Circadian Rhythms Strongly Influence Key Metabolic Pathways

The findings also led to the world’s first comprehensive liver metabolite map.

Of the more than 600 liver-originated metabolites identified in the study, approximately 60% were found to be dependent on the endogenous circadian clock--many more than expected, as only about 15 % of the body’s known genes have been shown to be regulated by it.

This 24-hour biologic clock governs fundamental cellular processes and adapts certain bodily functions to the appropriate time of day. Disruption of these cycles can seriously affect human health. Dr. Paolo Sassone-Corsi, lead author of the study and director of the Center for Epigenetics & Metabolism at the University of California, Irvine (UCI; USA), reported that this investigation liver metabolites revealed how the clock--through the main circadian gene, CLOCK--orchestrates the interplay between metabolites and signaling proteins.

Since external cues, such as day-night lighting patterns and nutrition, influence the circadian machinery, metabolites and their relationship to signaling proteins seem to be acutely tied to circadian disruption and may be associated with primary factors underlying metabolic-based diseases like diabetes. “This interplay has far-reaching implications for human illness and aging, and it is likely vital for proper metabolism,” said Dr. Sassone-Corsi.

Working with scientists from Metabolon, Inc. (Durham, NC, USA; www.metabolon.com), Sassone-Corsi and Kristin Eckel-Mahan, a UCI postdoctoral researcher and study coauthor, created the first liver metabolome--a dataset of liver metabolites. With this information, they also partnered with Dr. Pierre Baldi, director of UCI’s Institute for Genomics & Bioinformatics, and his graduate student Vishal Patel to analyze the data and build CircadiOmics, a Web-based data system that provides detailed profiles of metabolites and related genes, and the underlying networks through which they interact. “Within CircadiOmics, we were able to integrate this circadian metabolite data with multiple other data sources to generate the first comprehensive map of the liver metabolome and its circadian oscillations, and to develop regulatory hypotheses that have been confirmed in the laboratory,” said Dr. Baldi.

The integrated map illustrates how the circadian metabolome, transcriptome, and proteome are connected through specific nodes that operate in concert to achieve metabolic homeostasis. “CircadiOmics is being expanded with metabolic data about other tissues and conditions, and will be invaluable to further our understanding of the interplay between metabolism and circadian rhythms in healthy and diseased states,” Dr. Baldi added.

The study appeared in the March, 2012, early online edition of the Proceedings of the [U.S.] National Academy of Sciences USA.

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University of California at Irvine

Metabolon