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.

大脑对于确定我们吃了多少食物以及通过称为“能量平衡”的过程燃烧的能量至关重要。我的研究计划的长期目标是识别和研究调节能量平衡的大脑中的细胞类型。调节进食行为和能量使用的最重要的蛋白质之一是一种称为瘦素的马。缺乏瘦素发育的人类和小鼠深刻的肥胖症，与食物消耗和改善能量消耗有关。虽然瘦素是在脂肪细胞中产生的，但它可以通过在整个大脑的多种细胞类型上表达的瘦素受体（LEPR）传播到大脑，以减少进食并增加能量消耗。大脑的一个区域称为背侧下丘脑（DMH），含有高密度表达LEPR的神经元，并破坏了整个DMH的瘦素作用，从而增加了体重。但是，DMH是一个大型且复杂的下丘脑区室，我们不了解瘦素通过的DMH中哪些细胞类型。因此，为了更好地了解瘦素如何通过DMH来控制能量平衡，我们需要对表达LEPR的DMH亚型进行更彻底的研究。使用尖端技术，我们生成了初步数据，这些数据表明LEPR在两个不同的DMH神经元中表达。这两个LEPR DMH种群以其称为VGLUT2或VGAT的蛋白质表达（我们称为这两种细胞类型vglut2-Lepr dmh和vgat-lepr dmh细胞）。重要的是，这两个细胞群会产生独特的神经递质，因此我们预计VGLUT2-LEPR DMH和VGAT-LEPR DMH细胞具有独特的功能。我们还进行了关键的试点研究，这些研究表明当我们激活小鼠内的VGLUT2-LEPR DMH神经元时，这些动物会降低体重。基于此初步数据，我们的短期目标是了解VGLUT2-LEPRDMH和VGAT-LEPRDMH细胞在维持能量平衡以及瘦素信号在每种细胞类型中的作用中的作用。尽管我们的长期目标是了解不表达LEPR的VGLUT2和VGAT DMH细胞如何有助于能量平衡。该研究计划将共同阐明DMH控制能量平衡的瘦素依赖性和瘦素独立的机制。