Role of DMH LepR-b neurons in leptin action

描述（由申请人提供）：随着肥胖率的持续上升，了解其发病机制的需求变得更加迫切。激素瘦素通过其受体的长亚型（LepR-b）在中枢神经系统中发出信号，以调节能量平衡的各种决定因素，包括食物摄入，能量消耗和神经内分泌输出。然而，瘦素调节这些功能的具体神经元群体在很大程度上仍不确定。确定介导瘦素调节能量平衡的关键神经元群体对于开发适当靶向的抗肥胖疗法至关重要。LepR-b在脑中的表达分布在多个区域中，主要在下丘脑和脑干内。虽然下丘脑弓状核（ARC）对于能量平衡是重要的，并且在瘦素作用中起作用，但是瘦素作用于能量平衡的关键位点尚未被确定，并且许多组的研究表明， LepR-b神经元仍然知之甚少-包括背内侧下丘脑（DMH）中的神经元。DMH包含大量LepR-b神经元，该核与ARC和室旁核（PVH）紧密连接，这对于控制进食和整体能量平衡至关重要。这项研究的目的是了解DMH LepR-b神经元的神经生物学，以及它们在控制能量平衡和代谢参数中的作用。我们将使用分子遗传技术结合立体定位注射细胞特异性病毒系统来定义神经元传入和传出DMH LepR-b神经元，从而了解这些神经元的功能回路。我们还将使用分子技术结合立体定位注射来操纵DMH LepR-b神经元的生理学，以研究它们的功能。总之，这些研究将阐明瘦素调节能量平衡的神经机制，并将加强我们对瘦素在DMH中作用的理解。在这些研究完成后，我们希望获得关键的深入了解瘦素的作用机制，在中枢神经系统。

DESCRIPTION (provided by applicant): As the rates of obesity continue to rise, the need to understand its pathogenesis grows ever more pressing. The hormone, leptin, signals via the long isoform of its receptor(LepR-b) in the central nervous system to regulate diverse determinants of energy balance, including food intake, energy expenditure, and neuroendocrine output. The specific neuronal populations by which leptin modulates each of these functions remain largely undetermined, however. Identifying the crucial neuronal population(s) that mediate the regulation of energy balance by leptin is essential for the development of appropriately targeted anti-obesity therapies. LepR-b expression in the brain is distributed among a number of areas, primarily within the hypothalamus and brainstem. Although the hypothalamic arcuate nucleus (ARC) is important for energy balance and plays a role in leptin action, the key site for leptin action on energy balance has yet to be identified, and many sets of LepR-b neurons remain poorly understood - including those in the dorsomedial hypothalamus (DMH). The DMH contains a large population of LepR-b neurons and this nucleus is densely connected to the ARC and paraventricular nucleus (PVH), which are crucial for the control of feeding and overall energy balance. The goal of this research proposal is to understand the neurobiology of DMH LepR-b neurons, as well as their role in controlling parameters of energy balance and metabolism. We will use a molecular genetic techniques combined with stereotaxic injection of cell-specific viral systems to define neurons afferent and efferent to DMH LepR-b neurons and thus to understand the circuits in which these neurons function. We will also use molecular techniques in combination with stereotaxic injection to manipulate the physiology of DMH LepR-b neurons, in order to study their function. Altogether these studies will elucidate neuronal mechanisms through which leptin regulates energy balance, and will bolster our understanding of leptin action in the DMH. At the completion of these studies we hope to gain critical insight into the mechanisms of leptin action in the central nervous system.