Peripheral Circadian Clocks Take Center Stage In Homeostasis

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Charles Weitz found himself in an enviable position in 2002, following the discovery of functional, autonomous circadian clocks in peripheral tissue cells. The Robert Henry Pfeiffer professor of neurobiology possessed the tools to test two equally exciting, yet opposing hypotheses about the role of these pacemakers, which reside in a variety of tissues.

Researchers in the field wondered—do the clocks, which generate transcriptional rhythms, regulate the same genes everywhere to ensure that core physiological processes take place in parallel? Or do the clocks regulate genes in a tissue-specific manner, coordinating heterogeneous processes throughout the body?

“Usually, investigators hope for a particular experimental outcome,” explained Weitz. “We were so ignorant as a field, however, that either explanation for the abundance of clocks seemed appealing and informative.”

Weitz and colleagues compared the transcriptional profiles of liver and heart tissue at different times of the day and found little overlap between the two. Although circadian clocks share the same basic machinery in both tissues, they appear to direct different genes and physiological programs. But Weitz wanted to move beyond correlation.

Working with postdoctoral researchers Katja Lamia and Kai-Florian Storch, he demonstrated that the liver clocks contribute to homeostasis by triggering the release of stored glucose from hepatocytes during the resting phase in mice. The study appeared online Sept. 8 in Proceedings of the National Academy of Sciences. The new data support—and possibly extend—the leading hypothesis about the preponderance of peripheral pacemakers.

“Glucose levels need to be kept in a narrow range all the time, and we showed that the liver clocks keep mice from becoming hypoglycemic when they’re not ingesting food,” explained Weitz.

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“This study indicates that you need the liver clocks to counterbalance the brain clock,” said professor Ueli Schibler of the University of Geneva, who wrote a commentary on the paper, which will appear in the Sept. 30 issue of PNAS. The brain clock, located in the suprachiasmatic nucleus, drives our fasting–feeding cycle and thus regulates sugar ingestion.

The Weitz lab focused on the liver clock after reviewing the transcriptional profiles from the original experiment. Many of the genes involved with glucose metabolism in hepatocytes—including Glut2, G6pt1 and Gck—displayed beautiful circadian rhythms.

To rule out the possibility that these genes are slaves to the master brain clock, the team disabled Bmal1—a core component of the circadian clock—in hepatocytes alone. Bmal1 remained active in the brain clock and other peripheral clocks. The team combined a conditional Bmal1 allele with a Cre recombinase transgene under the control of an albumin promoter to achieve the hepatocyte-specific effect.

The resulting mice displayed hypoglycemia during their resting phase, as derelict hepatocytes kept stored glucose to themselves, despite a systemic need for sugar. Blood sugar levels returned to normal when the mice resumed eating during their active phase. Glut2, G6pt1 and Gck rhythms disappeared.

“This suggests that the liver clock contributes to systemic homeostasis by anticipating the glucose-level drop that accompanies fasting,” said first author Katja Lamia, who is now at the Salk Institute for Biological Studies.

The fasting–feeding cycle allows animals to anticipate when nutrients will become available, making physiologic processes more efficient. But it also poses homeostatic challenges. The liver clock overcomes one of these.

“Perhaps part of the function of peripheral clocks is to undo unwanted side effects of the fasting–feeding cycle,” said Weitz.

Schibler cautions against assuming that all peripheral clocks keep the brain clock from wreaking homeostatic havoc. He said that they seem to serve a variety of functions. “But the counterbalancing concept is original and interesting.”

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