Physiological processes including metabolism and behavior are governed in a circadian rhythm.  This 24h rhythm is maintained by a cell autonomous transcriptional/translational feedback loop composed of the transcription factors BMAL1 and CLOCK and their target genes, PER and CRY. The nuclear receptor REV-ERB also plays an important regulatory role in maintaining the circadian oscillator by direct regulation of the Bmal1 and Clock genes.  Appropriate oscillations in this molecular clock are required for normal physiological function and behavior.  In fact, abnormal clock function has been associated with a range of disorders including metabolic diseases, sleep disorders, mental disorders and cancer.  Using a chemical biology approach, we recently demonstrated that synthetic compounds that modulate the circadian expression of clock genes also alters metabolic processes.  We demonstrated that synthetic REV-ERB agonists increase the metabolic rate of mice leading to decreased fat mass.  Diet induced obese mice also display weight loss when the REV-ERB agonists is administered and, additionally, demonstrate improved plasma lipid profiles.  Here, I will describe recent results examining the effects of REV-ERB agonists in additional models of metabolic disorders as well as models of sleep and anxiety. In summary, our data indicate that drugs that modulate clock activity, REV-ERB agonists in particular, may have utility in treatment of human diseases.

Synthetic REV-ERB ligands: Tools for probing the chemical biology of the circadian clock

246th National Meeting (2013)

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