GPR40 and 120 in these effects. Specific Aim 3 addresses the poorly understood central pathways for control of feeding by MA, focusing on the orexigenic peptides, melanin concentrating hormone (MCH) and galanin, the only peptides so far known to be activated by MA. Results of the proposed experiments may be paradigm shifting with respect to our understanding of lipoprivic control of food intake and the broad spectrum of participation of free fatty acid receptors in this control. I addition, some results may have translational significance for diabetes, where beta cell GPR40 is already a target for drug development.