Now, researchers at the Salk Institute for Biological Studies shed light on the long missing connection: A metabolic master switch, which, when thrown, allows nutrients to directly alter the rhythm of peripheral clocks.
Since the body's circadian rhythm and its metabolism are closely intertwined, the risk for metabolic disease shoots up, when they are out of sync. "Shift workers face a 100 percent increase in the risk for obesity and its consequences, such as high blood pressure, insulin resistance and an increased risk of heart attacks," says Howard Hughes Medical Investigator Ronald M. Evans, Ph.D., a professor in the Salk Institute's Gene Expression Laboratory.
The researchers' findings, which are published in the Oct. 16, 2009, issue of Science, could have far-reaching implications, from providing a better understanding how nutrition and gene expression are linked, to creating new ways to treat obesity, diabetes and other related diseases. "It is estimated that the activity of up to 15 percent of our genes is under the direct control of biological clocks," says Evans. "Our work provides a conceptual way to link nutrition and energy regulation to the genome."
The clocks themselves keep time through the rhythmic waxing and waning of circadian gene expression on a roughly 24-hour schedule that anticipates environmental changes and adapts many of the body's physiological functions to the appropriate time of day. The most obvious one, the sleep-wake rhythm, is tightly linked to the night-day cycle. But so are physical activity and metabolism.
"When we get up in the morning we 'break the fast'," says Evans. While opening the fridge doesn't require a lot of physical activity, the situation for animals in the wild is quite different. "If you are a predatory animal you run to hunt. If you are prey, you run to get away."
But how pacemakers in peripheral tissues such as the liver and muscle knew that it was time to scurry and replenish their energy stores was still an open question. When postdoctoral researcher and first author Katja Lamia, Ph.D., started probing the relationship between metabolism and circadian cycles, she discovered a highly conserved phosporylation site in CRY1, short for cryptochrome 1. Cryptochromes originally evolved as a blue light photoreceptor in plants and, although no longer sensitive to light, are now an integral part of the clock in vertebrates.
The phosphorylation site is specific for AMPK, which acts like a gas gauge by sensing how much energy a cell has. When a cell has plenty of energy, AMPK remains inactive and the cell carries out its normal processes. Her experiments revealed that if a cell runs on empty, AMPK is turned on and attaches a phosphate molecule to CRY1, which initiates the destruction of CRY1. As a result the circadian rhythm speeds up and the clock is reset.
"The insertion of an AMPK phosphorylation site transformed a light sensor into an energy sensor, which now allows nutrients to provide metabolic input to circadian clocks," explain Lamia. "Insertion of a novel sensor into an existing signaling pathway is a very elegant solution to a rather complicated problem."
Genetic inactivation of AMPK in mice blocks these effects, stabilizing CRY1 and severely disrupting peripheral clocks. In contrast, treating mice with AICAR, a synthetic drug that directly activates AMPK, reset the clock in cultured cells as well as in animals, confirming that cryptochromes act as energy sensors that allow to circadian clocks.
Researchers who also contributed to the study include Uma M. Sachdeva and Craig B. Thompson at the Abramson Family Cancer Research Institute at the University of Pennsylvania School of Medicine in Philadelphia, Daniel F. Egan, Debbie S. Vasquez and Reuben Shaw in the Molecular and Cell Biology Laboratory, Elliot C. Williams and Henry Juguilon in the Gene Expression Laboratory as well as Luciano DiTacchio and Satchidananda Panda in the Regulatory Biology Laboratory, all at the Salk Institute for Biological Studies in La Jolla.
The work was funded in part by the National Institutes of Health, the Pew Charitable Trust and the Life Sciences Research Foundation.
About the Salk Institute for Biological Studies:
The Salk Institute for Biological Studies is one of the world's preeminent basic research institutions, where internationally renowned faculty probe fundamental life science questions in a unique, collaborative, and creative environment. Focused on both discovery and mentoring future generations of researchers, Salk scientists make groundbreaking contributions to our understanding of cancer, aging, Alzheimer's, diabetes, and cardiovascular disorders by studying neuroscience, genetics, cell and plant biology, and related disciplines.
Faculty achievements have been recognized with numerous honors, including Nobel Prizes and memberships in the National Academy of Sciences. Founded in 1960 by polio vaccine pioneer Jonas Salk, M.D., the Institute is an independent nonprofit organization and architectural landmark.
Gina Kirchweger | Newswise Science News
Further reports about: > AMPK > Biological Studies > CRY1 > Cellular > Expression > Food-Energy > Gene Expression > Laboratory > Nobel Prize > cell and plant biology > circadian clock > circadian rhythm > environmental change > groundbreaking contributions > metabolic disorders > physical activity > synthetic biology
Ion treatments for cardiac arrhythmia — Non-invasive alternative to catheter-based surgery
20.01.2017 | GSI Helmholtzzentrum für Schwerionenforschung GmbH
Seeking structure with metagenome sequences
20.01.2017 | DOE/Joint Genome Institute
An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...
Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
19.01.2017 | Event News
10.01.2017 | Event News
09.01.2017 | Event News
20.01.2017 | Awards Funding
20.01.2017 | Materials Sciences
20.01.2017 | Life Sciences