Time to Eat - A Personalized Circadian Eating Schedule Leads to Weight Loss Without Imposing Calorie Restriction: A Randomized Controlled Pilot Study

Reviewer #3 (Public review):

In this study, the authors tested a dietary intervention focused on improving meal regularity. Participants first utilized a smartphone application to track their meal frequencies, and then they were asked to restrict their meal intake to times when they most often eat to enhance meal regularity for six weeks. This, supposedly, resulted in some weight loss, supposedly independent of changes in caloric intake.

The concept is appealing, and it is interesting to use a smartphone app in participants' typical everyday environment to regularize food intake. It asks from participants to stick to meal intake times that are supported in many cultures, and it asks them not to eat outside of what are likely unhealthy habits such as grazing a refrigerator late at night. In essence, this is a restrictive diet, not restricting caloric intake but the timing of food intake, and it has many parallel to time restricted feeding. It is important to note that there are many restrictive diets, and a common problem with restrictive diets is that while they allow one to lose a couple of pounds for a couple of months just as with this diet, the long-term success is very poor because they depend on restriction. This issue is still not discussed.

Further, why the participants lose weight, whether this is indeed due to a reduction in food intake as implied, or if the weight loss occurred without a reduction in caloric intake as first stated by the authors and now suggested remains to be determined as the method of food diary as a method to assess caloric intake lacks rigor as has been well established and has been shown again and again to be misleading even though many readers without that knowledge draw conclusions from such studies and they should best have been omitted.

The authors hypothesize that the intervention improves metabolism by improving circadian rhythmicity. That's plausible, but the study provides only a subjective questionnaire and lacks more objective measures such as actigraphy.

While the authors now state now that this as a pilot study, the study falls short of providing mechanistic insights into what underlies the weight loss and the many correlations provided do not make up for this weakness.

Overall, while this pilot study introduces an interesting approach to meal regularity, its limitations highlight the need for more rigorous studies to validate these findings.

(1) Unreliable method of caloric intake

The trial's reliance on self-reported caloric intake is problematic, as participants tend to underreport intake. As pointed out earlier by me and now cited in the revised manuscript, the NEJM paper (DOI: 10.1056/NEJM199212313272701) reported that some participants underreported caloric intake by approximately 50%, rendering such data unreliable and hence misleading. The question is, why include such unreliable data that is more misleading than informative at all? These data should have been omitted. More rigorous methods for assessing food intake should have been utilized. I understand this requires more effort, such as providing participants with meals, or using better methods that photograph and weigh the meals, etc., but it is certainly feasible. It has been done many times in other studies. Further, the control group was not asked to restrict their diet in any way, and hence, asking for a restriction in timing in the treatment group may be sufficient to reduce caloric intake and induce weight loss.
Merely acknowledging the unreliability of self-reported caloric intake is insufficient, as it still leaves the reader with the impression that this weight loss is independent of caloric intake when, in reality, we actually have no idea if food intake contributes to it. A more robust approach to assessing food intake is imperative. Even if a decrease in caloric intake is observed through rigorous measurement, as I am convinced a more rigorous study would unveil testing this paradigm, this intervention may merely represent another restrictive diet among countless others that show that one may lose weight by going on a diet. Seemingly, any restrictive diet works for a few months. The trouble is they do not work long-term because they depend on restriction. I agree with the authors that their intervention seems common sense and has little downside, but one also needs to be realistic about the prospects of this intervention.

(2) Lack of objective data regarding circadian rhythm

The assessment of circadian rhythm using the MCTQ, a self-reported measure of chronotype, is subjective. More objective methods like actigraphy would have strengthened the study.

Actigraphy is considered better than a sleep questionnaire for assessing circadian rhythms because it provides objective data on activity patterns over time, offering a more accurate picture of sleep-wake cycles compared to subjective self-reported information from a questionnaire.

The authors' responses to my prior review are misleading.

I understand that this is a pilot study. Is it appropriate to point out weaknesses and flaws in the conclusion drawn from a pilot study? Absolutely, that is the reviewer's job.

I also understand that food intake can affect circadian rhythm, which was part of the rationale behind the study. Is it appropriate to criticize the study for not examining the effect of the intervention on circadian rhythm using objective measures provided by actigraphy? Yes, it is, as this would have provided mechanistic insights that are more rigorous. I understand that this was not the declared goal, but it should have been examined in a pilot study. To jump to the conclusion that based on prior studies, the intervention will improve circadian rhythms as the authors do is not rigorous and hence a weakness.

