Defining the neurocircuit activated by the VMH to control energy expenditure.

项目摘要

PROJECT ABSTRACT While body weight is tightly regulated in healthy individuals, obesity results from failed homeostatic mechanisms that protect individuals from metabolic disease. Obesity already plagues approximately 100 million people and costs approximately $200 billion dollars annually in this country. Thus, it is imperative that we find better ways to treat obesity before this problem gets out of control. The brain contains unexplored potential avenues for obesity treatment. While it has been clear that neural mechanisms can dramatically shift energy homeostasis, these mechanisms have been poorly described to this point. Specialized neurons detect changes in energy status. Because the brain exhausts almost a quarter of all nutrients in the body, it is especially important for the brain to keep energy levels in a normal range. Therefore, there are undiscovered, or not completely discovered, built-in systems into the brain that maintain energy homeostasis. Recent studies have aimed to understand the function of distinct sets of cells in the brain involved in individual aspects of metabolic function. This has recently been revealed to be the case for a key area of the brain called the ventromedial hypothalamus. We have published papers that identify a set of cells within this brain area is essential for hypoglycemic counterregulation, a critical factor for diabetes treatment. These cells are intermingled in the same area with others that are essential for energy balance by stimulating energy expenditure. Removing the neuropeptide pituitary adenylate cyclase activating polypeptide centered on the ventromedial hypothalamus induces obesity. Because there are no direct connections from the ventromedial hypothalamus with peripheral organ targets, these functions must be controlled through a downstream site to that responds to pituitary adenylate cyclase activating polypeptide. In this proposal, we aim to identify both the anatomical and the cellular targets in the regions that ventromedial hypothalamus neurons project. Our preliminary data indicate that ventromedial hypothalamus neurons only project to a few sites. These projections particularly overlay with the caudal divisions of the preoptic area, a region critical to energy expenditure control. We will employ genetic mouse models in conjunction with AAV-driven gain or loss of function experiments to test the hypothesis that dietary signals that communicate fuel adequacy to engage the neuropeptide in the ventromedial hypothalamus and action within the preoptic area on neurons that are inhibitory and contain the receptor for the neuropeptide. We will define the dietary signals that require the ventromedial hypothalamus neuropeptide and downstream communication by these cells. We will then determine the downstream regions that requires activation by the neuropeptide receptor and communication by these cells. Then, we will identify the inhibitory cells within the preoptic area that contain the neuropeptide receptor and the peripheral actions they engage to support energy balance through energy expenditure.