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Environmental Factor, August 2012

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Mediating the body’s clock and metabolism

By Robin Arnette

Anton Jetten, Ph.D.

Jetten explained the importance of RORs by saying, “Your physiology and metabolism are very different when you sleep than during the day or after you eat. The body constantly adjusts, and the central clock regulates this adjustment. RORs play a major role in everyday human life.” (Photo courtesy of Steve McCaw)

Yukimasa Takeda, Ph.D.

Takeda is first author on the paper and sacrificed much of his own sleep generating this data. (Photo courtesy of Steve McCaw)

Raja Jothi, Ph.D.

Jothi said that most of the data produced by ChIP-Seq weren’t included in this paper, but he and Jetten are working on another manuscript that will examine the new genes they found. (Photo courtesy of Steve McCaw)

Over the past several years, researchers have discovered that disturbances to a person’s natural 24-hour wake-sleep cycle impact the body’s metabolism, and increase the risk of developing some cancers, diabetes, and obesity. Scientists have also found evidence that several nuclear receptors play a role in this control. Now, an NIEHS study provides more details on how everything fits together.

According to Anton Jetten, Ph.D., head of the NIEHS Laboratory of Respiratory Biology, obesity is an important risk factor for developing insulin resistance and type 2 diabetes. His team found that mice, which lack the genes for retinoic acid-related orphan receptor (ROR) alpha or ROR gamma, remain sensitive to insulin and are much less susceptible to type 2 diabetes.

The work also demonstrated that ROR receptors are involved in this association, by regulating clock and metabolic genes in 24-hour intervals. Part of this research appeared online June 29 in Nucleic Acids Research and reveals, for the first time, that ROR gamma, rather than ROR alpha, is the primary mediator between the body’s clock and its regulation of metabolic genes.

Jetten and others have shown that RORs are not only targets for environmental chemicals and hormones, but also regulate an organism’s circadian rhythms, or the physiological changes that occur in response to light and darkness. He said these interactions are complex, but easy to understand if a person imagines himself or herself as ROR gamma. “When the alarm clock at home goes off in the morning, it tells you ROR gamma — to wake up and become active,” Jetten explained. “As you start doing things around the house, like taking a shower or getting food out of the refrigerator, these actions are like the metabolic genes that ROR gamma acts upon.”

RORs are key to the connection

Japanese Society for the Promotion of Science Research Fellow in Biomedical and Behavioral Research at NIH Yukimasa Takeda, Ph.D., joined Jetten’s group, because he was interested in this interplay. He used knockout mice — ROR alpha, ROR gamma, and double knockouts — to tease out the association. To measure the mice’s circadian rhythms, Takeda collected tissue from several mice every 4-6 hours, and then analyzed changes in gene expression over a 24-hour period.

“Using microarray analysis, we were able to identify a number of metabolic genes, but we didn’t know whether they were direct or indirect targets of RORs,” Takeda said.

That’s when Jetten turned to ChIP-Seq, a powerful high-throughput method to map protein-DNA binding sites on a genome-wide scale. He submitted samples from the two knockout mice and generated an enormous amount of genomic data. At this point, Jetten needed the bioinformatics expertise of NIEHS colleague Raja Jothi, Ph.D., who accepted the challenge of analyzing the information.

After the analysis was complete, ChIP-Seq determined that ROR gamma bound to the regulatory region of several clock and metabolic genes, while ROR alpha either displayed much weaker binding or no binding at all. The results confirmed that these clock and metabolic genes were directly regulated by RORs, and that ROR gamma was more important in this regulation than ROR alpha. Prior to this work, many in the nuclear receptor community believed that ROR alpha was more important.

Jetten said, although he and his team know that disturbances in the circadian clock can promote obesity and diabetes, and that loss of ROR gamma can inhibit this susceptibility, understanding the exact mechanism of how ROR gamma does its job needs further study.

“For a scientist,” Jetten continued, “that’s what drives you — finding out how things work.”

Citation: Takeda Y, Jothi R, Birault V, Jetten AM. 2012. ROR gamma directly regulates the circadian expression of clock genes and downstream targets in vivo. Nucleic Acids Res; doi:10.1093/nar/gks630 [Online 29 June 2012].

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