Lesson 12: “Chrononutrition”, the Timing of When We Eat

Table of Contents


Introduction

In the first 11 lessons we discussed quantitative and qualitative aspects of nutrition. In this lesson we will discuss considerations of “chrononutrition”, the timing of when we eat.

There are several different aspects regarding the timing of nutrition. With respect to dieting to lose weight, one consideration is to eat at a constant caloric deficit every day (“CER”: continuous energy restriction) vs breaking up dieting in daily, weekly, or longer periods (“IER”: intermittent energy restriction). With respect to nutrition in any one day, considerations include how many meals to consume each day, the timing of the meals, the size of the meals, and the total window of time within which to consume all calories (ie, a 4 hour vs 8 hour vs all day eating period). There is some overlap between these topics.

Note: Terminology in the research literature is not completely congruent with terminology used by the general public. For example, a popular eating strategy in the general public is intermittent fasting (“IF”), which is frequently done by consuming all of one’s calories in an 8 hour window any given day. In the research literature this strategy is referred to as time-restricted eating (“TRE”, also frequently referred to as time-restricted feeding (“TRF”), with some making a distinction that feeding occurs in animal studies and eating occurs in human studies), while IF is typically used similarly to intermittent energy restriction (“IER”) and can describe a diet such as the 5:2 diet where there are 2 days of intense energy restriction in any given week. I will mainly be using terms here that match the research literature. When there may be ambiguity I will attempt to make this clear.


Intermittent energy restriction (“IER”) and intermittent fasting (“IF”)

Note: In this section I am using IER and IF to refer to several different types of dieting protocols, including:

  • significant caloric restriction on some days of the week interspersed with days with less or no caloric restriction
  • complete fasting ≥1 days of the week interspersed with days with less or no caloric restriction
  • caloric restriction every day for ≥1 weeks interspersed with ≥1 weeks with less or no caloric restriction

I am not referring to TRE studies, where caloric consumption is restricted to a specific time period any given day.

When fasting for extended periods of time metabolism shifts in the body to primarily utilize ketone bodies, which can begin to rise after fasting 8-12 hours and continue rising further as fasting extends to ≥24 hours. Ketone bodies and fasting in general have been shown to help regulate several genes with health implications. This upregulation of various metabolic and genetic pathways while fasting has been associated with many potential health benefits regarding glucose homeostasis, blood pressure, resting heart rate, antioxidant utilization, autophagy, neuronal stress resistance, downregulation of inflammation, and may even impair energy metabolism in cancer cells.(de Cabo, 2020) Most of the literature supporting these benefits comes from animal studies and small human trials. While promising, it remains to be seen how much these benefits of fasting fully carry over to humans.

On that note, thus far many of the studies on CER, IF, the 5:2 diet, and even modified alternate day fasting (where every other day you consume up to 25% of your total daily energy expenditure in calories, and you alternate this with days where you eat as much as you want) likely do not incorporate long enough total fasting periods to observe any potential benefit of a prolonged fast, and the complete alternate day fasting trials (alternating days of no caloric intake) have generally been done with either no comparative group or a comparative group with confounding characteristics.(Templeman, 2020) Some of the TRE studies likely do contain long enough fasting windows as many of these incorporate fasting periods of ≥16 hours.

Additionally, as a general rule of thumb fasting protocols induce weight loss, and thus it is important to consider if the benefits are due to fasting or due to weight loss itself.


Overview of the research

  • A 2019 systematic review and meta-analysis (SR/MA) examining IER & TRE trials and their impact on BMI & glucose metabolism found that compared to CER there was a small but significant benefit for BMI (-0.75 kg/m2), fasting glucose level (-4.1 mg/dL), insulin resistance, adiponectin, and leptin.(Cho, 2019)
  • A 2020 SR/MA of randomized controlled trials (RCTs) of individuals with overweight or obesity who were put on various fasting protocols found small improvements in body weight and a variety of cardiometabolic markers; the control groups were on non-fasting protocols but were not necessarily matched for energy restriction.(Yan, 2020)
  • A 2020 SR/MA including both IER and TRE trials found no significant impact on weight, but in 5 studies exclusively enrolling patients with T2DM favorable effects were seen on measures of blood glucose control.(Welton, 2020)

Note: Regarding IF or IER protocols in patients with T2DM care must be taken to prevent hypoglycemic episodes.(He, 2021) Please discuss with your physician regarding any medication adjustments or other considerations if this applies to you.

