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血清素能调节的影响，美国肥胖率的迅速上升，加上这种情况对当前治疗方法的抵抗，突出了对调节能量平衡的神经行为机制的新见解的需要。尽管利用脑5 -羟色胺系统药理操作的治疗已证明有效，但5 -羟色胺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5-羟色胺受体亚型中，5- ht1b和5- HT2C受体与食物摄入的5-羟色胺能抑制关系最为密切。我们发现编码这些5-羟色胺受体亚型（htr1b-和htr2c-）的基因的零突变对自由喂养动物和禁食动物的摄食影响不同。这些和额外的初步数据表明，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药物治疗方法。在本研究中，我们验证了一种假设，即能量状态依赖的血清素能调节能量平衡是通过表达5-HT1B和5-HT2C受体的下丘脑弓状核神经元介导的。在Aim 1中，我们将检验htr1b-和htr2c-突变对食物摄入的能量状态依赖效应与能量状态依赖对能量平衡的生理和行为决定因素的影响相关的假设。这些受体基因的整体和细胞类型特异性突变将被执行，特别关注在下丘脑表达的受体亚群。在Aim 2中，我们将验证htr1b-和htr2c-突变对能量平衡生理和行为决定因素的能量状态依赖效应是通过涉及下丘脑弓状核神经元的途径介导的。为此，我们将研究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。在Aim 3中，将生成并验证条件突变小鼠在分别表达神经肽NPY/AGRP和POMC/CART的神经元中选择性地消除5-HT1B和5-HT2C受体的表达。

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.