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，是大多数组织在禁食和摄入高脂肪饮食期间使用的主要燃料。过去二十年的研究主要集中在储存脂肪产生的信号（尤其是瘦素激素）上，而循环脂肪可能改变食物摄入的机制却被忽视了。然而，循环脂肪酸具有影响食物摄入和其他体内平衡功能的内在潜力，因此在控制每日膳食的开始和大小方面可能具有特殊意义。脂肪酸对摄食的一个重要控制被称为脂促性控制，这是一种实验性的刺激摄食控制，如2-巯基乙酸酯（MA），可阻断脂肪酸氧化。尽管被广泛接受，但这种控制的潜在机制却知之甚少。虽然已知它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。在这个应用中，我们研究了进食中脂质控制的机制。到目前为止，人们一直认为这种进食控制完全是由脂肪酸氧化减少引起的。然而，我们最近发现，最常用于研究脂溶性控制的药物MA也可能对独立于脂肪氧化的g蛋白偶联受体（GPR40和/或GPR120）具有脂肪酸受体阻断作用。Specific Aim 1利用钙显像技术在多种组织中研究了这种MA的潜在机制，包括已知表达这些受体的培养细胞系和GPR40和GPR120敲除小鼠。利用体内方法，Specific Aim 2研究了MA刺激摄食的部分可能性，通过改变影响饥饿和饱腹感的肠道激素的分泌，包括MA在这些作用中可能与GPR40和120的相互作用。特异性目标3解决了鲜为人知的MA控制摄食的中心途径，重点关注摄氧肽、黑色素浓缩激素（MCH）和丙氨酸，这是迄今为止已知的唯一可被MA激活的肽。所提出的实验结果可能会改变我们对食物摄入的脂质控制和游离脂肪酸受体在这种控制中的广泛参与的理解。此外，一些结果可能对糖尿病具有翻译意义，其中β细胞GPR40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.