Regarding comparisons of IER and CER:

  • A review article discussing IF in humans and going over the various health benefits seen finds that the vast majority of health effects are comparable to CER.(Mattson, 2017)
  • Several SR/MAs that only considered IER vs CER found no benefit for weight loss, glucose, cholesterol/lipids, or blood pressure levels.(Headland, 2016; Cioffi, 2018; Roman, 2019; Enríquez Guerrero, 2020; Meng, 2020; Schwingshackl 2021)
  • A 2021 Cochrane review found no benefit of IER vs CER regarding body weight or glucose outcomes; results varied widely indicating there may be differences found as more studies are conducted.(Allaf, 2021) There were no overly significantly side-effects reported of IER, with only 4 trials reporting these and these mainly consisting of mild headaches.
  • A 2021 SR/MA comparing IER and CER RCTs that matched caloric intake found only small, likely clinically insignificant, differences in outcomes in favor of IER.(He, 2021)

A SR/MA considering IER of fairly long duration (energy restriction periods ranging from 2-12+ weeks at different levels of caloric deficits) found no significant benefit for weight loss compared to CER.(Harris, 2018) In contrast to this, the MATADOR study compared 2 week energy restriction blocks (at 67% maintenance calories) interspersed with 2 week energy maintenance blocks (8 dieting blocks total) to 16 weeks of CER (also at 67% maintenance calories) and found better results in the intermittent dieting group.(Byrne, 2018)

Note: In the MATADOR study the intermittent dieting group had 8×2 week blocks of energy restriction and 7×2 week blocks of energy maintenance (yielding 30 total weeks) compared to 16 weeks total for the CER group. All main meals were provided. The intermittent group that completed the protocol lost 14.1 kg compared to 9.1 kg for the CER group. It is unclear how much additional weight the CER group would have lost had they continued to 30 weeks.

The more interesting aspect of this study is that both groups had 16 weeks at 67% maintenance calories but the intermittent group lost significantly more weight (and also maintained significantly greater weight loss at 6 month follow-up). This may be due in part to amelioration of adaptive thermogenesis (discussed in Lesson 1) by eating at maintenance in the 2 week blocks or due to better dietary adherence (it is likely easier to adhere to a diet in 2 week blocks than for 16 weeks consecutively).

Following the MATADOR study, a trial comparing intermittent dieting in 1 week blocks to a 5:2 diet and also CER for a 1 year period was published; there were no differences in results.(Headland, 2020) Maximum weight loss was at 6-9 months in all groups with regain occurring after that. After an additional year follow-up beyond the end of the trial there were still no differences between the groups.(Headland, 2020)

Overall, there is very little evidence indicating superior outcomes of IF or IER protocols compared to continuous dieting schemes, and in fact the majority of the evidence suggests similar outcomes. A 2021 narrative review described the lack of additional benefit of various IER protocols relative to CER and the authors additionally noted potential side-effects, particularly in people with normal weight who engage in these eating patterns, which may include concerns about disordered eating.(Katsarou, 2021)

However, several of the above reviews mention that the attrition rate in studies of IER vs CER are typically similar. Thus, if anyone believes following an IER protocol will lead to greater adherence this should definitely be considered. It is possible with more research we will find other tangible benefits of fasting protocols similar to those seen in mice studies, but at this point in time the evidence base is not strong enough to support recommending prolonged fasting to support better health. Additionally, fasting protocols can yield side-effects such as hunger, poor sleep, irritability, fainting, and others, and it’s recommended that children, adolescents, the elderly, pregnant or lactating women, lean individuals, and individuals vulnerable to eating disorders do not engage in fasting protocols.(Aoun, 2020)


Considerations of lean body mass retention

Additionally, as alluded to in prior lessons, fasting for prolonged periods will likely lead to loss of lean body mass, which is generally undesirable. However, a recent SR/MA evaluating 8 studies (all ≤12 weeks duration with relatively small sample sizes and different fasting protocols) did not find any loss of lean body mass in the intermittent fasting groups compared to control groups.(Ashtary-Larky, 2021) Of note, the intermittent fasting groups maintained their protein intake in these studies relative to the control groups. A separate SR of 8 studies (1 with modified alternate day fasting, 3 with Ramadan IF, 4 with TRE) also found generally no loss of lean body mass with the various interventions, while several did show a loss of body fat.(Keenan, 2020) In a separate analysis, studies including Ramadan IF and TRE were not found to have an overly significant impact on various exercise performance measures, though sample sizes were small, and one difference was found; aerobic capacity decreased with Ramadan IF studies while it increased with TRE studies.(Correia, 2020)

Despite these positive findings, as recently reviewed, many of the studies that show no loss of lean body mass include short trial lengths and do not use the most accurate available assessments of skeletal muscle mass and hypertrophy.(Williamson, 2021) As it can take several months to notice significant levels of hypertrophy, perhaps if studies were done over longer time periods a negative impact on skeletal muscle mass would be noticed.

Tip: If a person is dieting and intends to go on vacation, this can be an excellent time to take a break from caloric restriction and attempt to eat at maintenance or a slight caloric surplus. This should allow the vacation to be more enjoyable and then dieting can be resumed after the vacation with renewed vigor. Similarly, if somebody feels run down from the dieting process this can be a good time to practice eating at maintenance to allow one to recharge and to reinforce practices to keep the weight off once dieting is complete.

