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Scripps Research scientists synthesize compounds that dramatically alter circadian rhythms
JUPITER, Fla.—In a study published last month in the journal Nature, scientists at the Florida campus of the Scripps Research Institute describe their synthesis of a pair of small molecules that have the potential to alter circadian rhythms—a finding that demonstrates the potential to treat metabolic disorders like obesity, diabetes, high cholesterol and sleep disorders.
The study, "Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists," was published on March 29 in an advance, online edition of Nature, and was led by Dr. Thomas Burris, a professor in Scripps Florida's Department of Metabolism & Aging. Burris' laboratory focuses on investigating nuclear hormone receptors that are ligand-activated transcription factors which regulate a variety of physiological functions, including development, metabolism, immune function and reproduction. His group has been using chemical biology approaches to characterize the physiological roles of these receptors, as well as develop drugs targeting nuclear receptors for treatment of diseases including type 2 diabetes, heart disease, cancer and Alzheimer's disease.
In the current study, Burris and his colleagues probed the synchronizing rhythms of behavior and metabolic processes, which are important for cardiovascular health and preventing metabolic diseases. In particular, they investigated the nuclear receptors REV-ERB-a and REV-ERB-b, which have an integral role in regulating the expression of core clock proteins driving rhythms in activity and metabolism, and described the identification of potent synthetic REV-ERB agonists with in-vivo activity.
"The idea behind this research is that our circadian rhythms are coupled with metabolic processes and that can you modulate them pharmacologically," says Burris. "I think these tools allow us to really explore some of the areas that we have not looked at because we have not been able to drug the circadian rhythm well. As it turns out, the effect of that modulation is surprisingly positive—everything has been beneficial so far."
Administering their synthetic compounds in diet-induced obese mice models twice a day for 12 days, the Scripps scientists observed that the small molecules altered circadian rhythms and the pattern of core clock gene expression in the brain's hypothalamus, the site of the master cellular clock that synchronizes daily rhythms in mammals. The circadian pattern of expression of an array of metabolic genes in the liver, skeletal muscle and adipose tissue was also altered, resulting in increased energy expenditure. Treatment of diet-induced obese mice with a REV-ERB agonist decreased obesity by reducing fat mass and markedly improving dyslipidemia and hyperglycemia.
In one of the study's more striking findings, both synthetic compounds were shown to reduce cholesterol production. Cholesterol in the blood of treated animal models decreased 47 percent; triglycerides in the blood decreased 12 percent.
"Not only did they lose weight, they had improved metabolic parameters like plasma glucose, about a 50-percent decrease in total cholesterol and a significant decrease in plasma triglycerides," says Burris. "They also had a decrease in inflammatory markers, which is expected when you have a decrease in obesity."
According to the research team, these results indicate that synthetic REV-ERB ligands that pharmacologically target the circadian rhythm may be beneficial in the treatment of sleep disorders as well as metabolic diseases. Because the two compounds also affected the animals' activity during periods of light and darkness, this also suggests that this class of compound may be useful for the treatment of sleep disorders, including jet lag.
"We are still working to improve the profile of these compounds, as they need to be optimized further," Burris notes. "They do not have extremely high affinity, and their pharmacokinetic properties have not been fully optimized. We're interested in looking at a wide range of behavioral assays to see hat kind of effect they will have."
The team is already looking for a commercial partner, "because these are not the types of studies you can fund through NIH methods," says Burris.
First authors of the study included Laura A. Solt and Yongjun Wang of Scripps Research. Other authors included Subhashis Banerjee, Travis Hughes, Douglas J. Kojetin, Thomas Lundasen, Youseung Shin, Jin Liu, Michael D. Cameron, Romain Noel, Andrew A. Butler, and Theodore M. Kamenecka of Scripps Research; and Seung-Hee Yoo and Joseph S. Takahashi of the Howard Hughes Medical Institute and University of Texas Southwestern Medical Center.