Time-Restricted Eating: Benefits, Mechanisms, and Challenges in Translation

Abstract

Eating out of phase with daily circadian rhythms induces metabolic desynchrony in peripheral metabolic organs and may increase chronic disease risk. Timerestricted eating (TRE) is a dietary approach that consolidates all calorie intake to 6-to 10-h periods during the active phase of the day, without necessarily altering diet quality and quantity. TRE reduces body weight, improves glucose tolerance, protects from hepatosteatosis, increases metabolic flexibility, reduces atherogenic lipids and blood pressure, and improves gut function and cardiometabolic health in preclinical studies. This review discusses the importance of meal timing on the circadian system, the metabolic health benefits of TRE in preclinical models and humans, the possible mechanisms of action, the challenges we face in implementing TRE in humans, and the possible consequences of delaying initiation of TRE. REGULATION OF CENTRAL AND PERIPHERAL CLOCK MACHINERYCircadian rhythms are ubiquitous periodic oscillations in internal biological process that direct behavior and metabolism such as hormonal signaling, body temperature, nutrient absorption, and metabolism (Dongen 2017;Espelund et al., 2005;Panda et al., 2002;Reppert and Weaver, 2002). At the molecular level, circadian rhythms arise from tightly controlled autonomous interlocked genetic transcriptional feedback loop that involves circadian locomotor output cycles kaput (clock) and brain and muscle ARNT like protein 1 (bmal1) as positive transcriptional factors for period (per1, per2, per3) and cryptochrome (cry1, cry2) genes (extensively reviewed in Hastings et al., 2018). The translation products of per and cry dimerize and act as negative regulators by inhibiting clock and bmal1. An additional feedback loop involves the transcriptional regulation of bmal1 by retinoic acid related orphan receptor (rora) and nuclear receptor subfamily 1, group D, member 1(rev-erba). One cycle of this feedback loop takes ~24 h and is the basis of circadian rhythms in many organisms. The suprachiasmatic nucleus (SCN) is considered the master regulator of circadian rhythms and is primarily entrained by the light-dark cycle. This feedback loop also operates in

Effect of time restricted eating on body weight and fasting glucose in participants with obesity: results of a randomized, controlled, virtual clinical trial

“…Furthermore, improvements in FBG were larger in individuals at risk for developing type 2 diabetes (FBG of at least 100 mg/dl). Although earlier studies on TRE have observed mixed effects on glucose and insulin sensitivity 3 , our data are consistent with more recent studies demonstrating that TRE improves glucose tolerance and insulin sensitivity, especially in individuals with greater cardiometabolic risk 3 , 13 , 27 . Fat mass, blood pressure, and lipids were not measured in this study because they posed additional logistical hurdles for a virtual study.…”

“…Preclinical studies demonstrate clear beneficial effects of TRE on glucose tolerance and insulin sensitivity, lipid metabolism, obesity, and the gut microbiome 19 . The benefits of TRE on body weight and cardiometabolic markers in humans have only recently been investigated, and most clinical trials of TRE in adults with obesity are of limited sample size and duration 3 , 5 , 15 , 19 , 20 , 22 – 26 . However, the majority demonstrate that, particularly in individuals with obesity, TRE produces weight loss and enhancements in cardiometabolic health, although the degree of improvements varies across studies and is likely influenced by differences in study population and design.…”

“…Time restricted eating (TRE) is an emerging dietary intervention strategy for weight management 1 – 4 . Common TRE schedules consist of fasting for 12–18 h each day, beginning in the evening or nighttime 3 , 5 . Restricting the nonfasting (eating) duration to 12 h or less during waking hours has been shown to improve measures of cardiometabolic health, and is increasing in popularity as a unique method for weight loss 1 – 4 .…”

“…This daily metabolic switch from glucose to ketones reinforces metabolic circadian rhythms, reduces oxidative stress and inflammation, and has numerous other benefits 1 – 4 , 8 – 10 . Studies of TRE suggest that extending the duration of the daily fast to periods longer than 12 h may yield further cardiometabolic benefits 3 ; however, daily fasting for durations of 16 h or longer usually necessitates missing a meal, which can reduce adherence 1 , 2 . Because fasting is difficult by nature, foods designed to mimic the ketogenic effect of fasting (i.e., high fat, low carbohydrate, and low protein) have been demonstrated by Longo and colleagues to have potential in providing relief from the hunger while maintaining ketosis, or metabolic fasting 1 , 11 , 12 .…”

“…TRE in humans and time restricted feeding (TRF) in animals have been shown to produce numerous beneficial effects that include improvements in visceral and total fat mass, glucose tolerance and insulin sensitivity, lipids, blood pressure, appetite, inflammatory markers, and the gut microbiome 2 , 3 , 5 , 13 – 25 . The cardiometabolic effects of TRE in humans has only recently begun to be explored, and the majority of clinical trials investigating the effects of TRE on body weight are small pilot studies 3 . Most of these clinical trials 5 , 19 , 20 , 22 – 24 , 26 , but not all 21 , 27 , demonstrated that TRE results in weight loss.…”