Energy Supply to the Brain During Fasting is Derived from Muscle

by Rajashri on Oct 6 2008 5:28 PM

A new study by scientists at the Salk Institute for Biological Studies has found out how the body regulates energy supply to the brain during fasting.

Dr. Marc Montminy, a professor of Peptide Biology who led the current study, says that when no food-derived glucose is available, the body must manufacture its own supply to maintain the brain in the manner to which it is accustomed.

He says that the body does so by taking energy from muscle in the form of protein, and converting it to glucose in the liver, a process known as gluconeogenesis.

Through the bloodstream, the sugar is later shipped to the brain to keep it running smoothly, adds the researcher.

According to the researchers, gluconeogenesis needs to be turned on rapidly in response to fasting, but shutting it off again is just as crucial.

"You don't want gluconeogenesis to be prolonged. Because it uses muscle as a protein source, it will eventually lead to muscle wastage," Nature magazine quoted postdoctoral researcher and co-first author Dr. Yi Liu as saying.

Montminy points out that two key proteins, CRTC2 and FOXO1, are needed to turn on glucose-making genes during fasting.

While CRTC2 is activated by glucagon, a hormone whose levels go up when we stop eating, FOXO1 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 because producing too much glucose would result in over-borrowing of energy from muscle tissue, and to uncover the mechanism that ensures that this doesn't happen, the researchers created mice containing the gene for luciferase, a light-emitting enzyme usually found in fireflies.

Experimenting with mice, the researchers found that the crucial switch from CRTC2 to FOXO1 comes in the form of SIRT1, a nutrient sensor that accumulates in the late fasting stage.

Yi said that SIRT1 has opposite effects on CRTC2 and FOXO1: it sends the former to the recycling bin, while it activates the latter.

The researcher said that CRTC2 acts as a rapid response unit to quickly produce high levels of glucose when it detects glucagons, while switching to FOXO1 later on slows down this production to more sustainable levels, and simultaneously helps produce ketone bodies, an alternative fuel the brain can use that does not require taking protein from muscle.

Montminy believes that the knowledge of how this nutrient switch is working may help design new drugs to regulate sugar levels in diabetes patients.

"This way we could provide control for patients with insulin resistance, as typically their blood sugars are elevated after overnight fasting because the switches that regulate the glucose-producing enzymes are too active," says Montminy.