Grant: Joint Canada-Israel Health Research Program

Metabolic diseases, including diabetes, obesity and non-alcoholic fatty liver disease are reaching epidemic levels worldwide. Improper cellular energy production, storage and utilization underlie many of these conditions. The enzymes that control glucose, fat, and ketone body production in the liver are under the control of numerous proteins called transcription factors. In response to fasting, a specific series of transcription factors are required to ensure proper activation of the enzymes important for maintaining fuel levels in the absence of an external food source. We will use specific gene knockout mouse models of these transcription factors combined with state-of-the-art DNA and RNA sequencing technologies to uncover the importance of these transcription factors in modifying the basic physiologic response to fasting and how these are modified in disease. We will also test novel small molecules that target these transcription factors for their ability to restore the proper fasting response in a mouse model of diet-induced obesity.