BioProject

During fasting the liver supplies the organism’s energy demands by producing glucose and ketones. More...

During fasting the liver supplies the organism’s energy demands by producing glucose and ketones. Fuel production during fasting is temporally organized whereby glucose serves as the major fuel produced in short-term fasting while ketones are produced in longer fasts as gluconeogenic precursors deplete1. However, the regulatory process dictating this temporally-organized metabolic output is unexplored. Here we show that a cascade of transcription factors (TFs) sequentially activated by hormonal signals, TF gene expression and assisted loading onto specific ‘fasting enhancers’ generate a framework for the temporal organization of fuel production during fasting. Fasting led to massive chromatin re-organization, exposing enhancers in which a complex set of regulatory signals converge to regulate transcription. Glucagon secreted in early fasting activates cAMP responsive element binding protein (CREB) leading to increased expression of many TF genes, including CCAAT enhancer binding protein β (C/EBPβ) which relaxes chromatin, thereby potentiating glucocorticoid receptor (GR) binding to fasting enhancers upon its activation by corticosterone in mid-term fasting. Then, GR augments glucagon-dependent gluconeogenesis but also supports a peroxisome proliferator receptor α (PPARα)-dependent ketogenic gene program to sustain ketogenesis during prolonged fasting. Our results bridge over a long-lasting gap between the characterized temporal organization of fuel output during fasting and the undefined role of transcription and chromatin regulation in generating this output. Because a de-regulated response to fasting is a hallmark of diabetes progression, these findings may promote our understanding of this complex disease Overall design: characterization of liver chromatin landscape during fasting using Dnase-I hypersensitive assay Less...