Impact of energy status on the serotonergic regulation of energy balance

描述(由申请人提供)：能量状态对能量平衡的5-羟色胺能调节的影响，美国肥胖率的迅速上升，以及这种疾病对当前治疗方法的抵抗，突显了对调节能量平衡的神经行为机制的新见解的必要性。尽管对大脑5-羟色胺系统进行药物操作的治疗方法已经显示出疗效，但5-羟色胺调节食物摄取和能量消耗的神经行为机制仍不清楚。在许多已知的5-羟色胺受体亚型中，5-HT1B和5-HT2C受体与5-羟色胺能抑制食物摄入的作用最为密切。我们发现，编码这些5-羟色胺受体亚型(htr1b-和htr2c-)的基因零突变对随意喂养的动物和禁食的动物的摄食有不同的影响。这些和更多的初步数据表明，动物的能量状态显著影响血清素系统调节能量平衡的方式。阐明能量状态依赖的5-羟色胺能调节能量平衡的神经机制有助于开发新的肥胖症药物治疗方法。在这个方案中，我们测试了能量状态依赖的5-羟色胺能调节能量平衡的假设，这是通过涉及表达5-HT1B和5-HT2C受体的下丘脑弓状核神经元的通路来介导的。在目标1中，我们将检验这一假设，即htr1b和htr2c突变对食物摄入量的能量状态依赖效应与能量状态对能量平衡的生理和行为决定因素的影响有关。这些受体基因的全局和特定细胞类型的突变都将特别关注在下丘脑中表达的受体亚群。在目标2中，我们将检验这一假设，即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的影响是通过涉及下丘脑弓状核神经元的通路来介导的。为此，我们将研究下丘脑神经肽基因的表达模式和禁食诱导的神经元激活模式。在Aim 3中，将产生并验证条件突变小鼠，以选择性地消除分别表达神经肽NPY/AGRP和POMC/CART的神经元中5-HT1B和5-HT2C受体的表达。 与公共卫生相关：美国肥胖症的发病率不断上升，以及肥胖症引发的疾病对公共卫生构成了重大挑战。这突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5-羟色胺系统是减肥药物开发的重要靶点。这里提出的工作将揭示两种主要的5-羟色胺受体亚型的能量调节效应是如何对动物的能量状态敏感的。这项工作提供的见解可以为开发考虑患者能量状况的新治疗策略提供指导。

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.