Though my scientific degrees are in chemistry and physics, I have always been interested in biological questions. My biochemical training in lipid nutrients and clinical training in pediatric endocrinology have culminated in a biomedical interest in the interplay of regulators of lipid metabolism with energy homeostasis and insulin sensitivity. My long-term goal is to become an independently funded physician-scientist, devoting 80-90% of my time to investigation of the interface of lipid physiology with hormonal systems. This proposal will facilitate my transition to this goal. I will receive expert direction from my mentor Professor C. Ron Kahn, a longstanding leading authority in the areas of insulin action and molecular physiology. Expert consultative mentoring in the area of lipid metabolism will come from Professor Art Spector, a recognized expert in this area for over three decades, I will learn greatly from the structured learning opportunities at the Joslin Diabetes Center and Children's Hospital Boston, as well as from unstructured daily interactions with local expert investigators. I have proposed didactic learning at local and national workshops, meetings and courses. I am just completing training in the responsible conduct of science. The experiments proposed herein stem from our recent observation that muscle specific loss of peroxisome proliferator activated receptor-gamma (PPAR(), a transcription factor which regulates lipid utilization, leads to obesity and hepatic insulin resistance. These findings advance the hypothesis that muscle PPAR( is part of the normal program regulating lipid metabolism in muscle and consequently energy homeostasis and insulin sensitivity in other tissues via crosstalk. This work proposes to further test this hypothesis by the following aims. (1) Determine the contribution of muscle PPARgamma to gene expression and fuel metabolism in this tissue, particularly in dynamic response to physiologic changes. (2) Dissect pathways of tissue crosstalk arising from loss of muscle PPAR( that lead to changes in insulin resistance in other tissues, altered fuel expenditure, and adiposity. These studies will not only enhance knowledge of the action of PPAR( in muscle, aid targeting of selective PPAR( modulators with desired tissue specific effects, and increase understanding of gene regulatory events that could be adapted to treat obesity, but will also lead my long-term expansion into biomedical research.
