Impact of energy status on the serotonergic regulation of energy balance

能量状态对能量平衡的血清素调节的影响

基本信息

批准号：
8129661
负责人：
Laurence H. Tecott
金额：
$ 48.21万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-15 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8129661
关键词：
Accounting American Animal Feed Animals Appetite Depressants Attention Behavioral Brain Cardiac Data Desire for food Development Disease Drug Delivery Systems Eating Effectiveness Energy Intake Energy Metabolism Epidemic Exhibits Fasting Feeding behaviors Fenfluramine Food Food Energy Gene Expression Generations Genes Hypothalamic structure Incidence Laboratories Mediating Metabolic Metabolism Mus Mutant Strains Mice Mutation Neuraxis Neurons Neuropeptide Gene Neuropeptides Obesity Pathway interactions Patients Pattern Pharmaceutical Preparations Phenotype Physical activity Physiological Property Public Health Receptor Activation Receptor Gene Regulation Relative (related person)Resistance Serotonin Serotonin Agonists Serotonin Receptor 5-HT1B Serotonin Receptor 5-HT2C Structure of nucleus infundibularis hypothalami System Testing Tissues United States Work cell type effective therapy energy balance feeding insight nerve supply neurobehavioral neuromechanism neuronal patterning neuroregulation novel null mutation obesity treatment public health relevance receptor receptor expression response serotonergic regulation serotonin receptor treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Impact of energy status on the serotonergic regulation of energy balance, the rapid escalation of obesity rates in Americans, combined with the resistance of this condition to current treatment approaches, highlights the need for new insights into neurobehavioral mechanisms regulating energy balance. Although treatments employing pharmacological manipulation of the brain serotonin system have demonstrated efficacy, the neurobehavioral mechanisms through which serotonin modulates food intake and energy expenditure remain unclear. Of the many known serotonin receptor subtypes, 5-HT1B and 5- HT2C receptors have been most strongly implicated in the serotonergic suppression of food intake. We have found that null mutations of genes encoding these 5-HT receptor subtypes (htr1b- and htr2c-) influence feeding differently in ad libitum fed animals vs. animals that had been fasted. These and additional preliminary data reveal that the energy status of an animal markedly influences the manner in which the serotonin system regulates energy balance. The elucidation of neural mechanisms underlying energy status-dependent serotonergic regulation of energy balance could facilitate the development of novel pharmacotherapeutic approaches to obesity. In this proposal we test the hypothesis that energy status-dependent serotonergic regulation of energy balance is mediated through pathways involving hypothalamic arcuate nucleus neurons that express 5-HT1B and 5-HT2C receptors. In Aim 1 we will test the hypothesis that energy status-dependent effects of the htr1b- and htr2c- mutations on food intake are associated with energy status-dependent influences on the physiological and behavioral determinants of energy balance. Both global and cell type-specific mutations of these receptor genes will be performed with a particular focus on receptor subpopulations expressed in the hypothalamus. In Aim 2 we will test the hypothesis that energy status-dependent effects of htr1b- and htr2c- mutations on the physiological and behavioral determinants of energy balance are mediated by pathways involving hypothalamic arcuate nucleus neurons. Toward this end, we will examine patterns of hypothalamic neuropeptide gene expression and patterns of neuronal activation induced by fasting. In Aim 3 will generate and validate conditional mutant mice to selectively eliminate 5-HT1B and 5-HT2C receptor expression in neurons expressing the neuropeptides NPY/AGRP and POMC/CART, respectively. PUBLIC HEALTH RELEVANCE: The escalating incidence of obesity in the United States, along with the diseases to which it predisposes poses a major public health challenge. This highlights the need for novel insights into the neural regulation of the behavioral and metabolic determinants of energy balance. The brain serotonin system is a significant target for the development of anti-obesity medications. The work proposed here will reveal how the energy regulatory effects of two major serotonin receptor subtypes are sensitive to the energy status of the animal. Insights provided by this work can provide leads for the development of novel treatment strategies that take into account patients' energy status.

描述（由申请人提供）：能量状态对能量平衡的血清素调节的影响，美国人肥胖率的迅速上升，加上这种情况对当前治疗方法的抵抗，强调需要对神经行为调节机制有新的见解能量平衡。尽管采用药物操纵大脑血清素系统的治疗方法已被证明有效，但血清素调节食物摄入和能量消耗的神经行为机制仍不清楚。在许多已知的血清素受体亚型中，5-HT1B 和 5-HT2C 受体与食物摄入的血清素抑制作用最为密切。我们发现，编码这些 5-HT 受体亚型（htr1b- 和 htr2c-）的基因的无效突变对随意喂养的动物和禁食的动物的喂养产生不同的影响。这些和其他初步数据表明，动物的能量状态显着影响血清素系统调节能量平衡的方式。阐明能量平衡的能量状态依赖性血清素能调节的神经机制可能有助于开发新的肥胖药物治疗方法。在本提案中，我们测试了以下假设：能量平衡的能量状态依赖性血清素调节是通过涉及表达 5-HT1B 和 5-HT2C 受体的下丘脑弓状核神经元的途径介导的。在目标 1 中，我们将检验以下假设：htr1b 和 htr2c 突变对食物摄入的能量状态依赖性影响与能量状态对能量平衡的生理和行为决定因素的影响相关。这些受体基因的整体突变和细胞类型特异性突变将特别关注下丘脑中表达的受体亚群。在目标 2 中，我们将检验以下假设：htr1b 和 htr2c 突变对能量平衡的生理和行为决定因素的能量状态依赖性影响是由涉及下丘脑弓状核神经元的通路介导的。为此，我们将检查下丘脑神经肽基因表达模式和禁食诱导的神经元激活模式。目标 3 将生成并验证条件突变小鼠，以选择性消除分别表达神经肽 NPY/AGRP 和 POMC/CART 的神经元中的 5-HT1B 和 5-HT2C 受体表达。公共卫生相关性：美国肥胖发病率不断上升，及其易患的疾病构成了重大的公共卫生挑战。这凸显了对能量平衡的行为和代谢决定因素的神经调节的新见解的需要。大脑血清素系统是抗肥胖药物开发的重要目标。这里提出的工作将揭示两种主要血清素受体亚型的能量调节作用如何对动物的能量状态敏感。这项工作提供的见解可以为开发考虑患者能量状态的新型治疗策略提供线索。