Defining the role of Leptin receptors on glutamatergic DMH neurons

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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.