When is the best time to not eat? Original paper

Time-restricted eating (TRE) is a form of intermittent fasting that involves restricting the daily eating window to a period of 4–10 hours. It is considered the most feasible way to obtain the potential benefits of extended bouts of fasting. Evidence suggests that TRE can reduce body weight and improve cardiometabolic risk factors, but the magnitude of these effects may depend on when the daily eating window takes place. Restricting food intake to early in the day (i.e., early time-restricted eating, eTRE) may be particularly beneficial,^[1][2][3][4] but more evidence is needed to determine if eTRE is superior to TRE protocols that limit food intake to later in the day.

In this 5-week randomized controlled trial, 82 participants (average age of 31 and BMI of 22) were assigned to eTRE, mid-day TRE (mTRE), or control. eTRE and mTRE were restricted to an 8-hour eating window each day. eTRE had to eat between 6 a.m. and 3 p.m, and mTRE had to eat between 11 a.m. and 8 p.m. During the fasting periods, the participants in eTRE and mTRE were allowed to consume water, flavored carbonated water, and unsweetened tea and coffee. The control group continued their usual diet with no restrictions. To monitor dietary adherence, the participants took photos of the food they consumed each day and posted them to an app.

The primary outcome was the change in the homeostatic model assessment of insulin resistance (HOMA-IR, an index of insulin resistance that is calculated using fasting blood glucose and insulin levels).

The secondary outcomes were changes in:

• Energy intake
• Fasting blood glucose
• Body mass
• Blood pressure
• Blood lipids
• Inflammatory markers interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha), and high-sensitivity C-reactive protein
• Liver enzymes aspartate transaminase (AST), alanine transaminase, and gamma-glutamyl transferase
• Gut microbiota alpha-diversity
• Sleep quality, measured using the Pittsburgh Sleep Quality Index
• Appetite

Compared to mTRE and control, eTRE decreased HOMA-IR (+0.39 and –0.05 vs. –1.08). There was no difference between mTRE and control.

With respect to secondary outcomes, compared to control, eTRE decreased fasting blood glucose (-0.59 vs. +0.16 mmol/L), body mass (-1.6 vs. +0.3 kg), body fat percentage (-0.60% vs. +0.42%), TNF-alpha (-0.81 vs. +0.39 pg/mL), IL-8 (-1.9 vs. +1.1 pg/mL), and AST (-3.0 vs. +0.4 U/L), and increased alpha diversity. There were no significant differences between eTRE and mTRE or mTRE and control for these outcomes. Lastly, energy intake decreased in eTRE and mTRE compared to control (-240 and -159 vs. +64 kcal/day), with no difference between eTRE and mTRE.

Early versus late time-restricted feeding

Blood samples were collected in the morning after an overnight fast of at least eight hours. The eTRE participants would have fasted longer than the other participants before the blood samples collected at the end of the trial, which may have influenced the results.

The circadian timing system is composed of a master clock in the brain (i.e., the suprachiasmatic nucleus in the hypothalamus) and peripheral clocks omnipresent in the body, including in the liver, the pancreas, the gastrointestinal tract, skeletal muscle, and adipose tissue. Virtually all biological processes — including those involved in regulating blood glucose levels — are controlled by the circadian timing system through a daily cycle of circadian rhythms, periodic patterns that repeat themselves approximately every 24 hours.^[5] This implies that certain processes are upregulated at some times of the day and downregulated at others.

Studies have consistently demonstrated that glucose tolerance is better in the morning than in the evening in healthy adults.^[6][7][8][9]PMID:29248250[PMID:22751690 Even relatively small differences in meal timing can have a meaningful effect on postprandial glucose levels. A study published in 2014 showed that a standardized meal consumed at 4:30 p.m. increased the postprandial glucose area under the curve by 46%, compared to when it was consumed at 1:00 p.m.^[10]

The variation in glucose tolerance during the day is mainly driven by two factors:

• Enhanced beta-cell responsiveness and insulin secretion in the morning, which seems to be driven by a greater and more rapid release of the incretin hormones glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide in response to food intake.^[11]
• Heightened insulin sensitivity in adipose tissue and skeletal muscle.^[5][12][13]

Furthermore, circulating levels of adiponectin — a hormone that contributes to glucose uptake and fatty acid metabolism — peak in the late morning.^[14] Additionally, circulating levels of melatonin peak in the evening. Melatonin induces the resting phase, whereas a spike in cortisol in the morning prepares the body for the activity phase. Compared to the activity phase, the ability to metabolize nutrients is diminished in the resting phase. Consequently, when melatonin levels are elevated, either by the production of melatonin within the body or exogenous supplementation, glucose tolerance is impaired.^[15][16]

Altogether, the above suggests that human metabolism is optimized for food intake in the morning, which has led to the hypothesis that the cardiometabolic benefits of TRE can be amplified by eating from the morning to the afternoon.

The first study to demonstrate the potential of eTRE was published in 2018.^[1] It was a 5-week randomized crossover trial in men with prediabetes. In the eTRE condition, the participants selected a 6-hour eating window between 6:30 a.m. and 3 p.m. In the control condition, the eating window was 12 hours. A strength of this study was that the research staff provided the participants with food and monitored them while they were eating, so energy intake and meal frequency were matched between conditions. Also, the diets were designed to maintain body weight.

Compared to the control condition, eTRE decreased fasting insulin and increased beta-cell responsiveness and insulin sensitivity during a 3-hour oral glucose tolerance test. Additionally, eTRE dramatically decreased systolic and diastolic blood pressure by 11 and 10 mmHg, respectively. Despite the impressive results, a notable limitation was the absence of a mTRE group. Without a comparison group, it’s unclear whether the benefits of eTRE were due to the timing of the eating window or just a consequence of restricting the length of the eating window.

Following these preliminary results, a few other studies were published. In a 4-day randomized crossover trial in healthy adults with overweight, eTRE reduced average 24-hour blood glucose levels (-4 mg/dL) and glycemic excursions (-12 mg/dL).^[2] In another study in young men with a normal BMI, two weeks of eTRE improved whole-body insulin sensitivity and skeletal muscle glucose uptake.^[3] However, these studies did not include a mTRE comparison group.

A third study compared eTRE with mTRE in men with prediabetes using a randomized crossover design.^[4] eTRE and mTRE produced similar improvements in the glycemic response to a test meal and average 24-hour blood glucose levels. Only eTRE reduced fasting blood glucose levels compared to baseline, but the change was small and not significantly different from mTRE. The major limitation of this study was that the interventions were only seven days long. It’s also worth noting that the eating window was slightly longer and extended to later in the day than the other studies.

The present study had a few strengths compared to those previously discussed:

• There were three groups.
• The intervention duration was a reasonable length of time.
• The participants were healthy and had a normal BMI.

The results add to a compelling body of evidence that suggests eTRE improves glycemic parameters, possibly to a greater extent than mTRE and in the absence of weight loss, but further studies are needed to support the latter idea.