Direct regulation of myocardial triglyceride metabolism by the cardiomyocyte circadian clock

Authors: TSAI, JU-YUN - Children'S Nutrition Research Center (CNRC); KIENESBERGER, PETRA - University Of Alberta; PULINILKUNNIL, THOMAS - University Of Alberta; SAILORS, MARY - Children'S Nutrition Research Center (CNRC); DURGAN, DAVID - University Of Alabama; VILLEGAS-MONTOYA, CAROLINA - Children'S Nutrition Research Center (CNRC); JAHOOR, ANIL - Children'S Nutrition Research Center (CNRC); GONZALEZ, RAQUEL - Children'S Nutrition Research Center (CNRC); GARVEY, MERISSA - Children'S Nutrition Research Center (CNRC); BOLAND, BRANDON - Children'S Nutrition Research Center (CNRC); BLASIER, ZACHARY - Children'S Nutrition Research Center (CNRC); MCELFRESH, TRACY - Case Western Reserve University (CWRU); NANNEGARI, VIJAYALAKSHMI - Children'S Nutrition Research Center (CNRC); CHOW, CHI-WING - Albert Einstein College Of Medicine; HEIRD, WILLIAM - Children'S Nutrition Research Center (CNRC); CHANDLER, MARGARET - Case Western Reserve University (CWRU); DYCK, JASON - University Of Alberta; BRAY, MOLLY - University Of Alabama; YOUNG, MARTIN - University Of Alabama

Submitted to: Journal of Biological Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/20/2009
Publication Date: 1/29/2010
Citation: Tsai, J., Kienesberger, P.C., Pulinilkunnil, T., Sailors, M.H., Durgan, D.J., Villegas-Montoya, C., Jahoor, A., Gonzalez, R., Garvey, M.E., Boland, B., Blasier, Z., Mcelfresh, T.A., Nannegari, V., Chow, C., Heird, W.C., Chandler, M.P., Dyck, J.R., Bray, M.S., Young, M.E. 2010. Direct regulation of myocardial triglyceride metabolism by the cardiomyocyte circadian clock. Journal of Biological Chemistry. 285(5):2918-2929.

Interpretive Summary: Despite a growing appreciation of the integral relation between circadian clocks and metabolism, little is known about the direct influence of a peripheral clock on cellular responses to fatty acids. To address this important issue, we utilized a genetic model of disrupted clock function in heart cells (CCM). Those with disrupted clock function, had altered myocardial (heart tissue) response to chronic high fat feeding as well as metabolic fluxes, suggesting the CCM clock regulates myocardial triglyceride metabolism. Analysis of key proteins influencing triglyceride turnover, suggest that the CCM clock inactivates hormone-sensitive lipase during the active/awake phase both at the transcriptional and post-transcriptional levels. Consistent with increased net triglyceride synthesis, high fat feeding toward the end of the active/awake phase resulted in marked cardiac steatosis. This data provides evidence for direct regulation of triglyceride turnover, by a peripheral clock and reveal a potential explanation for metabolic pathologies after circadian misalignment (e.g., crossing time zones).

Technical Abstract: Maintenance of circadian alignment between an organism and its environment is essential to ensure metabolic homeostasis. Synchrony is achieved by cell autonomous circadian clocks. Despite a growing appreciation of the integral relation between clocks and metabolism, little is known regarding the direct influence of a peripheral clock on cellular responses to fatty acids. To address this important issue, we utilized a genetic model of disrupted clock function specifically in cardiomyocytes in vivo (termed cardiomyocyte clock mutant (CCM)). CCM mice exhibited altered myocardial response to chronic high fat feeding at the levels of the transcriptome and lipidome, as well as metabolic fluxes, providing evidence that the cardiomyocyte clock regulates myocardial triglyceride metabolism. Time-of-day-dependent oscillations in myocardial triglyceride levels, net triglyceride synthesis, and lipolysis were markedly attenuated in CCM hearts. Analysis of key proteins influencing triglyceride turnover, suggest that the cardiomyocyte clock inactivates hormone-sensitive lipase during the active/awake phase both at transcriptional and post-translational (via AMP-activated protein kinase) levels. Consistent with increased net triglyceride synthesis during the end of the active/awake phase, high fat feeding at this time resulted in marked cardiac steatosis. This data provides evidence for direct regulation of triglyceride turnover by a peripheral clock and reveal a potential mechanistic explanation for accelerated metabolic pathologies after prevalent circadian misalignment in Western society.