Abstract 16612: Identification of Clock-modulating Small Molecules With Protective Roles against the Metabolic Syndrome
The circadian clock is our intrinsic timing system, driving a myriad of rhythmic metabolic and physiological processes. In particular, incidence of cardiovascular events such as heart attacks is known to exhibit clear daily rhythmic distribution, highlighting the importance of temporal control of cardiovascular functions. Furthermore, based on accumulating evidence from mouse and human studies, circadian dysregulation is increasingly appreciated as a risk factor for metabolic and cardiovascular diseases. However, the important question remains unanswered whether pharmacological manipulation of the clock can protect against these clock-related diseases. The objective of the current study is to identify small molecule modulators of the circadian clock and to investigate their putative protective roles against metabolic disorders, including elevated serum cholesterol levels well established as a risk factor for cardiovascular disease. To this end, we conducted high-throughput chemical screens and identified diverse classes of clock-modulating small molecules. Among the C lock amplitude-E nhancing small M olecules (CEMs), CEM5 was found to significantly improve energy metabolism and alleviate the metabolic syndrome in several mouse models (diet-induced obesity (DIO), ClockΔ19/Δ19, db/db and db/db ClockΔ19/Δ19) for metabolic and cardiovascular diseases. Interestingly, we showed that CEM5 potently reduced serum cholesterol levels in these mice. Furthermore, an analog of CEM5 inactive in circadian assays was found to be ineffective in correcting metabolic deficiencies, indicating a critical role of the circadian clock in physiological well-being. Molecular analysis revealed that CEM5 mainly potentiates the negative arm of the core clock loop, subsequently enhancing the clock and clock-controlled genes including Rev-erbs. Our study underscores the importance of maintaining a robust clock in physiological and cardiovascular health, and reveals a clock-modulating small molecule as an attractive therapeutic lead against clock-associated diseases.
- © 2013 by American Heart Association, Inc.