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
Innovative genetic tests for children with developmental disorders and epilepsy
11.07.2018 | Christian-Albrechts-Universität zu Kiel
Oxygen loss in the coastal Baltic Sea is “unprecedentedly severe”
05.07.2018 | European Geosciences Union
For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.
To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...
For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.
Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...
Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.
A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...
Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.
"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....
Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.
Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
19.07.2018 | Earth Sciences
19.07.2018 | Power and Electrical Engineering
19.07.2018 | Materials Sciences