Glucokinase Regulation of Hepatic Metabolism

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Project Summary My career goal is to lead a biomedical research group that investigates the causal underlying molecular mechanisms of hepatic dysfunction during insulin-resistant states such as diabetes and obesity. To acquire the specific training I will need to achieve this, I propose a project that uses state-of-the-art molecular and biochemical approaches to investigate how hormones and nutrients such as insulin and glucose coordinate hepatic metabolism in the postprandial state and how these processes become disrupted during metabolic disease. My career development plan will expand upon my primary expertise in hormone signaling and metabolic physiology and provide essential training in genome-wide transcriptional and bioinformatic analysis, and protein biochemistry. Since it is my goal to identify novel transcriptional and signaling mechanisms that regulate hepatic metabolism, my success as an independent researcher depends on these skills. The current research proposal is to study how hepatic glucokinase regulates liver gene transcription and metabolism and how these processes contribute to metabolic dysfunction during diabetes. I have developed a novel mouse model that dissociates the hepatic response to insulin and glucose, which is critical to define the specific contribution of each signal in regulating liver metabolism. Liver-specific expression of glucokinase in mice lacking hepatic Akt isoforms was sufficient to normalize glucose tolerance and to regulate “classically” defined insulin responsive genes. These data suggest increased glucose signaling bypasses the requirement of direct insulin action in liver to regulate transcription and metabolism. During this mentored career development award, I will gain the required expertise in genome-wide transcriptional and protein regulation techniques that are well established in my mentors' laboratories. I will test the hypothesis that defective glucose utilization by glucokinase leads to aberrant transcriptional regulation resulting in glucose intolerance and insulin resistance. Using state-of-the-art techniques learned during this K01 application, I will define the hepatic genome-wide transcriptional mechanisms that contribute to altered hepatic metabolism during diet- induced obesity and test the requirement of the transcription factor Foxo1 in mediating these processes. Moreover, I will formally delineate the relationship between reduced hepatic glucose utilization and increased Foxo1 activity in the development of insulin resistance. Finally, I will use my newly acquired expertise in transcriptional analysis to define the regulatory mechanisms and transcription factors, in addition to Foxo1, responsible for coordinating the hepatic transcriptional response to nutrient intake. This mentoring support coupled with my existing expertise will provide the framework for a successful independent academic career.