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β-肾上腺素能调节的影响，美国人肥胖率的快速上升，以及这种疾病对当前治疗方法的抵抗力，突出了对调节能量平衡的神经行为机制的新见解的需要。虽然采用药物操纵大脑5-羟色胺系统的治疗已被证明是有效的，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-HT 1B和5-HT 2C受体与食物摄取的多巴胺能抑制最密切相关。我们发现，编码这些5-HT受体亚型（htr 1b-和htr 2c-）的基因的无效突变对自由采食动物与禁食动物的摄食影响不同。这些和额外的初步数据表明，动物的能量状态显着影响的方式，其中5-羟色胺系统调节能量平衡。阐明能量状态依赖性多巴胺能调节能量平衡的神经机制有助于开发治疗肥胖的新药物。在这个建议中，我们测试的假设，即能量状态依赖性多巴胺能调节能量平衡介导的途径，涉及下丘脑弓状核神经元，表达5-HT 1B和5-HT 2C受体。在目标1中，我们将检验以下假设：htr 1b和htr 2c突变对食物摄入的能量状态依赖性影响与能量状态依赖性对能量平衡的生理和行为决定因素的影响相关。这些受体基因的全局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。在目的2中，我们将测试的假设，即能量状态依赖的影响的htr 1b和htr 2c突变的生理和行为的能量平衡的决定因素介导的通路，涉及下丘脑弓状核神经元。为此，我们将研究模式下丘脑神经肽基因的表达和模式的神经元激活诱导禁食。目标3将产生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5-HT 1B和5-HT 2C受体的表达。 公共卫生相关性：在美国，肥胖症的发病率不断上升，沿着的是肥胖症易患的疾病，这构成了一个重大的公共卫生挑战。这突出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。大脑血清素系统是开发抗肥胖药物的重要目标。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作用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考虑患者能量状态的新型治疗策略的开发提供线索。

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.