Molecular basis of circadian rhythms disruptions linked cardiometabolic disorders and their mitigation using dietary intervention

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Project Summary: Genetic and lifestyle perturbation of the circadian clock trigger cardiovascular diseases. The proposed study will examine how aging, obesity and circadian rhythm disruptions linked with cardiometabolic disorders, and how time-restricted feeding (TRF) mitigates these defects. The leading risk factors for cardiometabolic diseases are age, shift work, energy dense diet and aberrant eating/sleeping patterns. Each of these factors disrupts circadian rhythms, and it has been shown in model organisms that genetic perturbation of the circadian clock increases the incidence and severity of cardiac diseases. For example, an aberrant eating pattern in human, increases the risk of developing cardiovascular diseases by as much as 55%, after controlling for diet and lifestyle, possibly by disruption of circadian clock. Also, mutations of circadian clock genes prone to cardiac diseases and light-induced circadian disruptions further deteriorates cardiac abnormalities. Conversely, TRF paradigm without reducing caloric intake has been shown to prevent various metabolic disorders and attenuates age-linked cardiac dysfunction. However, pathogenic linkage of circadian clock disruptions with cardiometabolic diseases, or the potential benefit of TRF intervention has not been assessed at the molecular or genetic level. Thus, our scientific premise is that factors that affect circadian rhythms offer new avenues to understand the etiology and attenuation of cardiometabolic disorders. To address the mechanistic basis of this alarming public health issue, we have developed novel Drosophila melanogaster (fruit fly) models to mitigate age, obesity and circadian disruption-induced cardiac disorders by imposing feeding/fasting rhythms with TRF. Drosophila will serve as an excellent model system for basic discoveries in circadian rhythms, energy metabolism and cardiac muscle physiology. Aim 1 of the proposed study is to determine the molecular basis of the effectiveness of TRF in delaying age-, obesogenic challenges, and circadian disruption-induced deterioration of cardiac physiology in Drosophila. Aim 2’s goals are to monitor the effect of dietary intervention on the diurnal and long-term reprogramming of cardiac gene expression under aging, obesogenic challenges and circadian rhythms disruption. Aim 3 will employ genetic validation of circadian clock with other identified genes/pathways mediating the effect of eating pattern on cardiac health. Our study will use hypothesis-driven experiments to address the molecular basis of the alarming public health problem of age and obesity-induced cardiac dysfunction associated with circadian dysregulation. Successful completion of this proposal will dramatically accelerate our understanding of the impact of daily rhythms on cardiac muscle physiology. The TRF paradigm may prove applicable to human health through application of community-based approaches to ameliorating obesity-induced comorbidities and thereby improving cardiovascular and metabolic health.