Note: One concept that has emerged in the fitness world is the notion of “dietary refeeds”. This falls under an IER paradigm. The idea here is to be in a caloric deficit for say 5 days and then eat at maintenance or slightly above maintenance for 2 days (generally by adding in carbohydrates). This can serve several purposes, including refilling glycogen stores to aid exercise sessions, allowing easier adherence to a dietary strategy (particularly for people who tend to eat more on the weekends), and possibly even restoring some of the compensatory changes the body makes when undergoing adaptive thermogenesis.

There is not much direct research studying this approach. In 2020, one published study did evaluate dietary refeeds, comparing a 25% caloric deficit every day of the week to a 35% deficit on 5 consecutive days followed by 2 days at maintenance, each for 7 weeks, while consuming 1.8 grams of protein per kg of body weight daily.(Campbell, 2020) Only 27 of 58 recruited patients completed the study (13 in the refeed group, 14 in the continuous group). They engaged in 4 resistance training sessions weekly. Both groups lost a similar amount of weight (3.2 kg and 3.6 kg on average in the refeed and continuous groups, respectively), but the refeed group was able to maintain dry fat-free mass more effectively (-0.2 kg vs -1.9 kg, respectively).

Thus, in this one small study, the refeed strategy was effective at maintaining non-water fat-free mass while losing weight. More research is needed but this initial result is promising.


Meal frequency

  • A 2016 review found increased meal frequency to be potentially beneficial for lean mass preservation in a caloric deficit (without otherwise impacting body weight or appetite).(Hutchison, 2016) Within this review the authors noted concern from one cited study indicating increased meal frequency may be metabolically harmful in a caloric surplus.
  • A 2017 review indicated there is mixed evidence from epidemiologic studies indicating that higher meal frequency aids cardiovascular disease (CVD) and diabetes markers, while in trials there seems to be mild benefit of increasing meal frequency on cholesterol levels, with no significant benefit on triglycerides, blood pressure, fasting glucose, or insulin.(St-Onge, 2017) Of note, many of the included trials in this review are very small.
  • A 2019 review suggested there is not much difference in weight loss with varying meal frequency though higher frequency may lead to less hunger (but also less satiety after eating), decreased protein oxidation, and more stable blood glucose & insulin levels.(Oke, 2019) More stable blood glucose and insulin is logical given caloric consumption would be spread out more with higher meal frequency; this does not contradict the prior review stating there is no impact on fasting glucose and insulin as those measurements would be obtained from a single time point and not significantly related to a prior meal.
  • A 2020 observational study did find benefit to higher meal frequency regarding lower BMI, however, those who ate more frequently also ate earlier in the day, which has also been shown to yield health benefits (see the TRE section below).(Zerón-Rugerio, 2020)
  • A 2020 network MA including 22 RCTs found that meal frequency has no meaningful impact on body weight changes, while 2 meals vs 6 meals daily may have a small beneficial impact on waist circumference (but no benefit was seen with 3 meals vs 6 meals daily).(Schwingshackl, 2020)
  • A 2021 SR/MA of RCTs evaluating the effect of meal frequency on cardiometabolic biomarkers evaluated 21 studies and found(Abdollahi, 2021):
    • no impact on fasting glucose, insulin, hemoglobin A1c, or HOMA-IR (a measure of insulin resistance), though removing 1 outlier study yielded a significant decrease in insulin of -1.12 μU/mL when consuming higher meal frequency
    • no impact on triglycerides
    • a benefit for total cholesterol of -6.08 mg/dL with higher meal frequency (removal of 1 outlier study makes this no longer significant)
    • a benefit for LDL cholesterol (the “bad” cholesterol) with -6.82 mg/dL with higher meal frequency (removal of 1 outlier study makes this no longer significant)
    • no effect on HDL cholesterol (the “good” cholesterol)
    • a small increase in the LDL/HDL ratio of 0.22 (this was from 3 studies with a total of only 45 participants)
    • no significant effect on free fatty acids, apolipoproteins, or leptin
  • A 2021 narrative review found that increased eating frequency was associated with lower adiposity and metabolic syndrome risk but this may be due to increased eating frequency correlating with better diet quality.(Garcidueñas-Fimbres, 2021)

Tip: This same review also examined the role of eating speed and found a decreased eating speed was associated with better outcomes regarding adiposity and metabolic syndrome risk.(Garcidueñas-Fimbres, 2021) Thus, for individuals who are attempting to lose weight it may be helpful to eat more slowly. There are a variety of tools out there to help with decreasing portion sizes (ie, small utensils, glasses shaped in a specific way to slow the pace of drinking, etc), though it seems these do not work well in isolation.(Vargas-Alvarez, 2021)

Perhaps using these strategies with a cognitive effort to eat more slowly will prove more effective. Other tricks include using your off-hand (ie, your left hand if you are naturally right-handed), chewing more with each bite, putting your utensils down between bites, or restricting yourself to a small first portion size and waiting 15 minutes prior to consuming a second portion. Eating with others and having a conversation during a meal can also work very well. Ultimately all of these strategies provide more time for various gut hormones to release and send signals to the brain where they decrease hunger and increase satiety; this can lead to a natural decrease in overall caloric consumption for people who would otherwise eat/drink too quickly for these signals to take effect.

