(Philadelphia, PA) - Researchers at the University
of Pennsylvania School of Medicine discovered that a key
receptor protein is a critical component of the internal molecular
clock in mammals. What’s more, this molecule - called Rev-erb
- is sensitive to lithium and may help shed light on circadian rhythm
disorders, including bipolar disorder. The findings, which also
provide insight into clock-controlled aspects of metabolism, are
reported in this week’s issue of Science.
“We’re interested in the internal control of metabolism
because feeding behavior is on a daily cycle, and hormonal activities
that regulate this are circadian,” says senior author Mitch
Lazar, MD, PhD, Director of the Institute for Diabetes,
Obesity, and Metabolism at Penn. “Many studies, including
those here at Penn, suggest a relationship between the human circadian
clock and metabolism. Proteins are the gears of the clock, and not
much is known about what regulates protein levels within the cell.”
was known to be a key component of the clock that exists in most
cells of the body. Rev-erb inhibits clock genes called bmal
and clock, but within a normal 24-hour circadian cycle
the Rev-erb protein is destroyed within the cell, allowing bmal
and other clock proteins to increase. Among other actions, these
clock genes cause Rev-erb to increase, which again inhibits bmal
and clock. “The time it takes for that to happen
determines the length of the cycle-roughly 24 hours-and keeps the
clock going,” explains Lazar.
Penn colleague and coauthor Peter Klein, MD, PhD,
Assistant Professor of Medicine, discovered a few years ago that
the drug lithium, used to treat biopolar illness, inhibits GSK3,
an enzyme known to regulate circadian rhythm in several animal species.
In the present study, the researchers showed that the destruction
of Rev-erb, a receptor shown previously by Lazar and others to play
a role in maintaining normal metabolism, is prevented by GSK3 in
mouse and human cells. “It’s like pulling a pin out
of the gears of the clock, to allow them to turn in a synchronized
manner,” says Lazar.
Lithium blocks this action of GSK3, tagging Rev-erb for destruction,
which leads to activation of clock genes such as bmal1.
“We suggest that just as our cells in the incubator need to
have their internal clocks reset, maybe this is what happens in
some people with circadian disorders,” says Lazar. “One
effect of lithium may be to reset clocks that become stuck when
Rev-erb levels build up.”
These results point to Rev-erb as a lithium-sensitive component
of the human clock and therefore a possible target for developing
new circadian-disorder drugs. Some patients taking lithium have
developed kidney toxicity and other problems. Lazar surmises that
new treatments that lead to the destruction of Rev-erb would have
the potential of providing another point of entry into the circadian
Noting that Rev-erb is present in metabolically active tissues,
Lazar and his team at the Institute for Diabetes, Obesity, and Metabolism
are also interested in the relationship between the control of the
circadian clock and metabolic diseases such as obesity and diabetes.
“There is a dynamic interplay between circadian rhythms and
metabolism,” Lazar says. “You don't eat while you are
sleeping, and the body needs to take this into account.”
Study co-authors are Lei Yin and Jing Wang, both from Penn. The
research was funded by the National Institute of Diabetes &
Digestive & Kidney Diseases and the National Institute of Mental
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