How hormones regulate our genes to survive fasting?

The liver plays an important role in the adaption to fasting. In the fasted state, the liver synthesizes glucose through gluconeogenesis. Amino acids (AA) derived from muscle serve as the main precursors for gluconeogenesis. During fasting, corticosterone and glucagon levels rise and stimulate gluconeogenesis, mostly by initiating transcriptional programs. Here we investigate which genes related to AA metabolism and uptake are induced after fasting, what hormonal signals regulate them and who are the responsible transcription factors (TF). We fasted mice for 24 hours and measured their transcriptome by RNA-seq. We found that 38 AA-related genes were induced by fasting. To study the responsible fasting-related signal, we treated primary mouse hepatocytes with glucagon, corticosterone and the combination of both. A subset of genes was induced by corticosterone treatment alone while most genes were induced in a synergistic manner in the combined treatment. This synergistic effect was further augmented when AAs were supplemented in excess to the culture media. To examine the mechanism behind this synergistic effect, we performed chromatin immunoprecipitation followed by qPCR and high throughput sequencing to both GR and CREB. As expected, binding of GR and CREB was significantly enriched after corticosterone and glucagon treatments respectively. Importantly, we observed increased enrichment of CREB in the combined treatment, which indicates that CREB and GR cooperate on the chromatin template to synergistically induce AA-related genes. In summary, these findings implicate that there is a complex transcriptional program regulating AA-related genes during fasting resulting from crosstalk between CREB and GR.