April 22, 2005
A Healthy Internal Clock Keeps Weight Off
Staying up past bedtime, skipping meals, and snacking constantly all
add up to weight gain, fatty livers, and high cholesterol levels for an
unlucky group of mice whose internal biological clocks are genetically
disrupted.
Researchers at Northwestern University and the Howard Hughes Medical
Institute have identified wide-ranging molecular and behavioral changes
in mice that have a faulty circadian system. In people, similar changes
in body fat and metabolic activity are known as metabolic syndrome,
which can lead to cardiovascular disease and type 2 diabetes.
“The tissues important in metabolism have to be conducted properly. But in the Clock mutant, each tissue plays to its own beat, which creates cacophony at the biological level that sets up the animal for obesity and metabolic disregulation.”
Joseph Bass
The research team, which included co-author Joseph S. Takahashi, a
Howard Hughes Medical Institute investigator at Northwestern
University, published its report on April 21, 2005, in Science
Express, which provides rapid electronic publication of select
articles from the journal Science. The study suggests a
surprising new angle for understanding and eventually preventing and
treating obesity and related disorders in people.
"Timing is critical to keep the metabolic symphony in tune," said
corresponding author Joseph Bass, assistant professor of medicine and
neurobiology at Northwestern University and head of the endocrinology
and metabolism division at Evanston Northwestern Healthcare. Quoting
Duke Ellington, Bass added, "It don't mean a thing if it ain't got that
swing.”
The mice have defective Clock genes that control daily
rhythms in the brain and throughout the body, including sleeping and
eating. The gene was discovered eight years ago by Takahashi's
laboratory. Since then, Takahashi and other researchers have shown that
the Clock gene and a half-dozen other proteins run 24-hour
oscillating clocks in most cells in the body and in a specific part of
the brain that controls appetite and wakefulness. About 3-10 percent of
the genes in any given tissue turn on and off in circadian rhythm.
The project started when circadian rhythm expert Fred Turek, lead
author of the paper and professor of neurobiology and physiology at
Northwestern, noticed that the Clock mutant mice gained more
weight with age than other mice.
Experiments soon revealed the cause. Mice with the mutant
Clock gene ate more than normal mice, so they gained more
weight, especially on a high-fat diet, which was evident within six
weeks of birth. The chubby Clock mutants put on about as much
extra weight as did the normal mice that were switched to a high fat
diet.
The Clock mutant mice lost both their alarm clocks and their
internal dinner bells. Mice typically sleep during the day and then eat
a meal at the beginning and at the end of their active nocturnal day,
akin to breakfast and dinner. Instead, the Clock mutant mice
skipped their meals, stayed awake far into the usual rest time, and
snacked often.
The insomniac mice also were a little more sluggish, as measured by
infrared sensors in their cages. The researchers removed the exercise
wheels normally used to gauge mouse activity, because regular spins can
help the mice reset their biological clocks, just as a daily walk might
help a person sleep better at night.
In repeated round-the-clock measurements, the researchers found
signs of further trouble emerging in the mice's early adult months. The
circadian-challenged mice developed high cholesterol, high
triglycerides, high blood sugar, low insulin, bloated fat cells, and
lipid-engorged liver cells. Some of these changes appeared to be
independent of the weight gain, Bass said.
Using sensitive techniques in Takahashi's lab, the researchers found
changes in the key proteins in the hypothalamic region of the brain
that manages feeding, energy balance, and sleep-wake regulation.
Takahashi and his colleagues suspect the metabolic changes are caused
more directly by misregulated genes in various tissues normally
controlled by the Clock gene, rather than by the effects of the
weight gain.
"It's like an orchestra," said Bass, a former HHMI postdoctoral
fellow. "The tissues important in metabolism have to be conducted
properly. But in the Clock mutant, each tissue plays to its own
beat, which creates cacophony at the biological level that sets up the
animal for obesity and metabolic disregulation."
"The Clock finding reinforces the idea of important
interactions between circadian rhythms, sleep and metabolism," said
Emmanuel Mignot, an HHMI investigator at Stanford University. He and
his colleagues recently reported that even partial sleep deprivation
changes the blood levels of several appetite-regulatory hormones,
including leptin and Ghrelin, an effect likely to increase food intake
and obesity in the general population. "The study also shows the
importance of working across multiple scientific disciplines—in
this case, circadian rhythm and energy metabolism," Mignot noted.
"Indeed, who would have considered Clock as a metabolic
candidate gene?"
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