Previous work by the Montminy lab and others has shown that two key proteins, CRTC2 and FOXO1, are needed to turn on glucose-making genes during fasting. CRTC2 is activated by glucagon, a hormone whose levels go up when we stop eating. FOXO1, on the other hand, is activated when levels of the food-stimulated hormone insulin drop below a certain threshold. CRTC2's and FOXO1's activity needs to be tightly regulated, since producing too much glucose would result in over-borrowing of energy from muscle tissue.
To uncover the mechanism that ensures that this doesn't happen, the Salk researchers created mice containing the gene for luciferase, a light-emitting enzyme usually found in fireflies, engineered in such a way that it was only turned on when CRTC2 was active. Using imaging equipment, they could then detect CRTC2 activity in the livers of live mice simply by measuring how much they glowed.
When the mice were fasted, CRTC2 was rapidly activated, and the livers lit up, but to the scientists' surprise, after six hours the light went out. Experimentally decreasing the levels of CRTC2 or FOXO1 confirmed there was a two-stage fasting-response. Lowering CRTC2 reduced gluconeogenesis only early on, while less FOXO1 only affected late glucose production. As in a relay race, during fasting the baton for glucose production appeared to be passed from CRTC2 in stage one to FOXO1 in stage two.
The crucial switch from CRTC2 to FOXO1 comes in the form of SIRT1, a nutrient sensor that accumulates in the late fasting stage. Yi discovered that SIRT1 has opposite effects on CRTC2 and FOXO1: it sends the former to the recycling bin, while it activates the latter, and thus the baton is safely transferred from CRTC2 to the FOXO1.
|Contact: Gina Kirchweger|