Abstract 15771: Genetic and Pharmacological Regulation of Circadian Energy Metabolism
The circadian clock governs essential metabolic and physiological processes. For example, the sharp rise of blood pressure in the morning coincides with peak incidence rate for cardiovascular episodes such as heart attacks. The objective of the current studies is to elucidate novel mechanisms of genetic and pharmacological regulation of circadian clock and clock-related energy metabolism important for cardiovascular health. On the one hand, we investigated the functional mechanism of the Clockdelta19 mutation. Homozygous mutant mice (Clk/Clk) for this mutation have been shown to exhibit a wide spectrum of metabolic and cardiovascular disorders, correlated with a severe circadian misalignment or loss of rhythmicity in these mice. In comparison, Clockdelta19/+ heterozygous (Clk/+) mice showed sustained circadian rhythms, yet with significantly lengthened periodicity and dampened amplitude. We showed that Clk/+ mice exhibited improved glycemic control and resistance to circadian behavioral period lengthening under high-fat diet (HFD). Molecular analysis revealed that BMAL1 protein levels in Clk/+ mouse liver were upregulated compared with wild-type (WT) mice under HFD conditions. Mechanistic studies further demonstrated that CLOCKdelta19 stabilized BMAL1 proteins. Consistent with an important role of BMAL1 in glycemic control, enhanced activation of insulin signaling was observed in Clk/+ mice relative to WT. This study reveals an unforeseen plasticity of the circadian and metabolic networks, providing important insight into potential therapeutic intervention of clocks under disease conditions. On the other hand, we also identified small molecule modulators of the circadian clock. These small molecules, termed Clock amplitude-Enhancing small Molecules (CEMs), were able to enhance circadian amplitude of reporter rhythms in cardiomyocyte cells in vitro and improve energy expenditure and reduce cholesterol levels in vivo in a clock-dependent manner. Our studies together elucidate novel regulatory mechanisms for the circadian clock, and suggest novel therapeutic targets and drug candidates against clock-associated metabolic and cardiovascular diseases.
Author Disclosures: K. Jeong: None. B. He: None. S. Yoo: None. Z. Chen: None.
- © 2015 by American Heart Association, Inc.