Time-Restricted Eating to Prevent and Manage Chronic Metabolic Diseases

Abstract

Molecular clocks are present in almost every cell to anticipate daily recurring and predictable changes, such as rhythmic nutrient availability, and to adapt cellular functions accordingly. At the same time, nutrient-sensing pathways can respond to acute nutrient imbalance and modulate and orient metabolism so cells can adapt optimally to a declining or increasing availability of nutrients. Organismal circadian rhythms are coordinated by behavioral rhythms such as activity-rest and feeding-fasting cycles to temporally orchestrate a sequence of physiological processes to optimize metabolism. Basic research in circadian rhythms has largely focused on the functioning of the self-sustaining molecular circadian oscillator, while research in nutrition science has yielded insights into physiological responses to caloric deprivation or to specific macronutrients. Integration of these two fields into actionable new concepts in the timing of food intake has led to the emerging practice of time-restricted eating. In this paradigm, daily caloric intake is restricted to a consistent window of 8-12 h. This paradigm has pervasive benefits on multiple organ systems.

Keywords: circadian rhythms; metabolic disease; time-restricted eating; time-restricted feeding.

Figure 1

The extensive roles of the circadian clock in regulating nutritional and energetic balance, from behavior to molecules. The master clock controls daily rhythms in activity–rest and associated feeding–fasting behaviors. Accordingly, metabolic functions oscillate between nutrient digestion and energy storage during satiety and between nutrient excretion and energy mobilization during hunger. This nutritional and energetic equilibrium engages multiple organs to ensure balanced digestion and excretion (for example, the salivary glands, pancreas, digestive tract, microbiome, liver) and balanced energy storage and utilization (for example, the liver, muscle, adipose tissue). The secretion of digestive enzymes and hormones, as well as gut peristalsis also vary during the day. At the molecular level, metabolic rhythms are associated with daily oscillations in the activity of gene networks, protein expression, posttranslational modifications, the level of metabolites, and redox state. The master clock and peripheral clocks play critical roles in the daily temporal coordination of these processes.

Figure 2

From molecular circadian oscillations to daily rhythms in metabolic regulators. (a) Representation of the core cell-autonomous circadian transcriptional–translational feedback loop. Activators are depicted in blues and repressors in red. (b) Schematic of the daily peak of clock components (messenger RNA expression), liver metabolic regulators (pathway activity), and hormones (serum level) both in diurnal primates and humans and nocturnal mice and rats. Abbreviations: AKT, protein kinase B; AMPK, adenosine monophosphate–activated protein kinase; CREB, cyclic adenosine monophosphate response element binding protein; Ccg: clock-controlled genes; mTOR, mammalian target of rapamycin; SREBP, sterol regulatory element binding protein.

Figure 3

Pervasive benefits of time-restricted feeding. Chronic circadian rhythm disruption is a risk factor for metabolic diseases. Studies in animal models (flies, mice, rats) and emerging studies in humans show that time-restricted feeding protects metabolic tissues from metabolic disturbances. Time-restricted feeding may also benefit brain health and could delay the development of neurodegenerative diseases. Abbreviations: ETC, electron transport chain; ROS, reactive oxygen species; UCP, uncoupling protein.