Given the lack of strong findings above, the fact that there is no technical definition of what constitutes a meal(St-Onge, 2017) (and thus hard to do well-designed consistent trials), and the fact that while many people report having 3 meals daily their actual daily intake does not reflect this(Gill, 2015), there is not a strong enough literature base at this time to recommend a specific meal frequency. As stated in Lesson 4, spreading protein intake throughout the day will likely benefit muscle protein synthesis. Thus, I recommend a minimum of two distinct protein (and hence meal) feedings on a daily basis, and there may be additional benefit with three.

Note: Below in the TRE section there are several studies discussed that indicate a benefit to consuming calories in a restricted window, which would seem to necessitate fewer meals, yet some of the evidence above weakly suggests more meals may be beneficial. This may seem confusing but can can be consistent with the below TRE literature when considering:

  • some of the above literature compared 1 meal daily to multiple meals while most TRE protocols still allow 2-3 meals daily
  • some of the above literature evaluating 2-3 meals had them consumed far apart (ie, 8am, 1pm, 6pm, plus a snack), such that there was no prolonged fasting window – this is not consistent with TRE

Thus, these findings should not be considered inconsistent with the TRE findings discussed below.


Timing of meals

There has been emerging evidence that suggests eating at consistent daily times with similar intake throughout(Aqeel, 2020) or more intake preferentially early in the day may lead to better health outcomes.(Almoosawi, 2016; Pot, 2016; Patterson, 2017; Boege, 2020; Dashti, 2020; Zerón-Rugerio, 2020) This latter finding extends to those with diabetes.(Han, 2020) This is thought to be related to the various circadian rhythms in the body, the prominent one being from the suprachiasmatic nucleus in the hypothalamus, with additional ones found in peripheral organs as well.(Chaix, 2019) This leads to various metabolic changes throughout the day, one example being decreased postprandial glucose and insulin levels in the morning relative to the evening, possibly due to improved insulin sensitivity in the morning.(Leung, 2020) Some studies also indicated a greater thermic effect of feeding (discussed in Lesson 1 of this course) as well as carbohydrate oxidation in the morning, with greater lipid oxidation in the evening.(Boege, 2020)

However, there is not much strong evidence indicating a significant benefit to breakfast consumption, though it is possible that uncontrolled late night eating may mitigate benefits that would otherwise be seen in intervention trials(Gwin, 2018):

  • A 2020 MA of 7 cohort studies did find that breakfast skipping was associated with a 22% increased risk of CVD and a 25% increased risk of all-cause mortality relative to consuming breakfast regularly; however, the authors note that breakfast skipping is associated with many different unhealthy dietary and lifestyle behaviors, and thus it is possible residual confounding variables account for the observed associations.(Chen, 2020)
  • A 2020 SR/MA of RCTs evaluating people assigned to breakfast or no breakfast groups found no significant differences in any measured anthropometric outcome.(Bohan Brown, 2020)
  • This was mirrored in a separate 2020 SR/MA, though 3 studies with a total of 92 subjects did find an association of increased LDL cholesterol (+9.24 mg/dL) in individuals who skipped breakfast; due to the lack of multiple hypothesis testing correction, small sample size, and the association of breakfast skipping with some unhealthy nutritional components it’s unclear if this cholesterol finding represents a legitimate physiologic aspect of skipping breakfast.(Bonnett, 2020)
  • A 2021 SR/MA found breakfast skipping is associated with weight gain in retrospective and prospective cohort studies; however, there are many known confounding effects, most studies do not adjust for all of these, and there are quite possibly additional unmeasured confounding variables beyond this.(Wicherski, 2021)

A 2020 review on the topic of breakfast similarly concludes we need more trials to help determine if breakfast is beneficial, as there are associations between breakfast intake and beneficial cardiovascular outcomes but when non-habitual breakfast consumers begin to consume breakfast regularly they typically gain weight.(Santos, 2020) It may ultimately come down to whether or not eating breakfast helps or hinders any given individual with maintaining an overall healthy diet.

