How Effective is Time-Restricted Feeding?

With the Christian observance of Lent upon us and Ramadan, the Muslim holy month of fasting, coming up, what better time to re-examine the evidence surrounding the effects of fasting in humans? Modern dietary advice often focuses on what and how much one eats but often leaves out a crucial third component of when one eats.

Time-restricted feeding (TRF) is the practice of limiting calorie intake to a specified time period. Since the average American eats over a 12-hour period, time-restricted feeding is generally defined as a form of intermittent fasting that involves limiting daily food intake to a period of 10 hours or less, followed by a daily fast of at least 14 hours.

Is Time-Restricted Eating Helpful for Weight Loss?

In September 2020, a randomized controlled trial published in JAMA Internal Medicine suggested that time-restricted eating provided neither weight loss nor metabolic benefits. Ethan Weiss, a cardiologist at UCSF and one of the study authors, even pointed to the negative results of this trial as justification to no longer participate in fasting over the Jewish holiday Yom Kippur.

Weiss first became interested in time-restricted feeding after coming across the research of Satchin Panda of the Salk Institute. Panda's research demonstrated clear metabolic benefits associated with time-restricted feeding in mice, but human clinical trial data were still lacking at the time, so Weiss and his team decided to set up a trial of their own in 2018.

• The study enrolled men and women aged 18 to 64 who were either overweight or obese (BMI of 27 to 43).
• 59 participants were assigned to the time-restricted eating (TRE) group and instructed to eat as much and as often as desired (ad libitum) but only between the hours of noon and 8:00 p.m. every day for three months.
• 57 participants in the consistent meal timing (CMT) group were instructed to eat three structured meals per day.
• The study assessed the impact of TRE on weight loss (primary outcome) as well as fat mass, lean mass, fasting insulin, fasting glucose, hemoglobin A1c levels, estimated energy intake, total energy expenditure, and resting energy expenditure.
• Participants in the TRE group lost an average of just 2 to 3.5 pounds, which was only slightly more than the control group and not statistically significant. The majority of that weight loss was not fat, but lean muscle mass.
• Because lean muscle mass is positively correlated with numerous health benefits as we age, including a lower risk of falls and fractures and reduced all-cause mortality, this latter finding may be concerning if valid.
• No differences in insulin or glucose, lipids, sleep, activity, resting or total energy expenditure, or fat mass were observed between the TRE and CMT groups.

Study Limitations and Considerations:

• Participant compliance was not monitored and only measured through self-reports, which revealed that 92.1% complied with CMT and 83.5% complied with TRE.
• Non-compliance in the CMT group was not clearly defined. For example, did non-compliance mean skipping breakfast or eating four meals a day? Were failure to comply once and failure to comply consistently given equal weight?
• Out of the 116 participants included in the analysis, only 105 completed the entire 12-week intervention. Significant attrition in the treatment arm further diminishes the value of the results.
• Previous research suggests that an eating window earlier in the day (e.g., from 8:00 a.m. to 4:00 p.m.) might produce better results, since our bodies are better primed to metabolize calories in the morning.
• Calorie intake was not tracked nor was caloric matching employed between the two groups. This oversight introduces a significant confounding variable.
• The study did not track macronutrient intake even though the authors acknowledge "that adequate/excessive protein consumption during weight loss can mitigate losses in lean mass."
• Caucasian preponderance in the control group (64%) can skew results, as the normal BMI range differs considerably according to race. Similarly, descriptions of BMI, waist-to-hip ratio, waist circumference and fat mass do not account for differences by sex.

Due to the numerous shortcomings associated with this study, the authors cannot definitively conclude that TRE is not effective for weight loss.

Can Time-Restricted Feeding Improve Metabolic Health in Men with Prediabetes?

Eric Ravussin, a human physiology professor at Pennington Biomedical Research Center in Baton Rouge, Louisiana, conducted a small randomized, crossover, isocaloric controlled study examining the effects of early time-restricted feeding (eTRF) in eight men with prediabetes.

Researchers first randomly assigned participants to follow an eTRF schedule (6-hour feeding window, with dinner before 3:00 p.m.) or a control schedule (12-hour feeding window) for five weeks. After the initial five weeks, men crossed over and followed the opposite schedule.

Metabolic ward-adjacent conditions ensured compliance, as participants were required to eat all meals at the research clinic or be supervised via remote video monitoring. Diets consisted of 50% carbohydrates, 35% fats, and 15% proteins, and each meal provided about one-third of each participants' daily energy requirements.

To make sure that participants maintained their weight, participants were weighed daily during the first couple weeks and and weekly thereafter, and any changes in weight were counterbalanced by adjusting calorie intake.

While on the eTRF schedule, individuals experienced improved blood pressure, insulin sensitivity, and oxidative stress levels in the absence of weight loss. The study authors concluded that "eTRF is an efficacious strategy for treating both prediabetes and likely also prehypertension." Because eTRF reduces lipid peroxidation, it may also reduce the risk of atherosclerosis.

Interestingly, relative improvement in the oxidative stress levels (measured by plasma levels of 8-isoprostane) of the eTRF group was driven by a worsening in the control arm, suggesting that eTRF prevented oxidative stress from worsening when participants ate the provided study foods. The increased oxidative stress levels observed in the control group may be a consequence of the high proportion of processed and refined foods included in the study diet.

Similar observations have been made in other animal models, as mice fed an ad libitum inflammatory diet exhibited high oxidative stress marked by reduced levels of the antioxidant glutathione and high levels of proinflammatory eicosanoids. The same diet consumed under TRF conditions attenuated levels of proinflammatory lipids and promoted glutathione enrichment in the liver.

