Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Food for Thought—Regulating Energy Supply to the Brain During Fasting

06.10.2008
If the current financial climate has taught us anything, it's that a system where over-borrowing goes unchecked eventually ends in disaster. It turns out this rule applies as much to our bodies as it does to economics. Instead of cash, our body deals in energy borrowed from muscle and given to the brain.

Unlike freewheeling financial markets, the lending process in the body is under strict regulation to ensure that more isn't lent than can be afforded. New research by scientists at the Salk Institute for Biological Studies reveals just how this process is implemented.

"We have all seen the sub-prime mortgage crisis," says Marc Montminy, M.D., Ph.D., a professor in the Clayton Foundation Laboratories for Peptide Biology who led the current study. "If you take out a loan, sooner or later you've got to pay your debt, and the same is true in fasting metabolism."

The Salk researchers' findings, which are published ahead of print in the Oct. 5 edition of the journal Nature, may pave the way for novel therapies for sufferers of metabolic diseases in whom such regulation can spiral out of control.

Most tissues in our bodies respond to fasting by switching from their usual high-octane energy source—glucose—to burning a low-octane, cheaper alternative-fat. For our brains, however, only the high-performance fuel will do. If 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. It 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. The sugar is then shipped via the bloodstream to the brain to keep it running smoothly.

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," says postdoctoral researcher and co-first author Yi Liu, Ph.D. "Because it uses muscle as a protein source, it will eventually lead to muscle wastage." Adds Montminy, "The question has always been how is the production of glucose turned on, and how is shut off again?"

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.

Why does the body want to change between these two regulators of glucose production? Again, it comes down to body economics. CRTC2 acts as a rapid response unit to quickly produce high levels of glucose when it detects glucagon. Switching to FOXO1 later on slows down this production to more sustainable levels, while at the same time helping to produce ketone bodies, an alternative fuel the brain can use that does not require taking protein from muscle. "It is just like paying your loan back," says Montminy. "Later on you produce blood sugar at a different rate than you did at the beginning."

Knowledge of how this nutrient switch is working may help design new drugs to regulate sugar levels in diabetes patients. In, particular, chemical activators of the SIRT1 switch may be key. "This way we could provide control for patients with insulin resistance," says Montminy, "as typically their blood sugars are elevated after overnight fasting because the switches that regulate the glucose-producing enzymes are too active." Perhaps, then, a pharmacological rescue package for patients whose lending systems have been left unregulated may be on the horizon.

Other researchers contributing to this study were the co-first authors Renaud Dentin, Ph.D., at the Salk Institute and Danica Chen, Ph.D., at the Massachusetts Institute of Technology, Cambridge, along with Susan Hedrick and Kim Ravnskjaer in Montminy’s laboratory; Simon Schenk and Jerrold Olefsky at the University of California, San Diego; Jill Milne at Sirtris Pharmaceuticals, Inc., Baltimore; David J. Meyers and Phil Cole at the Johns Hopkins University School of Medicine; John Yates III at The Scripps Research Institute; and Leonard Guarente at MIT.

The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health, and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.

Gina Kirchweger | Newswise Science News
Further information:
http://www.salk.edu

Further reports about: Brain CRTC2 FOXO1 Fasting Food Gluconeogenesis SIRT1 blood sugar enzyme fasting metabolism

More articles from Studies and Analyses:

nachricht Real-time feedback helps save energy and water
08.02.2017 | Otto-Friedrich-Universität Bamberg

nachricht The Great Unknown: Risk-Taking Behavior in Adolescents
19.01.2017 | Max-Planck-Institut für Bildungsforschung

All articles from Studies and Analyses >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Safe glide at total engine failure with ELA-inside

On January 15, 2009, Chesley B. Sullenberger was celebrated world-wide: after the two engines had failed due to bird strike, he and his flight crew succeeded after a glide flight with an Airbus A320 in ditching on the Hudson River. All 155 people on board were saved.

On January 15, 2009, Chesley B. Sullenberger was celebrated world-wide: after the two engines had failed due to bird strike, he and his flight crew succeeded...

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

New pop-up strategy inspired by cuts, not folds

27.02.2017 | Materials Sciences

Sandia uses confined nanoparticles to improve hydrogen storage materials performance

27.02.2017 | Interdisciplinary Research

Decoding the genome's cryptic language

27.02.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>