Mechanisms of Fatty Acid Control of Feeding Behavior

脂肪酸控制摄食行为的机制

• 批准号: 8694028
• 负责人: W. Sue Ritter
• 金额: $ 32.84万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-05 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8694028
• 关键词: Acyl CoA Dehydrogenases; Address; Afferent Neurons; Agonist; Area; Attenuated; Beta Cell; Brain; Calcium; Capsaicin; Carnitine O-Palmitoyltransferase; Cell Line; Chemical Structure; Cholecystokinin; Data; Dependence; Desire for food; Diabetes Mellitus; Diet; Drug Formulations; Drug usage; Eating; Energy-Generating Resources; Fasting; Fatty Acids; Fatty acid glycerol esters; Feeding behaviors; Food Energy; G-Protein-Coupled Receptors; Galanin; Glucose; Goals; Hormones; Human; Hunger; Image; In Vitro; Insulin; Intake; Investigation; Knockout Mice; Leptin; Mammals; Measures; Mediating; Medium chain fatty acid; Membrane; Metabolic; Metabolic Control; Mitochondria; Monitor; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Pathway interactions; Peptides; Peripheral; Pharmaceutical Preparations; Rattus; Research; Role; Satiation; Serotonin; Signal Transduction; Site; Stimulus; System; Testing; Tissues; Triglycerides; Work; acyl-CoA dehydrogenase; base; cell type; drug development; energy balance; etomoxir; fatty acid metabolism; fatty acid oxidation; feeding; ghrelin; glucagon-like peptide 1; in vivo; insulin secretion; interest; long chain fatty acid; melanin-concentrating hormone; neglect; novel; oxidation; public health relevance; ratiometric; receptor; research study; response; therapeutic target

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.

描述（由申请人提供）：脂肪是一种主要的代谢燃料，是在禁食期和摄入高脂饮食期间大多数组织使用的主要燃料。在过去的二十年中，研究集中在源自储存脂肪的信号（尤其是激素瘦素）上，而循环脂肪可能会改变食物摄入的机制已被忽略。然而，循环脂肪酸具有影响食物摄入量和其他稳态功能的固有潜力，因此在控制日常餐食的发作和大小中可能具有特殊意义。脂肪酸对喂养的一种重要控制称为脂源对照，这是对阻断脂肪酸氧化的2-羟乙酸（MA）等药物进行实验诱发的喂养的刺激控制。尽管被广泛接受，但该控制的基本机制知之甚少。尽管众所周知，它取决于迷走性感觉神经元，但尚不清楚MA唤起食物摄入的作用部位，作用机理和中心途径。在此应用中，我们检查了脂源控制的基础机制。一直假定到现在，这种对喂养的控制完全是由于脂肪酸氧化减少而产生的。但是，我们最近发现，最常用用于研究脂肪对照的药物也可能在G蛋白偶联受体（GPR40和/或GPR120）上具有脂肪酸受体阻断作用，这些效应与脂肪氧化无关。具体目标1使用各种组织中的钙成像检查了这种MA的潜在机制，包括已知表达这些受体以及GPR40和GPR120敲除小鼠的培养细胞系。使用体内方法，特定目标2研究了MA通过改变影响饥饿和饱腹感的肠激素的分泌而刺激喂养的可能性，包括MA可能与GPR40和120的相互作用在这些效果中的相互作用。特定的目标3解决了较少了解的中心途径，用于控制MA的喂养，重点是甲状腺素肽，黑色素浓缩激素（MCH）和Galanin，这是迄今为止唯一被MA激活的肽。提出的实验的结果可能是我们对食物摄入的脂肪对照的理解以及游离脂肪酸受体参与该对照的广泛参与。我补充，某些结果可能对糖尿病具有翻译意义，其中Beta细胞GPR40已经成为药物开发的目标。