Fibroblast Growth Factor and Energy Metabolism

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 DESCRIPTION (provided by applicant): Obesity is occurring at epidemic rates in the United States and worldwide, impacting the risk and prognosis of many diseases, especially type 2 diabetes mellitus, cardiovascular disorders, hypertension, and certain cancers. Therefore, developing prevention and treatment strategies for obesity and its co-morbidities is of the utmost importance for the healthcare and scientific research communities. Brown fat plays a pivotal role in adaptive thermogenesis, a physiological process during which energy is dissipated in response to environmental changes, such as cold temperature and diet. Although brown fat was once considered only necessary in infants, recent studies have provided evidence that, contrary to prior belief, this tissue is present and active in adult humans. The unique property of brown fat to mediate energy expenditure and thermogenesis depends on the presence of uncoupling protein 1 (UCP1), a mitochondrial ion carrier that is uniquely expressed in brown fat and permits proton translocation through the mitochondrial inner membrane, thereby uncoupling respiration from ATP synthesis and facilitating fatty acid oxidation and dissipation of energy. Thus, identification of agents that promote UCP1 expression and function would provide potential avenues for the development of new anti-obesity therapies. We have recently discovered that members of the paracrine Fibroblast Growth Factor (FGF) family can robustly induce UCP1 expression and increase mitochondrial function. Building on these preliminary data, we hypothesize that the paracrine FGF functions as a new regulator of mitochondrial activity and thermogenesis by inducing UCP1 expression and promoting fuel utilization. We propose to directly test this hypothesis by determining the cellular and molecular mechanisms mediating FGF's effect on UCP1 expression and mitochondrial function using both in vitro and in vivo systems. Success of the proposed studies would not only launch a new paradigm of energy regulation but also create potential therapeutic approaches to treat obesity and its many related disorders.