Role of NTS POMC neurons in energy homeostasis

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Obesity is a major health problem in the Western wodd and is a leading contributor to cardiovascular disease and diabetes mellitus. The causes of obesity are multifactorial. However, its severity and early onset in children with monogenic mutations in the proopiomelanocortin (POMC) and metanocortin-4 receptor genes highlight the importance of the POMC system in the regulation of energy balance. Remarkably, the cell bodies of POMC neurons are located in only two regions of the brain: the arcuate nucleus of the hypothalamus (ARC) and the nucleus of the solitary tract (NTS) in the medulla. As any pharmacological intervention using either melanocortin or opioid drugs will affect the signaling from both regions, it is critical to determine the function of the NTS-POMC neurons for rational predictions concerning the long-term consequences of drug therapy aimed at these targets. However, although the NTS receives visceral sensory inputs and is interconnected with regions proposed to act as feeding centers, the role of the POMC neurons in the NTS in energy homeostasis remains unknown. I hypothesize that these NTS-POMC neurons are a vital component of neural pathways that control energy homeostasis and are capable of integrating the sensory afferent and hormonal input into the NTS. This research plan uses a multi-disciplinary approach to address key aspects of this hypothesis. The Low lab has recently developed transgenic mice in which the POMC neurons are identified by EGFP, allowing the examination of the rote of these POMC neurons in the NTS pathways, using both electrophysiologicat and immunocytochemical techniques The proposed specific aims wilt identify neuroanatomic, neurochemical, regulatory, and molecular properties of NTS-POMC neurons, tn addition, I plan to ablate the NTS-POMC neurons to directly determine if they are important for energy balance. An important aspect of this proposal are the training goals. Dr. Michael Andresen's knowledge and experience with his unique set up for studying NTS neurons and their regulation by afferent inputs are critical for this proposal to characterize the NTS POMC neurons using electrophysiological approaches. Additionally, 1plan to expand my training in immunocytochemicat and retrotabeting studies by utilizing the extensive experience and knowledge in this area available at OHSU, as these techniques will be invaluable for my long-term career goal of becoming an independent investigator.