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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.