The role of ventromedial hypothalamic steroidogenic factor-1 neurons in exercise-related metabolism

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PROJECT SUMMARY Nearly half of the American population is classified as obese and just under one in ten suffer from type 2 diabetes mellitus (T2DM). Exercise protects against a number of deleterious metabolic changes that correspond with obesity and T2DM, including impaired glucose metabolism and altered energy balance. The ventromedial nucleus of the hypothalamus (VMH) is critical for the regulation of whole-body metabolism. Co-sponsor Dr. Joel Elmquist has shown that the expression of the transcription factor steroidogenic factor-1 (SF1) in the dorsomedial VMH (VMHdm) is required for normal energy homeostasis in response to metabolic challenges including exercise. While preliminary work in sponsor Dr. J. Nicholas Betley’s laboratory has shown that the activity of VMHdm SF1 neurons substantially increases following exercise, it remains unknown how SF1 neural activity may mediate the metabolic effects of exercise. The main goals of the proposed research are to characterize the neurophysiology of VMHdm SF1 neurons and their two major subtypes—those that express the leptin and insulin receptors (LEPR and INSR)—during exercise training; and to determine the role of SF1, LEPR, and INSR neural activity in exercise-driven changes in energy balance and glucose homeostasis. Specific Aim I experiments will use fiber photometry and endoscopic calcium imaging to monitor the neural activity of VMHdm SF1, LEPR, and INSR neurons during and immediately following both acute exercise and chronic exercise training. Specific Aim II experiments will combine optogenetic manipulation of VMHdm SF1, LEPR, and INSR neurons in in exercising and sedentary mice with metabolic chamber monitoring and glucose tolerance tests to test the necessity and sufficiency of these neural populations to drive exercise-related changes in energy balance and glucose homeostasis. Collectively, these experiments will open avenues for future research into the specific mechanisms by which VMHdm neural activity contributes to the whole-body homeostatic response to metabolic challenges such as exercise. The training plan included in this application builds upon the applicant, Dr. Ryan Post’s prior expertise in systems neuroscience, optogenetics, and fiber photometry as he develops his skills in endoscopic calcium imaging and metabolic techniques, and enters the field of metabolism. The application’s sponsor, Dr. J. Nicholas Betley, and co-sponsors, Drs. Joel Elmquist and Junhyong Kim, will be instrumental in Ryan’s completion of the proposed research and training plan. Given Dr. Betley’s expertise in the contribution of the central nervous system to metabolism, Dr. Elmquist’s experience as a leader in the field of hypothalamic research and metabolism, and Dr. Kim’s standing as a pre-eminent cell biologist and successful mentor, they will serve as invaluable resources to Ryan in his development as an independent scientist. Drs. Betley, Elmquist, and Kim will also oversee Ryan’s professional development as he attends international conferences in neuroscience and metabolism. The training and research proposed in this application will take place at the University of Pennsylvania, a world-class institution with a number of resources that will augment Dr. Post’s development.