Time-restricted feeding for prevention and treatment of cardiometabolic disorders

Abstract

The soaring prevalence of obesity and diabetes is associated with an increase in comorbidities, including elevated risk for cardiovascular diseases (CVDs). CVDs continue to be among the leading causes of death and disability in the United States. While increased nutritional intake from an energy-dense diet is known to disrupt metabolic homeostasis and contributes to the disease risk, circadian rhythm disruption is emerging as a new risk factor for CVD. Circadian rhythms coordinate cardiovascular health via temporal control of organismal metabolism and physiology. Thus, interventions that improve circadian rhythms are prospective entry points to mitigate cardiometabolic disease risk. Although light is a strong modulator of the neural circadian clock, time of food intake is emerging as a dominant agent that affects circadian clocks in metabolic organs. We discovered that imposing a time-restricted feeding (TRF) regimen in which all caloric intakes occur consistently within ≤ 12 h every day exerts many cardiometabolic benefits. TRF prevents excessive body weight gain, improves sleep, and attenuates age- and diet-induced deterioration in cardiac performance. Using an integrative approach that combines Drosophila melanogaster (fruit fly) genetics with transcriptome analyses it was found that the beneficial effects of TRF are mediated by circadian clock, ATP-dependent TCP/TRiC/CCT chaperonin and mitochondrial electron transport chain components. Parallel studies in rodents have shown TRF reduces metabolic disease risks by maintaining metabolic homeostasis. As modern humans continue to live under extended periods of wakefulness and ingestion events, daily eating pattern offers a new potential target for lifestyle intervention to reduce CVD risk.

Keywords: TCP-1 ring complex chaperonin; cardiac physiology; cardiometabolic disorders; circadian rhythm; metabolic regulation; mitochondrial electron transport chain; time restricted feeding.

Figure 1. Relationship among potential pathways linked with TRF‐induced cardiac benefits and their impact in ameliorating cardiometabolic disorders

A, as reported before (Gill et al. 2015), flies are maintained on a 12:12 h light–dark cycle. The TRF flies have access to food for 12 h whereas ALF flies have access to food for 24 h. B, cardiac parameters were calculated from mechanical (M)‐mode traces (showing the movement of the heart tube edge (y‐axis) over time (x‐axis)). Age‐associated alterations of cardiac parameters shown with upward and downward arrows. C, TRF down‐regulates expression of mitochondrial ETC components in Drosophila hearts and cardiac‐specific knock‐down of ETC genes CG5389 (Mitochondrial ATP synthase), CG9762 (NADH dehydrogenase) and CG18809 (spliceosome‐associated protein‐18) delays age‐associated cardiac defects. D, up‐regulation of cytoplasmic chaperonin (TCP/TRiC/CCT) was cardiac specific under TRF and mutation of TCP/TRiC/CCT eliminated the TRF benefit. E, mutation of circadian cock genes (Clk, Cyc, Per and Tim) eliminated the TRF benefit. Therefore, circadian genes are required for cardioprotection under TRF. Synchrony between feeding–fasting and light–dark cycles synergistically optimize metabolism by driving anabolic and catabolic processes at appropriate times of the day, which in turn lessens ROS and sustains cytoarchitecture (Gill et al. 2015).