Looking at a few specific studies:

  • One study randomized women with an average BMI of 33 (without diabetes) to two different isocaloric protocols: either 700/500/200 kcal for breakfast/lunch/dinner or 200/500/700 kcal for breakfast/lunch/dinner.(Jakubowicz, 2013) The group eating more kcals at breakfast had better results with triglycerides, cholesterol, glucose, insulin, had lower ghrelin (the “hunger” hormone) throughout the day, and had lower postprandial glucose and insulin levels after the 700 kcal meal.
  • A different study took 420 people with overweight or obesity and put them on a weight loss program based on the Mediterranean diet, a moderate physical activity intervention, and cognitive behavioral therapy, among other education.(Garaulet, 2013) No advice was given with respect to the time of day they should eat or when they should consume most of their calories. Lunch was the largest meal of the day for this group and people who ate lunch earlier had better weight loss outcomes starting at week 5 of the intervention despite no differences in reported energy intake or energy expenditure.
  • A rather interesting study not only considered when people eat most of their calories but also the relationship of this to when they typically wake up and go to sleep.(Xiao, 2019) Here the authors looked at >800 adults and considered the midpoint of time in bed as a cutoff; those whose midpoint was earlier than the median midpoint were considered as “early chronotypes” and those whose midpoint was later than the median midpoint were considered as “late chronotypes”. They found that while a higher percentage of energy intake early in the day is associated with reduced odds of overweight & obesity, this is more strongly seen in those with an early chronotype. Similarly, they found that that more energy intake at night is associated with higher odds of overweight and obesity moreso in those with a late chronotype. They found this mainly associates with carbohydrate and protein but not fat intake.

Note: I suspect over time with more research we will find this concept of chronotype and relation of normal wake/sleep time to eating patterns has a fairly significant role in the health implications of “chrononutrition”. At this point in time the vast majority of studies evaluating the timing of nutrition do not consider normal wake and sleep times. Future studies should consider this as chronotype may serve as a significant confounding variable otherwise. Much more research remains to be done to elucidate the full role that chronotype plays on the implication of eating times for overall health.

  • Another study took ~80 women with BMI between 27-35 who normally were late night eaters and split them into two groups; one group ate their evening meal between 19:00-19:30 and the other between 22:30-23:00.(Madjd, 2021) Both groups were placed on a diet with a 500-1,000 kcal deficit, plenty of fruits/vegetables/fiber, and encouraged to build up to 60 minutes of exercise on 5 days a week. Both groups had improvements in a variety of health markers but the early evening group had better overall weight loss (-6.8 kg vs -4.85 kg) as well as better improvements in waist circumference, total cholesterol, triglycerides, fasting insulin, and HOMA-IR (a measure of insulin resistance).
Thus, at this point evidence indicates a benefit to eating the majority of one’s calories early in the day, but it is not yet clear exactly how to define “early” (ie, based on the time of day or based on relation to when a person wakes up) or what proportion of one’s calories should be consumed early to yield greater benefits. It’s also not clear if this would change when consuming calories in a deficit, maintenance, or surplus. Additionally, these studies have not included any intense exercise interventions; for people who do workout in the evening it is conceivable these results may not apply to the same degree. Nonetheless, the research overall is promising that greater intake earlier in the day will yield health benefits.

Time restricted eating (“TRE”)

TRE, or the concept of consuming all of one’s calories in a specific window of time, has become quite popular in the general public, with some people choosing to consume all of their calories in one large meal and others choosing to consume all of their calories in timed windows ranging from 4-12 hours. There is evidence collectively that this may influence the various circadian rhythms alluded to above and thus may benefit health beyond simply leading to decreased caloric consumption.(Waldman, 2020) Some reviews of TRE studies have shown small benefits regarding weight and metabolic outcomes, but these reviews have included Ramadan studies.(Rothschild, 2014; Pellegrini, 2020) Given that Ramadan goes directly against the circadian rhythm with respect to the time of eating it is possible this will underscore the actual benefits of a TRE approach.

Reviews of TRE studies

Here I will highlight findings of reviews of TRE studies that do not incorporate Ramadan. If you do not wish to read through findings of each review I include a summary paragraph at the end of this TRE section. The following figure is from the last cited review demonstrating some of the possible benefits of TRE in individuals with components of metabolic syndrome.
an image showing some of the benefits of time-restricted eating
Reproduced from: Świątkiewicz I, Woźniak A, Taub PR. Time-Restricted Eating and Metabolic Syndrome: Current Status and Future Perspectives. Nutrients. 2021 Jan 14;13(1):221. doi: 10.3390/nu13010221. PMID: 33466692; PMCID: PMC7828812.

