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Coordinating the circadian clock: Molecular pair controls time-keeping and fat metabolism
Date:4/6/2012

PHILADELPHIA The 24-hour internal clock controls many aspects of human behavior and physiology, including sleep, blood pressure, and metabolism. Disruption in circadian rhythms leads to increased incidence of many diseases, including metabolic disease and cancer. Each cell of the body has its own internal timing mechanism, which is controlled by proteins that keep one another in check.

One of these proteins, called Rev-erb alpha, was thought to have a subordinate role because the clock runs fairly normally in its absence. New work, published in Genes and Development this month, from the lab of Mitchell Lazar, MD, PhD, director of the Institute for Diabetes, Obesity, and Metabolism at the Perelman School of Medicine, University of Pennsylvania, found that a closely related protein called Rev-erb beta serves as a back-up for Rev-erb alpha. When both are not functioning, the cellular clock loses its time-keeping function.

The two Rev-erbs work together to control fat metabolism, and in their absence, the liver fills with fat. These findings establish the Rev-erbs as major regulators of both clock function and metabolism.

Lazar, postdoctoral fellow Anne Bugge, PhD, and the team knocked out Rev-erb alpha in mice and didn't see a large effect on the liver. When they knocked out both Rev-erb alpha and Rev-erb beta, they saw a loss of the rhythmic cycling of the clock protein Bmal 1's messenger RNA. They concluded that the Rev-erb system is an integral part of the human clock, not ancillary.

Prior to this paper, the Lazar team discovered molecules that act as "shift workers" to maintain the daily rhythm of fat metabolism. When those molecules do not do their jobs, the liver also dramatically fills with fat.

In normal mice, the team of molecules migrates to the genome of liver cells during the daytime. Rev-erb, one of the team members, delivers the molecular workers to thousands of specific locations in the liver geno
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Contact: Karen Kreeger
karen.kreeger@uphs.upenn.edu
215-349-5658
University of Pennsylvania School of Medicine
Source:Eurekalert

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