Defining the role of Leptin receptors on glutamatergic DMH neurons

定义瘦素受体对谷氨酸能 DMH 神经元的作用

• 批准号: RGPIN-2022-03390
• 负责人: Sabatini, Paul
• 金额: $ 2.7万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=760833
• 关键词: Defining; role; Leptin; receptors; glutamatergic

The brain is critically important for regulating how much food we eat and how much energy we burn through a process termed "energy balance". The long-term goal of my research program is to identify and study cell types within the brain that regulate energy balance. One of the most important proteins that regulate feeding behaviour and energy use is a hormone called leptin. Humans and mice that lack leptin develop profound obesity, associated with increased food consumption and decreased energy expenditure.  While leptin is produced in fat cells, it travels to the brain where it acts through the leptin receptor (Lepr) expressed on a multitude of cell types across the brain to decrease feeding and increase energy expenditure. One region of the brain termed the dorsomedial hypothalamus (DMH) contains a high density of Lepr-expressing neurons and disrupting leptin action across the entire DMH increases body weight. However the DMH is a large and complex hypothalamic compartment and we do not understand which  cell types within the DMH that leptin acts through. Therefore, to better understand how leptin acts through the DMH to control energy balance, we require a more thorough study of the DMH subtypes that express Lepr. Using cutting-edge technology, we generated preliminary data which demonstrate that Lepr is expressed on two distinct populations of DMH neurons. These two Lepr DMH populations are distinguished by their expression of proteins called Vglut2 or Vgat (We are terming these two cell types Vglut2-Lepr DMH and Vgat-Lepr DMH cells). Importantly, these two populations of cells produce unique neurotransmitters and we therefore expect Vglut2-Lepr DMH and Vgat-Lepr DMH cells to have unique functions. We have also performed key pilot studies that show when we activate the Vglut2-Lepr DMH neurons within mice, these animals lose body weight. Based on this preliminary data, our short-term goals are to understand the roles for Vglut2-LeprDMH and Vgat-LeprDMH cells in maintaining energy balance and the role of leptin signaling in each cell type. While our long-term goals are to understand how the Vglut2 and Vgat DMH cells that do not express Lepr contribute to energy balance. Together this research program will illuminate define the leptin-dependent and leptin-independent mechanisms through which the DMH controls energy balance.

大脑在调节我们摄入多少食物和消耗多少能量的过程中起着至关重要的作用，这个过程被称为“能量平衡”。我的研究计划的长期目标是识别和研究大脑中调节能量平衡的细胞类型。调节进食行为和能量使用的最重要的蛋白质之一是一种叫做瘦素的荷尔蒙。缺乏瘦素的人类和小鼠会患上严重的肥胖症，这与食物消耗的增加和能量消耗的减少有关。虽然瘦素是在脂肪细胞中产生的，但它会通过大脑中多种细胞类型上表达的瘦素受体(Lepr)作用于大脑，减少摄食，增加能量消耗。大脑的一个区域被称为背内侧下丘脑(DMH)，含有高密度的Lepr表达神经元，破坏整个DMH的瘦素活动会增加体重。然而，DMH是一个巨大而复杂的下丘脑隔区，我们不知道瘦素通过DMH中的哪些细胞类型起作用。因此，为了更好地了解瘦素是如何通过DMH控制能量平衡的，我们需要对表达Lepr的DMH亚型进行更彻底的研究。利用尖端技术，我们产生了初步数据，证明Lepr在两个不同的DMH神经元群体上表达。这两个Lepr DMH群体的不同之处在于它们表达的蛋白质称为Vher2或Vgat(我们将这两种细胞类型命名为Vlu2-Lepr DMH和Vgat-Lepr DMH细胞)。重要的是，这两类细胞产生独特的神经递质，因此，我们预计Vher2-Lepr DMH和Vgat-Lepr DMH细胞将具有独特的功能。我们还进行了关键的试点研究，表明当我们激活小鼠体内的Vher2-Lepr DMH神经元时，这些动物的体重就会减轻。基于这些初步数据，我们的短期目标是了解Vher2-LeprDMH和Vgat-LeprDMH细胞在维持能量平衡中的作用，以及瘦素信号在每种细胞类型中的作用。我们的长期目标是了解不表达Lepr的Vher2和Vgat DMH细胞如何促进能量平衡。这项研究计划将阐明DMH控制能量平衡的瘦素依赖和非瘦素依赖的机制。