Diurnal rhythm in nutrient metabolism for metabolic homeostasis

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Abstract Disruption in metabolic homeostasis is increasingly recognized as the root cause of obesity, insulin resistance, nonalcoholic steatohepatitis, hyperlipidemia, and cardiovascular diseases. Current efforts on prevention and therapies are focused on key components that mediate nutrient utilization, interconversion and storage. However, metabolic diseases are complex in nature with disruption in multiple pathways, often requiring progressively more complex combination therapies. Novel intervention that is effective both as a preventative method and to augment therapy is urgently needed. The circadian regulation of metabolism and physiology offer a novel promising avenue for the prevention and the treatment of these diseases. There is growing evidence that disruption of natural circadian rhythm in sleep and nutrition as occurs in people doing shiftwork is associated with increased incidence of metabolic diseases in humans. Furthermore, even among the general population, the daily rhythm of sleep and nutrition is significantly disrupted. Therefore, behavioral changes that sustain robust circadian function are considered to be beneficial against challenges that predispose to metabolic diseases. Time-restricted feeding (TRF), in which animals are fed within an 8-12 hour time interval during their natural circadian wakeful hours is both preventative and therapeutic against metabolic diseases in both mice and insects. There is growing precedence that the time of food intake has a profound impact on body weight regulation in humans. While these preliminary findings are encouraging, major questions remain to be answered before any potential human translation. Is TRF beneficial under a shiftwork paradigm that chronically disrupts circadian rhythm? And what are the potential mechanisms underlying TRF benefits? This proposal will test these questions in mice that are effectively used to model circadian rhythm disruption and metabolic diseases.