Scripps Research scientists synthesize compounds that dramatically alter circadian rhythms

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

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JUPITER, Fla.—In a study published last month in the journalNature, scientists at the Floridacampus of the Scripps Research Institute describe their synthesis of a pair ofsmall molecules that have the potential to alter circadian rhythms—a findingthat demonstrates the potential to treat metabolic disorders like obesity,diabetes, high cholesterol and sleep disorders.
The study, "Regulation of circadian behaviour and metabolismby synthetic REV-ERB agonists," was published on March 29 in an advance, onlineedition 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 thatare ligand-activated transcription factors which regulate a variety ofphysiological functions, including development, metabolism, immune function andreproduction. His group has been using chemical biology approaches tocharacterize the physiological roles of these receptors, as well as developdrugs targeting nuclear receptors for treatment of diseases including type 2diabetes, heart disease, cancer and Alzheimer's disease.
In the current study, Burris and his colleagues probed thesynchronizing rhythms of behavior and metabolic processes, which are importantfor cardiovascular health and preventing metabolic diseases. In particular,they investigated the nuclear receptors REV-ERB-a and REV-ERB-b, which have anintegral role in regulating the expression of core clock proteins drivingrhythms in activity and metabolism, and described the identification of potentsynthetic REV-ERB agonists with in-vivoactivity.
"The idea behind this research is that our circadian rhythmsare coupled with metabolic processes and that can you modulate thempharmacologically," says Burris. "I think these tools allow us to reallyexplore some of the areas that we have not looked at because we have not beenable to drug the circadian rhythm well. As it turns out, the effect of thatmodulation is surprisingly positive—everything has been beneficial so far."
Administering their synthetic compounds in diet-inducedobese mice models twice a day for 12 days, the Scripps scientists observed thatthe small molecules altered circadian rhythms and the pattern of core clockgene expression in the brain's hypothalamus, the site of the master cellularclock that synchronizes daily rhythms in mammals. The circadian pattern ofexpression of an array of metabolic genes in the liver, skeletal muscle andadipose tissue was also altered, resulting in increased energy expenditure.Treatment of diet-induced obese mice with a REV-ERB agonist decreased obesityby reducing fat mass and markedly improving dyslipidemia and hyperglycemia.
In one of the study's more striking findings, both syntheticcompounds were shown to reduce cholesterol production. Cholesterol in the bloodof treated animal models decreased 47 percent; triglycerides in the blood decreased12 percent.
"Not only did they lose weight, they had improved metabolicparameters like plasma glucose, about a 50-percent decrease in totalcholesterol and a significant decrease in plasma triglycerides," says Burris."They also had a decrease in inflammatory markers, which is expected when youhave a decrease in obesity."
According to the research team, these results indicate thatsynthetic REV-ERB ligands that pharmacologically target the circadian rhythmmay be beneficial in the treatment of sleep disorders as well as metabolicdiseases. Because the two compounds also affected the animals' activity duringperiods of light and darkness, this also suggests that this class of compoundmay be useful for the treatment of sleep disorders, including jet lag.
"We are still working to improve the profile of thesecompounds, as they need to be optimized further," Burris notes. "They do nothave extremely high affinity, and their pharmacokinetic properties have notbeen fully optimized. We're interested in looking at a wide range of behavioralassays to see hat kind of effect they will have."
The team is already looking for a commercial partner, "becausethese are not the types of studies you can fund through NIH methods," saysBurris.
First authors of the study included Laura A. Solt andYongjun 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 ofScripps Research; and Seung-Hee Yoo and Joseph S. Takahashi of the HowardHughes Medical Institute and University of Texas Southwestern Medical Center.

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