In a 2020 SR/MA with TRE studies published through 4/3/2020, 19 studies were evaluated (11 RCTs, 2 non-randomized controlled trials, 1 historically controlled trial, 5 trials with one group using a pretest-posttest design).(Moon, 2020) In total there were 475 subjects, 10 studies with healthy individuals and 9 studies with participants with metabolic abnormalities (8 studies in people with overweight/obesity, 1 study in people with non-alcoholic fatty liver disease). Results when looking at all studies include:

  • 12 studies examined the impact on weight loss and found a small impact (-0.90 kg)
    • looking just at the studies with people with metabolic abnormalities yielded a larger impact (-3.19 kg vs no impact in healthy individuals), however removing one influential study negated the impact
  • 10 studies examined the impact on body composition, finding an overall decrease in body fat percentage (-0.56%) and fat mass (-1.58 kg)
    • with subgroup analysis in 5 healthy studies there was a decrease of -0.79 kg but in the 2 studies with metabolic abnormalities only one found a decrease
    • there was no change in fat-free mass
  • 6 studies examined blood pressure and found no impact on diastolic blood pressure but a decrease in systolic blood pressure of -3.07 mmHg
    • in 4 studies with metabolic abnormalities the decrease was -5.42 mmHg
    • in 2 studies with healthy subjects there was no decrease
  • 10 studies examined fasting glucose concentrations and there was a decrease of -2.96 mg/dL
    • in 5 studies with metabolic abnormalities there was a statistically significant decrease of -2.29 mg/dL
    • in 5 studies with healthy participants there was a non-statistically significant decrease of -3.65 mg/dL
  • 14 studies examined changes in lipid profiles and found a decrease in triglycerides of -11.60 mg/dL but without significant results in healthy or metabolically unhealthy subgroups (-13.22 mg/dL and -7.12 mg/dL, respectively, but with wide confidence intervals), and there was no change in HDL or LDL cholesterol
  • When considering only the 11 RCTs and 3 controlled clinical trials without randomization, the effect of TRE:
    • on weight change was not significant
    • fat mass did decrease -1.27kg
    • there was no change in fat-free mass
    • there was no change in fasting glucose, triglycerides, or HDL or LDL cholesterol

A 2020 SR found 22 TRE trials published through September, 2020 and provided general descriptions of the literature.(Adafer, 2020):

  • Trials lasted from 4 days to 4 months, had sample sizes of 8 to 105, 10 were RCTs, 3 were non-randomized controlled studies, 8 were single-arm non-controlled trials. The authors noted many more trials that are larger were in progress at the time of their data search.
  • 50% of the trials used an 8 hour feeding window, some did an earlier eating window during the day but most use a later window or a self-selected window.
  • Some purposefully utilized isocaloric protocols while most allowed as much food consumption during the eating window as desired.
  • Of 10 studies that reported adherence, 8 studies had >80% adherence and 2 studies had >70% adherence. Adherence was mainly self-reported. One trial that was a 12 week intervention found that 63% of participants continued to engage in TRE to some degree 16 months after the intervention ended.
  • Studies reporting changes in hunger found no negative influence from TRE.
  • On average caloric consumption decreased 20% with TRE despite participants not being instructed to decrease their intake.
  • In various studies there were improvements in fat loss, systolic blood pressure, glycemic control and insulin resistance, lipid profiles, and adiponectin levels.

In a 2021 SR/MA including only randomized controlled trials published through 10/1/2020 that evaluated early-TRE (eTRE, meaning caloric consumption was limited to the earlier portion of the day).(Pureza, 2021) Nine studies were included in the qualitative analysis (n = 264 participants) & eight studies were included in the quantitative analysis (n = 184 participants). Results include:

  • 7 studies evaluated fasting blood glucose and found a decrease of -2.75 mg/dL
    • removing one study yielding heterogeneity increased the magnitude to -3.27 mg/dL
    • a similar result was seen in studies with weight loss and weight maintenance, though there was evidence of publication bias
  • 6 studies evaluated insulin levels and found no differences
  • 4 studies evaluated HOMA-IR, all with weight maintenance, and found a small decrease with eTRE (-0.50 μU/mL)
  • 3 studies evaluated ghrelin levels (a hormone that stimulates hunger) and found no differences
  • 6 studies evaluated triglycerides and found no differences
  • 3 studies evaluated total cholesterol and found no collective difference, however in the subgroup of studies in weight maintenance there was an increase of 11.18 mg/dL
    • of note, this subgroup included 2 studies with a longer fasting duration of 18 hours and this may cause an increase in cholesterol measurements
  • 4 studies evaluated HDL and LDL cholesterol and there were no differences

A 2021 review of TRE studies and their impact on various aspects of metabolic health found 13 trials and collectively described(Gabel, 2021):

  • In trials allowing ad libitum intake there was a 1-4% loss in body weight in subjects with overweight or obesity corresponding to a ~350-500 calorie deficit daily. Weight loss was not seen in studies that incorporated exercise. It’s not clear if the length of the eating window or time of day of the eating window is influential for weight loss. Body fat and fat-free mass loss was similar compared to other dieting protocols, and there was no loss of visceral fat mass.
  • Improvements in blood pressure were noted in studies where people had borderline hypertension.
  • Cholesterol levels and triglycerides were not generally affected, but most studies had individuals with normal levels at baseline.
  • There was no influence on inflammatory markers. However, there was a benefit seen for markers of oxidative stress.
  • Regarding adverse effects, there was no increase in minor side-effects such as headaches and constipation throughout the interventions. There was also no negative impact on sleep.
  • There were no increases in disordered eating symptoms in one study that gauged this, though that study excluded individuals with a history of eating disorders at baseline.

