Darkness Unveils Vital Fuel Switch Between Sugar and Fat

Paper in Nature reveals a new molecular target for diabetes, obesity and emergency care research

A search in the dark for the trigger of mammalian hibernation has illuminated a molecule with fascinating long-term implications for emergency care, diabetes and obesity.

Cheng Chi Lee, Ph.D.

Reporting in the prestigious journal Nature, a research team led by Cheng Chi Lee, Ph.D., professor of biochemistry and molecular biology at The University of Texas Medical School at Houston, showed that constant darkness throws a molecular switch in mice that shifts the body’s fuel consumption and induces a state of torpor.

A series of experiments pinpointed a key molecular mediator of this constant darkness effect, converting mice from a glucose-burning, fat-storing state to a fat-burning, glucose-conserving lethargy. This switch from sugar to fat also occurs in active mammals – a bear foraging for food or a human running a marathon – as glucose is consumed first, followed by a change to burning fat.

“How does the body know when to switch? The molecule we identified here, known as five prime adenosine monophosphate (5’AMP), is the signal. It’s the same metabolic system, whether we are talking about hibernation or not,” said senior author Lee, an expert in circadian rhythms – the internal body clock that regulates biological processes.

The team started with a basic question: What sets off hibernation? “These animals dig deep burrows, or move into caves,” Lee said. “They are constantly in the dark. Why not darkness as a switch?”

Mice do not hibernate, but they can slip into a similar, short-term state of torpor. Lee and colleagues started with a microarray analysis of genes expressed in the livers of mice that were subject to the usual light-dark cycle and those kept in the dark for 48 hours.

One gene fired up in the dark – procolipase, which produces an enzyme required for degrading dietary fat. The enzyme previously was thought to be limited to the pancreas and gastrointestinal tract. Yet there it was in the livers of mice exposed to prolonged dark, an unexpected, even doubtful, finding.

They repeated the experiment in mice with natural, or “wild type,” genomes and three strains of mutant mice with impaired circadian rhythms. With few exceptions, mice exposed to regular light-dark cycles showed no sign of the enzyme in their livers – it remained in the pancreas and stomach.

All four genotypes of mouse kept in constant darkness had signs of the enzyme not only in their livers, but also in all peripheral tissue except the brain and kidneys.

“This is the first example of a gene that is turned on by darkness, where darkness itself is a signal,” Lee said. “Twelve hours of darkness didn’t do the job; it had to be at least 48 hours.”

Follow-up tests showed that after the darknessinduced buildup, it took five to seven hours of light exposure to inhibit the gene’s expression in the liver. These time delays pointed to production of the fatburning enzyme being mediated by something in the blood.

A lab test showed elevated levels of 5’ AMP in the blood of mice exposed to constant darkness, compared to those kept in the regular light-dark cycle.

To confirm the connection, the team injected 5’ AMP into mice exposed to a regular light-dark cycle. Three to four hours after injection, the gene was expressed in the livers of these mice and further tests showed expression in all tissues except the brain.

The mice injected with 5’ AMP soon had a sharply lower core body temperature, a sign of torpor. Mice kept in constant dark also ate less, lost weight, and showed evidence of increased fat consumption, all hallmarks of hibernation in larger mammals.

The paper notes that 5’AMP had been shown to regulate enzyme activity for glucose usage and production. The brain requires glucose to function. By switching the primary source of energy in other organs from glucose to fat, 5’AMP conserves sugar for the brain.

This pivotal signaling role in the body’s metabolic balancing act between sugar and fat consumption raises the longer-term possibility of basing new therapies for obesity or type 2 diabetes on 5’AMP, Lee and colleagues reported.

The molecule’s ability to quickly drop core body temperature in mice might be of even more immediate interest, Lee said. Swift cooling of patients is desired in emergency care for cardiac arrest and for head injury, for example. Lee’s team documented 10-degree temperature drops in mice induced in a matter of minutes by injection of 5’ AMP.

Guy Clifton, M.D., holder of the Nancy, Clive and Pierce Runnells Distinguished Chair in Neurosurgery at the Medical School and an expert in hypothermia research for head injury, notes that present methods of chilling patients take hours to drop core temperatures 7-8 degrees. A method that works much faster could greatly minimize damage to the brain, Clifton said.

Study co-authors are Michael Blackburn, Ph.D., associate professor of biochemistry and an expert in adenosine signaling; first author Jianfa Zhang, Ph.D., a post-doctoral fellow in biochemistry; and Krista Kaasik, Ph.D., now at the Institute of Molecular and Cell Biology at Tartu University in Estonia. Lee and Blackburn also hold faculty appointments at the UT Graduate School of Biomedical Sciences at Houston.

By Scott Merville, Public Affairs