Mechanisms of Fatty Acid Control of Feeding Behavior

描述(申请人提供)：脂肪是一种主要的代谢燃料，也是大多数组织在禁食和高脂肪饮食期间使用的主要燃料。在过去的二十年里，研究的重点是储存脂肪产生的信号(特别是激素瘦素)，而循环脂肪可能改变食物摄入量的机制被忽视了。然而，循环脂肪酸具有强烈影响食物摄入量和其他体内平衡功能的固有潜力，因此在控制每日一餐的开始和数量方面可能具有特殊的意义。通过脂肪酸控制摄食的一种重要控制被称为脂溢性控制，这是一种由2-巯基乙酸酯(MA)等阻止脂肪酸氧化的药物在实验中引起的对摄食的刺激性控制。尽管人们很好地接受了这一点，但人们对这种控制的潜在机制知之甚少。虽然已知MA依赖于迷走感觉神经元，但MA引起食物摄取的作用部位、作用机制和中枢通路尚不清楚。在这项应用中，我们研究了脂溢性控制喂食的机制。到目前为止，人们一直认为这种摄食控制完全是由于减少了脂肪酸的氧化。然而，我们最近发现，最常用于研究脂控的药物MA也可能在G蛋白偶联受体(GPR40和/或GPR120)上具有脂肪酸受体阻断作用，这种受体不依赖于脂肪氧化。具体目的1利用钙成像在不同组织中检测MA的这一潜在机制，包括已知表达这些受体的培养细胞系以及GPR40和GPR120基因敲除小鼠。使用体内方法，特殊目的2研究了MA部分通过改变影响饥饿和饱腹感的肠道激素的分泌来刺激摄食的可能性，包括MA与GPR40和120在这些影响中可能的相互作用。具体目标3涉及MA控制摄食的中枢途径，了解甚少，重点是促食欲素、黑色素浓缩激素(MCH)和甘丙素，这是迄今已知的唯一被MA激活的多肽。拟议的实验结果可能会改变我们对脂溢性控制食物摄入量的理解，以及自由脂肪酸受体参与这一控制的广泛范围。此外，一些结果可能对糖尿病具有翻译意义，因为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.