A 2021 narrative review focusing on the impact of TRE in 13 studies (some with multiple publications) of individuals with various components of metabolic syndrome found(Świątkiewicz , 2021):

  • Generally adherence was >80%.
  • A loss of 3-4% in body weight, body fat percentage, and waist circumference was seen along with a decrease in visceral fat in some studies, but some studies found no loss in body fat and some had a loss in lean body mass.
  • Caloric consumption decreased 9-20%.
  • Some studies found improvement in markers of glucose control, lipid profiles, and blood pressure, but none of these findings were universal.
  • Various studies found subjective improvement in sleep, energy level, hunger at bedtime, quality of life, and well-being.
  • There were no serious adverse events and mild side-effects typically diminished throughout the interventions.
  • Barriers included work schedules, family commitments, and social events.

Combining TRE with resistance training

As one of the concerns with TRE is decreased muscle protein synthesis from decreased meal frequency, I have highlighted the various published TRE studies that incorporate resistance training below (as resistance training should help maintain lean body mass with any given dieting or nutrition scheme). Collectively these show that engaging in TRE while performing a resistance training program does not lead to lean body mass loss.

In 2016 Tinsley et al. published an 8 week trial with 28 individuals split into a TRE or normal diet (“ND”) group with a full body workout being done 3 days weekly.(Tinsley, 2017) The TRE group employed a 4 hour feeding window between 4pm and midnight on nontraining days. N=10 completed the trial in the TRE group and n=8 completed the trial in the ND group. There were no significant differences in body weight, body composition, muscle cross-sectional area, or strength between the two groups at the completion of the trial. However, the ND group did gain 2.3 kg of lean body mass compared to a loss 0.2 kg in the TRE group. Of note, the protein intake averaged 1.4 grams/kilogram (g/kg) for the ND group but only 1.0 g/kg for the TRE group, which may have hampered the TRE group’s results.

In 2016 Moro et al. published an 8 week trial with n=34 resistance-trained males split into a TRE group and a normal diet (“ND”) group, both consuming maintenance calories.(Moro, 2016) The TRE group consumed calories at 1pm (40%), 4pm (25%), and 8pm (35%). The ND group consumed calories at 8am (25%), 1pm (40%), and 8pm (35%). Three exercise sessions were done weekly between 4-6pm. The TRE group lost more body fat (-16.4% vs -2.8%) while both groups maintained their fat-free mass. The TRE group had more substantial beneficial changes in blood glucose, insulin, triglycerides, and adiponectin. The only potential negative findings in the TRE group (from a muscle hypertrophy standpoint) that were not seen in the ND group were decreases in total testosterone and IGF-1, though these values were still within normal reference ranges.

In 2019 Tinsley et al. published an 8 week trial in resistance-trained females with an 8 hour TRE window from 12:00-20:00.(Tinsley, 2019) Protein intake was at least 1.4 grams/kilogram/day (g/kg/d) and they aimed for a 250 kcal/d deficit. They trained 3 times weekly with training sessions between 12:00-18:00. There were 2 separate TRE arms, one of whom was given supplemental β-hydroxy β-methylbutyrate (HMB) (thought to decrease muscle protein breakdown when in a catabolic state), as well as a control arm. The intention to treat analysis had n=40 while the per protocol analysis had n=24. There was no difference in results between the groups, indicating TRE did not inhibit skeletal muscle hypertrophy or strength acquisition, and HMB did not prove beneficial.

In 2020 Stratton et al. published a 4 week trial with a TRE group (n=13, 8 hour window from 12-8pm or 1-9pm) compared to a normal diet group (n=13) combined with resistance training and a 25% caloric deficit with at least 1.8 grams/kilogram of daily protein.(Stratton, 2020) While various changes were seen in both groups over time, between the two groups there were no meaningful differences regarding body composition, strength gains, muscular hypertrophy, testosterone, leptin, or adiponectin. TRE did not negatively impact response to training (regarding metrics mentioned above), recovery, energy, or hunger; however, the surveys for the latter items were completed during the feeding window which likely impacted the measurements.

In 2020 McAllister et al. published a study with n=16 healthy male firefighters undergoing TRE for 10 hours (time period not specified) for 6 weeks while following a resistance training program. Decreases were seen in advanced oxidation protein products (~31%) as well as advanced glycation end products (~25%), both of which are thought to have negative health effects. No differences were seen in the hunger hormones, cholesterol or glucose/insulin levels, or other inflammatory markers. Without a control group it’s unclear if the observed improvements were due to the TRE, the resistance training program, or some other mechanism.