Study Limitations and Considerations:

• The trial included only eight men (6 Caucasian, 1 African-American, 1 South Asian), and results need to be replicated in a larger trial (that includes women and better representation of racial minorities) to draw more definitive conclusions.
• Prior to testing, fasting duration was not matched between the groups. Labs were drawn after 18 hours of fasting in the eTRF arm and 12 hours of fasting in the control arm, so improvements in insulin sensitivity may have been underestimated.
• The longer fasting duration in the eTRF group also explains the (likely transient) increase in triglycerides and total cholesterol, but additional investigations are needed to confirm this observation isn't indicative of pathophysiology.
• While the authors observed no difference in morning glucose levels, eTRF may still lower mean 24-hr glucose levels simply by shifting the timing of meals to earlier in the day since circadian rhythm optimization promotes better glucose tolerance.
• Because the trial was designed to isolate and measure the physiologic effects of eTRF, the study doesn't provide any insights into the feasibility of implementing such regimens in the general population.
• The study authors note that eTRF may prove "particularly efficacious" by combining daily intermittent fasting and eating in alignment with circadian rhythms. Studying the effects of eTRF in the setting of a non-processed, non-refined, whole foods-based diet may reveal additional benefits.

Is Time-Restricted Feeding Beneficial for Human Health?

While Weiss focused on weight loss as the primary outcome, Ravussin aimed to investigate whether TRF provides intrinsic benefits - independent of weight loss - and measured glucose tolerance, postprandial insulin, and insulin sensitivity as the primary endpoints. Between the two studies, the only objective measures in common were fasting glucose, fasting insulin, triglycerides, cholesterol levels, and blood pressure.

Neither Weiss nor Ravussin observed any differences in LDL or HDL levels between study groups, but Ravussin did report an increase in the triglyceride levels of the eTRF group. However, as previously mentioned, since the eTRF group fasted for a longer period prior to blood draw, the observed increase may simply reflect triglyceride synthesis in response to lipolysis, the breakdown of fats.

Weiss reported no significant differences in fasting glucose or fasting insulin between groups. Ravussin discovered that 5 weeks of eTRF had no effect on fasting glucose but decreased fasting insulin. Even after the 7-week washout period, all but one participant who completed the eTRF intervention first entered the second arm of the trial with substantially lower (≥25%) mean postprandial insulin levels, implying that eTRF may provide benefits even after discontinuation.

No significant differences in systolic or diastolic blood pressure were observed between groups in Weiss' study. On the other hand, Ravussin found that the eTRF group experienced dramatically lowered morning levels of systolic and diastolic blood pressure.

Since elevated insulin levels can directly increase blood pressure, the authors speculate that improvements in blood pressure were driven by reduction in insulin levels. The blood pressure changes may also be attributed to increased sodium excretion as a result of consuming more salt earlier in the day.

So why the discrepancy between the two studies? Is time-restricted feeding beneficial for human health or isn't it? To answer these questions, let's take a closer look at some of the differences in study design and implementation:

• Unlike Weiss' study, caloric intake was kept identical (isocaloric) between the two study groups in Ravussin's trial.
• Additionally, the feeding window was both shorter (6 hours vs 8 hours) and much earlier during the day (8:00 a.m. to 2:00 p.m. vs 12:00 p.m. to 8:00 p.m.).
• Moreover, compliance was much higher. Across both arms of the study, participants were nearly 100% compliant in eating the provided meals and adhering to meal times.

In other words, the more rigorously time-restricted feeding is studied, the more apparent its metabolic health benefits. To borrow the researchers' words, Ravussin's trial aimed "to measure the pure physiologic effects of eTRF uncontaminated by non-adherence."

Other Time-Restricted Feeding Trials in Humans

A 2015 study by Gill and Panda involving self-reported smartphone data found that eight overweight participants who restricted daily caloric intake to a self-selected 10-hour period reported a 4% reduction in body weight over 16 weeks, and this weight loss was maintained for up to one year. Subjects also reported improved sleep at night and elevated alertness during the day.

For half the participants, the self-selected eating window extended past 8pm. However, in contrast to rodent studies, the participants adhering to a TRF schedule reduced their daily caloric intake by up to 20%, some of which was due to elimination of late-night alcohol and snacking. The concomitant reduction in caloric intake in this particular trial introduced a confounding variable, making it difficult to draw conclusions about the impact of TRF alone.

A 2019 study examining the effects of time-restricted feeding in patients with metabolic syndrome also utilized a self-selected 10-hour feeding window and reported that TRF promoted weight loss; reduced waist circumference, percent body fat, and visceral fat; and lowered blood pressure, atherogenic lipids, and glycated hemoglobin.

The results of TRF trials in humans seem to be largely dependent on the timing of the eating window. Restricting food intake to the middle of the day (mid-day TRF) reduced body fat, fasting glucose and insulin levels, and inflammation while limiting food intake to the late afternoon or evening (late TRF) worsened insulin sensitivity, blood pressure, and lipid levels.

Given the continually emerging evidence for the role of circadian rhythms in dictating human health, these findings are unsurprising and indicate that the health benefits associated with fasting interventions depend not only on shorter feeding windows but circadian optimization.

If you're considering implementing a fasting regimen, choosing an earlier feeding window may be a better option than one later in the day. As always, consult a healthcare professional before making any dietary or lifestyle changes!

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