Time-of-Day-Dependent Feeding Influences Myocardial Function

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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.