In 2021 Kotarsky et al. published a study with n=21 physically inactive adults aged 35-60 with overweight or obesity (BMI 25.0-34.9) undergoing a normal diet (n=10) or TRE for 8 hours (12:00-8:00pm, n=11) while following a concurrent resistance training and aerobic training program. The TRE group lost 4kg weight compared to none for the normal eating group, lost 2% body fat compared to 1% for the normal eating group, and did not lose any lean mass in the process.

In 2021 Gonzalez et al. published a study with n=16 healthy male firefighters undergoing TRE for 10 hours (time period not specified) for 7 weeks while following a resistance training program (2 days most weeks). Overall there were no changes in anthropometric outcomes or muscular performance, there was a decrease in absolute and relative VO2 peak (though the authors provide a legitimate rationale for why this may not be a valid finding), and there was an improvement in absolute and relative ventilatory threshold; the authors believe this improvement may be due to changes in substrate utilization while following a TRE protocol. Overall there were not many changes and there was no control group to help determine what impact TRE itself had.

In 2021 Ribeiro et al. published a study with n=24 physically active adults with overweight or obesity aged 18-40 in an 8 week trial including 12 individuals in a CER group and 12 individuals in a TRE group, both at a 20% kcal deficit daily and incorporating 1 hour of exercise (aerobic training, resistance training, and balance/proprioception training) three times weekly. Both groups lost similar amounts of weight, waist circumference, and fat mass, but the TRE group did not lose any fat free mass, total body water, or skeletal muscle mass while the CER group lost 2.6%, 2.2%, and 2.3%, respectively. There were no major differences in cardiometabolic markers or leptin, but only the CER group had an increase in cortisol levels (the “stress hormone”).


Summary of the TRE evidence

So what does this body of research suggest overall? From a health standpoint most of these studies show that following a TRE protocol leads to a natural reduction in caloric intake and subsequent weight loss (from body fat without loss of lean body mass). Beyond this, several (though not all) studies show benefits for glucose and insulin levels, cholesterol, and blood pressure. These are seen across varying protocols in different populations of individuals. Of note, several trials were in metabolically healthy individuals; this may preclude seeing benefits that would be seen in metabolically unhealthy individuals. Additionally, it’s important to keep in mind that all of these studies were small, and most were done for ≤8 weeks. This would make it harder to find statistically significant differences and thus may underscore the overall effects.

Importantly, there do not seem to be many significant adverse effects, hunger levels do not increase, sleep is not negatively affected, and adherence is typically >80%. All of this is positive. However, caution must be taken when drawing strong conclusions from a small body of research that includes small trials of relatively short duration. Thus, overall, TRE seems quite promising and at this point can likely be considered a viable dietary strategy, possibly with significant benefits for health and dieting purposes, but until larger trials are done I believe it is premature to provide strong recommendations to follow a TRE protocol. Additionally, certain medical conditions or medications may make prolonged fasting periods dangerous; consider consulting with your healthcare provider prior to making any drastic dietary changes if this is a concern.

Note: In trials compliance was an issue at times when the eating window was earlier in the day because this precluded social eating at night. As discussed earlier in this lesson there is evidence that shifting caloric intake earlier in the day leads to health benefits, and this may also extend to TRE, but there were also benefits seen in TRE trials here that started midday. Thus, if a person wants to try TRE and use a feeding window that includes evening social events to aid compliance, I do not see any particular reason to discourage this at this time given these trials still collectively showed benefit.

Tip: Anecdotally many people find TRE helps to stabilize/control hunger levels. It is likely that TRE will need to be used for several days or even ≥1 week before physiologic adjustments in appetite/hunger stabilize. Thus, if attempting TRE I would commit to it for at least 1 week prior to giving up on it as a viable strategy.


Conclusion

There are several different aspects of “chrononutrition” as discussed above. TRE seems like a valid approach that can be employed with resistance training as long as protein intake is sufficiently high. IER additionally seems valid and may aid compliance with a diet. If doing this I would prioritize protein intake on the restricting days. Eating at regular times is likely beneficial for overall health and consuming most of one’s calories earlier in the day also seems beneficial, though a conclusive benefit to adding in breakfast for individuals who prefer to skip it has not been found. Research thus far does not promote extended fasting in humans, though more research is needed. Additionally, more research is warranted relating timing of nutrition to one’s normal wake & sleep times.

Most of this research does not consider people who are actively exercising; for those who exercise in the evening it may make more sense to consume calories in the evening. Anyone with medical conditions that may preclude fasting periods should discuss these dieting strategies with their provider. People who perform shift work, particularly night shifts, may minimize the metabolic risks by eating at similar times each day; more research needs to be done regarding time-restricted feeding protocols in night shift workers.

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