Regulation of neuronal function by mitochondrial uncoupling - PROJECT SUMMARY / ABSTRACT Obesity is a major contributor to the epidemic of metabolic diseases including type II diabetes, hypertension, cardiovascular disease, and liver disease. Excess weight gain is the result of a chronic imbalance between caloric intake and energy expenditure, and while several pharmacological agents target energy intake to promote body weight loss, no current options are successful in the long-term management of obesity. Thus, a greater understanding of the central mechanisms that contribute to obesity are required for both its prevention and treatment. Numerous studies have implicated mitochondrial dysfunction in neurons because of excess consumption of nutrients in the pathogenesis of obesity. Previous publications have demonstrated that the inner mitochondrial membrane protein uncoupling protein 1 (UCP1), renowned for its role in heat production in thermogenic adipose tissue, is also expressed in the central nervous system (CNS), however, the function of neuronal UCP1 is completely unknown. Our preliminary data unexpectedly demonstrates that UCP1 is expressed in the ventromedial hypothalamus (VMH) of adult mice and that its expression is metabolically regulated. Consequently, there is a need to understand how UCP1 functions and whether it’s activation within the CNS can also regulate energy homeostasis as it does in brown adipose tissue. The next steps addressing these needs are to pursue the overall objective of this application: (i) determine the extent to which UCP1 in the VMH influences energy balance, and (ii) investigate if neuronal UCP1 activity attenuates the production of reactive oxygen species (ROS) to regulate energy homeostasis. We will investigate our central hypothesis that activation of UCP1 within the VMH chronically reduces ROS to promote negative energy balance. We will test our hypothesis using novel genetic mouse models and viral vector constructs that knockout or overexpress UCP1 specifically in the VMH to determine whether modulation of neuronal UCP1 activity regulates body weight following cold exposure or consumption of high fat diet. Moreover, we will be able to investigate whether UCP1 in the VMH can chronically reduce ROS to regulate energy homeostasis, as well as determine how modulating its expression regulates mitochondrial dynamics. The experiments proposed in this application are expected to identify novel signaling pathways that provide new insights into the treatment and prevention of obesity. Rationale for this project is that discovering the function of central UCP1 may contribute to future discovery efforts to identify and test new therapeutic targets to treat obesity. In addition, an outlined career development plan to elevate my knowledge of mitochondrial biology by leveraging mentorships, technical training, seminars, conferences, and R01 workshops is described in the application. The University of Iowa has committed its support and facilities to allow Dr. Claflin to complete the proposed research and participate in their extensive training seminars. Completion of the proposed 5-year research and training plans will prepare Dr. Claflin for an independent research career and assist in securing an R01 from the NIDDK.
