Amylin Modulates Food Reward

胰淀素调节食物奖励

基本信息

批准号：
9023149
负责人：
MATTHEW R HAYES
金额：
$ 40.84万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9023149
关键词：
Acute Adipose tissue Agonist Animal Model Animals Anti-Obesity Agents Appetite Depressants Basic Science Behavior Behavior Therapy Behavioral Behavioral Mechanisms Binge Eating Biological Assay Body Weight Brain Stem Brain region Cell Nucleus Clinical Combination Drug Therapy Consumption Cues Data Development Diabetes Mellitus Diet Dopamine Eating Electrophysiology (science)Epidemic Exposure to FDA approved Fatty acid glycerol esters Food Future Genetic Goals Hormones Human Hyperphagia Immunohistochemistry Incidence Insulin Intake Investigation Knowledge Lead Leptin Literature MAP Kinase Gene Mediating Metabolic Molecular Mono-S Neurobiology Neurons Neuropeptides Neurotransmitters Non-Insulin-Dependent Diabetes Mellitus Nucleus Accumbens Nutrient Obesity Pharmacologic Substance Pharmacotherapy Phenotype Physiological Population Process Rattus Receptor Activation Receptor Signaling Reporting Research Rewards Risk Role STAT3 gene Scanning Signal Transduction Site Stimulus Structure of area postrema Structure of beta Cell of islet Sucrose System Techniques Time Transgenic Organisms Tyrosine 3-Monooxygenase United States Ventral Tegmental Area Weight Gain amylin receptor analog bariatric surgery base blood glucose regulation cognitive process dopaminergic neuron effective therapy energy balance feeding gastrointestinal improved in vivo innovation islet amyloid polypeptide knock-down leptin receptor mesolimbic system neural circuit novel novel strategies obesity treatment preference public health relevance recombinase reduced food intake relating to nervous system research study response reward processing success

项目摘要

DESCRIPTION (provided by applicant): The proposed research focuses on the neuropeptide amylin and its role in controlling for palatable food intake and body weight through action in the ventral tegmental area (VTA) of the mesolimbic reward system. FDA-approved amylin analogs for the treatment of Type II Diabetes Mellitus produce improvements in blood glucose regulation and, in addition, produce meaningful reductions in food intake and body weight in both humans and animal models. While the literature has largely focused on the area postrema (AP) of the caudal brainstem as the primary site mediating the anorectic effects of amylin signaling, it is important to note that amylin receptors are also expressed in brain regions associated with reward and cognitive processes [e.g. VTA, nucleus accumbens (NAc)] and little-to-no investigation has been done to examine their contribution to energy balance control. Indeed, humans treated with an amylin analog report improved perceived control of eating and a 45% reduced risk of binge eating. Moreover, humans treated with amylin receptor agonists reduce their intake of highly palatable food more so than less-palatable food. Given that the excessive food intake contributing to obesity is driven, in part, by exposure to external stimuli associated with palatable food, it is of critical importance to investigate neurobiological systems that function to reduce excessive food seeking and consumption in response to food-related stimuli. It is also critical to evaluate the potential for amylin to interact with other physiological systes to produce an augmented reduction in food intake given that combination drug therapy holds greater promise than monotherapy for obesity treatment. Indeed, emerging basic science and clinical evidence shows that combined signaling by amylin and the adipose-tissue derived hormone leptin can lead to enhanced (potentially synergistic) suppression of food intake. Endogenous signaling by either leptin or amylin in the VTA is necessary for the normal control of food intake, thus highlighting the VTA as a potential neural locus mediating the amylin-leptin interaction. Experiments in this proposal will utilize novel approaches that combine behavioral, molecular, electrophysiological, electrochemical, neuropharmacological, genetic, and transgenic techniques to examine: [1] the neuronal and behavioral mechanisms mediating the role of endogenous VTA amylin receptor signaling in excessive feeding; [2] whether VTA amylin receptor signaling modulates NAc dopamine and NAc neural activity in response to food cues; [3] whether VTA processing mediates the food intake reducing interaction between amylin and leptin signaling. The research proposed will provide a novel framework for the development of more effective amylin-mediated treatment options for obesity.

描述（由适用提供）：拟议的研究重点介绍神经肽淀粉纤维及其在控制可口的食物摄入量和体重中的作用，该作用是通过在中龙奖励系统的腹侧细盖区域（VTA）中的作用。通过FDA批准的链氨酸酯类似物用于治疗II型糖尿病，可改善血糖调节，此外，在人类和动物模型中，食物摄入和体重的有意义减少。虽然文献主要集中在尾脑干的区域（AP）上，这是介导链淀粉蛋白信号传导的厌食作用的主要部位，但重要的是要注意，在与奖励和认知过程相关的大脑区域也表达了淀粉纤维接收器[e.g. VTA，伏隔核（NAC）]和几乎没有投资来研究它们对能量平衡控制的贡献。实际上，用淀粉蛋白模拟报告治疗的人类改善了人们对饮食的控制，45％降低了暴饮暴食的风险。此外，接受淀粉纤维受体激动剂治疗的人类比易于镇痛的食物更能减少对高度可口的食物的摄入量。鉴于多余的食物摄入导致肥胖是通过暴露于与可口食品相关的外部刺激的一部分驱动的，因此研究神经生物学系统至关重要，这些神经生物学系统起着作用，以减少与食物相关刺激的响应，以减少多余的食物寻求和消费。考虑到组合药物疗法比单一治疗疗法对肥胖症治疗的前景更大的前景，评估淀粉蛋白与其他物理系统相互作用的潜力也至关重要。实际上，新兴的基础科学和临床证据表明，淀粉蛋白和脂肪组织衍生的马酮瘦素的联合信号传导可导致对食物摄入的增强（可能协同）的抑制。 VTA中的瘦素或淀粉蛋白的内源性信号对于对食物摄入的正常控制是必需的，因此将VTA强调为介导淀粉蛋白链蛋白相互作用的潜在神经元基因座。该提案中的实验将利用新颖的方法结合了行为，分子，电生理学，电化学，神经药物，遗传和转基因技术来进行检查：[1]介导内源性VTA淀粉蛋白受体信号传导在多余进食中的作用的神经元和行为机制； [2] VTA Amylin受体信号传导是否会根据食物提示调节NAC多巴胺和NAC中性活性； [3] VTA加工是否介导了食物摄入量减少淀粉蛋白酶和瘦素信号传导之间的相互作用。拟议的研究将为对象性开发更有效的链淀粉介导的治疗选择提供新的框架。