Common environmental factors within Western society, such as excess caloric intake, physical inactivity, and sleep deprivation are strongly associated with the development of modern day epidemics, including obesity, type 2 diabetes mellitus, and cardiovascular disease (CVD). In terms of diet, research efforts have focused attention primarily on the quantity and/or quality (i.e., nutritional content) of calories ingested as a means of interrogating the mechanisms responsible for diet-induced pathology. Despite the fact that humans consume the majority of their calories during discrete meals, to date animal-based studies designed to interrogate the influence of nutrition on cardiometabolic diseases have allowed rats/mice contiguous access to a single diet of distinct nutritional content. The consequence of overlooking discrepancies between human and laboratory rodent feeding behavior was recently highlighted by our laboratory;mice fed a caloric-dense high fat meal at the end of the active/awake period develop a cardiometabolic syndrome phenotype (weight gain, adiposity, glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and hyperleptinemia, compared to mice fed the same meal at the beginning of the active/awake period). This meal-feeding effect was independent of total daily quantity or quality of calories ingested. However, currently it is not known whether temporally disproportionate consumption of calories at the end of the waking period significantly influences CVD susceptibility. These observations have lead to the following broad objective of this proposal: to test the innovative hypothesis that the time-of-day at which caloric-dense meals are ingested significantly influences heart function (baseline and/or following ischemia/reperfusion), and to reveal the molecular mechanism(s) by which this occurs. In the latter case, we hypothesize that a mechanism intrinsic to the cardiomyocyte, known as the circadian clock, plays a critical role. The cardiomyocyte circadian clock not only influences myocardial metabolism and contractile function, but is also exquisitely sensitive to changes in dietary behavior. We plan to address the broad objective of this proposal through completion of the following specific aims:
Specific Aim 1 - Elucidate whether time-of-day-restricted Western diet feeding influences myocardial contractile in a cardiomyocyte circadian clock dependent manner;
and Specific Aim 2 - Determine whether time-of-day-restricted feeding rescues myocardial contractile dysfunction arising from obesity and diabetes in db/db mice. Successful completion of the proposed studies will establish whether timing of caloric intake is of comparable importance to the quantity and quality of calories ingested, in terms of heart function/disease. The concept that a dietary intervention, which is readily translatable to humans, can improve heart function independent of caloric quantity or quality is unprecedented. Such findings could significantly re-shape human nutritional guidelines to include information on the appropriate time-of-day at which calorie-dense meals are consumed.

Public Health Relevance

Diet strongly influences the development of obesity, type 2 diabetes mellitus, and cardiovascular disease in humans. Studies to date have mainly focused on the quantity and quality (i.e. nutritional content) of calories consumed, as opposed to the time of day at which meals are eaten. The current proposal outlines studies designed to investigate whether the time of day at which caloric-dense meals are eaten significantly influences heart function.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory/Developmental Grants (R21)
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Myocardial Ischemia and Metabolism Study Section (MIM)
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Ershow, Abby
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University of Alabama Birmingham
Internal Medicine/Medicine
Schools of Medicine
United States
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Young, Martin E (2016) Temporal partitioning of cardiac metabolism by the cardiomyocyte circadian clock. Exp Physiol 101:1035-9
Peliciari-Garcia, Rodrigo A; Goel, Mehak; Aristorenas, Jonathan A et al. (2016) Altered myocardial metabolic adaptation to increased fatty acid availability in cardiomyocyte-specific CLOCK mutant mice. Biochim Biophys Acta 1860:1579-95
McGinnis, Graham R; Young, Martin E (2016) Circadian regulation of metabolic homeostasis: causes and consequences. Nat Sci Sleep 8:163-80
Martino, Tami A; Young, Martin E (2015) Influence of the cardiomyocyte circadian clock on cardiac physiology and pathophysiology. J Biol Rhythms 30:183-205
Bailey, Shannon M; Udoh, Uduak S; Young, Martin E (2014) Circadian regulation of metabolism. J Endocrinol 222:R75-96
Young, Martin E; Brewer, Rachel A; Peliciari-Garcia, Rodrigo A et al. (2014) Cardiomyocyte-specific BMAL1 plays critical roles in metabolism, signaling, and maintenance of contractile function of the heart. J Biol Rhythms 29:257-76
Gamble, Karen L; Berry, Ryan; Frank, Stuart J et al. (2014) Circadian clock control of endocrine factors. Nat Rev Endocrinol 10:466-75
Tsai, Ju-Yun; Villegas-Montoya, Carolina; Boland, Brandon B et al. (2013) Influence of dark phase restricted high fat feeding on myocardial adaptation in mice. J Mol Cell Cardiol 55:147-55
Bray, M S; Ratcliffe, W F; Grenett, M H et al. (2013) Quantitative analysis of light-phase restricted feeding reveals metabolic dyssynchrony in mice. Int J Obes (Lond) 37:843-52
Chatham, John C; Young, Martin E (2013) Regulation of myocardial metabolism by the cardiomyocyte circadian clock. J Mol Cell Cardiol 55:139-46

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