PROJECT SUMMARY: Obesity and obesity-related cardiometabolic diseases are growing causes of morbidity and mortality in the U.S. and around the world. Obesity develops when nutrient intake exceeds the body's energy demands, leading to storage of excess calories and weight gain. As such, mechanisms regulating the body's energy demands serve as attractive targets for treating obesity and related diseases. Brown adipose tissue (BAT) is an important organ regulating energy use in mammals. During exposure to cold, BAT activates UCP1, which uncouples nutrient consumption from ATP production, releasing the energy instead as heat, a process called thermogenesis. BAT thermogenesis relies on utilization of a variety of metabolic substrates. An underexplored metabolic substrate in the context of BAT thermogenesis is lactate. Under basal conditions, lactate metabolism plays a predominant role in whole-body carbon flux. However, it remains unknown how systemic and BAT lactate metabolism changes during cold exposure or what role lactate metabolism plays in thermogenesis. BAT activation induces expression of lactate dehydrogenase (LDH), the enzyme mediating interconversion of lactate to pyruvate. Stimulation of BAT also causes tissue lactate levels to fall, suggesting lactate may be consumed during thermogenesis. Thus, I hypothesize that during cold exposure, BAT consumes lactate via LDH and that this contributes to thermogenesis. In Aim 1, I will utilize stable isotope tracing approaches in mice to determine how cold exposure affects systemic and BAT lactate fluxes. Further, I will inhibit LDH activity in BAT via an inducible UCP1- driven knockout of LDHA, the primary LDH isoform in BAT, to test whether BAT net consumes or produces lactate by measuring whether lactate levels rise or fall relative to other substrates following LDH inhibition. In Aim 2, I will utilize my genetic model to test whether LDH is important for BAT thermogenesis by measuring cold tolerance and β adrenergic-induced BAT activation in the knockout mice relative to controls. These studies serve as the basis for my pre-doctoral fellowship application awarded to M.D./Ph.D. applicants. My training plan is focused on preparing me for a career as a physician-scientist. Through this highly clinically relevant research, combined with continued exposure to clinical medicine, I will develop the skills necessary to successfully blend basic science and clinical practice in my career. Under the excellent mentorship of Dr. Zoltan Arany, a physician- scientist himself, and as part of the well-established M.D./Ph.D. program at the University of Pennsylvania, I am in the perfect environment to pursue this exciting career.