Clock Molecules Shed Light on Bipolar Disorder

Clocks play an important role,
even in our body; © Hemera

“We’re interested in the internal control of metabolism because feeding behaviour 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 University of Pennsylvania.

Rev-erb 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.”; Source: University of Pennsylvania