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Biochim Biophys Acta. 2016 Oct;1861(10):1579-95. doi: 10.1016/j.bbalip.2015.12.012. Epub 2015 Dec 22.

Altered myocardial metabolic adaptation to increased fatty acid availability in cardiomyocyte-specific CLOCK mutant mice.

Author information

1
Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; Institute of Biomedical Sciences-I, Department of Physiology and Biophysics, University of Sao Paulo, Sao Paulo, SP, Brazil; Department of Biological Sciences, Federal University of Sao Paulo, Diadema, SP, Brazil.
2
Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
3
Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, USA.
4
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
5
Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
6
Division of Behavioral Neurobiology, Department of Psychiatry, University of Alabama at Birmingham, Birmingham, AL, USA.
7
Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: meyoung@uab.edu.

Abstract

A mismatch between fatty acid availability and utilization leads to cellular/organ dysfunction during cardiometabolic disease states (e.g., obesity, diabetes mellitus). This can precipitate cardiac dysfunction. The heart adapts to increased fatty acid availability at transcriptional, translational, post-translational and metabolic levels, thereby attenuating cardiomyopathy development. We have previously reported that the cardiomyocyte circadian clock regulates transcriptional responsiveness of the heart to acute increases in fatty acid availability (e.g., short-term fasting). The purpose of the present study was to investigate whether the cardiomyocyte circadian clock plays a role in adaptation of the heart to chronic elevations in fatty acid availability. Fatty acid availability was increased in cardiomyocyte-specific CLOCK mutant (CCM) and wild-type (WT) littermate mice for 9weeks in time-of-day-independent (streptozotocin (STZ) induced diabetes) and dependent (high fat diet meal feeding) manners. Indices of myocardial metabolic adaptation (e.g., substrate reliance perturbations) to STZ-induced diabetes and high fat meal feeding were found to be dependent on genotype. Various transcriptional and post-translational mechanisms were investigated, revealing that Cte1 mRNA induction in the heart during STZ-induced diabetes is attenuated in CCM hearts. At the functional level, time-of-day-dependent high fat meal feeding tended to influence cardiac function to a greater extent in WT versus CCM mice. Collectively, these data suggest that CLOCK (a circadian clock component) is important for metabolic adaption of the heart to prolonged elevations in fatty acid availability. This article is part of a Special Issue entitled: Heart Lipid Metabolism edited by G.D. Lopaschuk.

KEYWORDS:

Chronobiology; Contractile function; Diabetes; Gene expression; Metabolism; Nutrition

PMID:
26721420
PMCID:
PMC4917492
DOI:
10.1016/j.bbalip.2015.12.012
[Indexed for MEDLINE]
Free PMC Article

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