Body clock drug protects against metabolic syndrome in mice
Essential biological processes are managed by an internal timer or body clock. When the body clock gets out of whack, conditions such as metabolic syndrome can occur.
A research team led by biochemists at The University of Texas Health Science Center at Houston (UTHealth) conducted an investigation to see if improving the body clock would protect against metabolic syndrome and their study produced promising results in mouse models. Findings appear in the journal Cell Metabolism.
Metabolic syndrome strikes about a third of the adults in the United States and involves multiple risk factors for heart disease and other health issues. A body of research shows that people with metabolic disease often have weaker body clocks. The body clock is also called the circadian clock.
Reasoning that boosting the clock may be beneficial, Zheng “Jake” Chen, Ph.D., the study’s senior author and assistant professor of biochemistry and molecular biology at John P. and Kathrine G. McGovern Medical School at UTHealth, launched a search for a clock amplitude-enhancing small molecule.
Chen’s team screened more than 5,000 compounds before identifying a clock-enhancing compound derived from citrus peels called Nobiletin. “Citrus peels have been used in traditional cuisine and medicine for millennia. But, it is unclear how they actually work,” Chen said.
The researchers wanted to see if improving the body clock would reduce one of the hallmarks of metabolic syndrome – obesity. In their experiment, mice getting the compound lost 40 percent of their excess weight.
Chen tested Nobiletin on obese mice with and without a functional clock. The mice with the clock lost weight. Conversely, the drug had no impact on the mice without the clock. The drug works by increasing activity level and promoting energy expenditure.
Chen’s team also discovered the body clock receptor that Nobiletin binds to – retinoid acid receptor-related orphan receptors (RORs). “The Holy Grail of small molecule research is to know which protein the drug directly binds to. We now have both the drug and the protein it targets,” he said.
Chen said his research also has implications in the care of other issues associated with a weakened body clock such as aging and sleep disorders.
“The idea of manipulating the body clock to protect against the metabolic syndrome is highly imaginative. Jake has the ambition and talent to tackle this challenging line of research, and succeeded in demonstrating a potential new strategy to fight metabolic disease,” said Rodney E. Kellems, Ph.D., chair of the Department of Biochemistry and Molecular Biology at McGovern Medical School.
“Two other circadian biology laboratories in the department, those of Seung-Hee “Sally” Yoo, Ph.D., and Cheng Chi Lee, Ph.D., also made important contributions to this work, highlighting the collaborative spirit among our faculty and our research expertise in this fascinating area of biology,” he added.
Noting that diet and weight loss surgery are often recommended for the care of metabolic syndrome, Heinrich Taegtmeyer, M.D., D.Phil., professor of cardiovascular medicine at McGovern Medical School, said, “This drug amplifies the biological rhythms of metabolic genes to the extent that the animals burn more fuel and store less fuel. It revs up the metabolism with the result that there is no weight gain in spite of increased caloric intake. This is an attractive approach.”
He added, “The question now is if it works in mice, does it also work in man?”
Chen, Kellems, Lee, Taegtmeyer and Yoo are on the faculty of The University of Texas Graduate School of Biomedical Sciences at Houston.
Chen’s co-authors from UTHealth are Baokun He, Ph.D.; Kazunari Nohara, Ph.D.; Yong-Sung Park, M.S.; Zhaoyang Zhao, Ph.D.; Lee and Yoo.
Other co-authors include Noheon Park, Ph.D., and Joseph S. Takahashi, Ph.D., of the UT Southwestern Medical Center in Dallas; Bobby Guillory, Ph.D. and Jose M. Garcia, M.D., Ph.D., of Baylor College of Medicine; and Nobuya Koike, Ph.D., of the Kyoto Prefectural University of Medicine in Kyoto, Japan.
The study titled, “The small molecule Nobiletin targets the molecular oscillator to enhance circadian rhythms and protect against metabolic syndrome,” was supported in part by The Welch Foundation (AU-1731), the American Heart Association (11SDG7600045) and National Institutes of Health (R01AG045828 and R01GM114424).