A less rigorous method, such as a food questionnaire, to assess caloric intake can result in inadequately supported and potentially misleading conclusions. By including it, the reader may conclude that there was no change in caloric intake when indeed we do not know. I disagree with the authors that this is a minor issue. The associations and correlations the authors provide do not solve the issue. Hence, to make it very clear, it remains to be studied if this intervention reduces weight by reducing caloric intake or other mechanisms. Including this data reduces the study's rigor as it suggests that there is no difference in food intake.

I did not suggest to only use an actimeter (which is a device); I suggested actigraphy. Actigraphy is widely recognized in the field for its utility in circadian rhythm research and provides objective data, while the questionnaire used is subjective. The authors do quote papers comparing their survey to actigraphy by correlation analysis, but the fundamental difference of the two approaches remains. Does an objective measure increase rigor compared to a subjective assessment? Yes, it does.

Similarly, I did not state "that any form of imposed diet appears to lead to weight loss over several months." I said that many forms of restrictive diets do induce weight loss of a similar magnitude to this diet.

The authors should have discussed the fundamental confounder of the study in that the treatment group is asked to restrict food intake to specific times while the control group is not asked to restrict in any way and the potential contribution of this to the weight loss observed.

Author response:

The following is the authors’ response to the previous reviews.

We would like to remind the editors and reviewers that the present project is a pilot study that does not claim to produce definitive results. Pilot studies are exploratory preliminary studies to test the validity of hypotheses, the feasibility of a study as well as the research methods and the study design. From our point of view, our hypotheses and the feasibility of the pilot study have been confirmed to such an extent that the implementation of a larger study is justified. At the same time, it became clear during the pilot that the methods and design need to be adapted in some areas in order to increase the reliability of the results - a finding that pilot studies are usually conducted to obtain. We discussed these limitations in detail in order to explain the planned changes in the follow-up study. What the reviewers and editors interpret as incompleteness is therefore due to the nature of a pilot study. We consider it necessary that appropriate standards are taken into account in the evaluation of the present work.

In addition, we would like to make a counterstatement as to what our main claims, which should be used to assess the strength of evidence, are - and what they are not:

In the introduction, we describe the background that led to the formation of our hypotheses: Previous animal and human studies show that food, along with light, serves as the main Zeitgeber for circadian clocks. It has also been shown that chrononutrition can lead to weight loss and improved well-being. Based on this, we hypothesized that individualized meal timing can enhance these positive effects. This hypothesis has been validated on the basis of the available results. Contrary to what the editors and reviewers stated, the assumption that the observed beneficial effects are indeed related to an alteration or resetting of endogenous circadian rhythms was not intended to be investigated in this study and is not one of our main claims. This has already been sufficiently demonstrated and, in our view, need not and should not be repeated in every study on chrononutrition. Accordingly, this assumption was not formulated as a working hypothesis or main claim. It is described in the paper as a potential mechanism, the assumption of which is justified on the basis of previous studies. The lack of a corresponding examination and the erroneous insinuation that corresponding results were nevertheless listed by us in the paper as a main claim should therefore not be used as a criterion for downgrading the assessment of the strength of evidence.

The main criticism of our study is the collection of data using self-reported food and food quantities. This form of data collection is indeed prone to error, as there is little control over the accuracy of the reported data. However, we believe that this problem is limited in scope.

(1) Contrary to what the editors and reviewers claim, at no point do we write that we are convinced that food intake has not changed. On the contrary, in Figure 2 we explicitly show that there was a change in what some participants reported to us regarding their food intake. We make it clear throughout the text that we could not find any correlation between weight change and the changes in the reports of food quantities/meals. These statements are correct and only what are actual and formulated main claims should be included in the evaluation of the study.

(2) As previously stated, we conducted analyses that suggest that an unreported reduction in food intake is unlikely to be the cause of weight loss. For the most part, participants did not change their reporting behavior during the exploration and intervention phases. That is, participants who underreported food intake reported similar amounts in both phases of the study, but lost weight only in the intervention phase. To explain their weight loss with imprecise reporting, it would have to be assumed that these participants began to eat less in the intervention phase and at the same time report more in order to achieve similar calorie counts and food composition in the evaluation. We consider such behavior to be very unlikely, especially since it would apply to numerous participants.

(3) The editors and reviewers reduce the results to the absence of a correlation between weight loss and reported food quantity and composition. In their assessment of the significance of the findings, however, they ignore the fact that we did find a significant correlation in our analyses, namely between weight loss and an increase in the regularity of food intake. There is no correlation between an increase in regularity and a reduction in reported calories (R² = 0.01472). This is credible in our view, as it is unlikely that the more regularly participants ate, the more pronounced the error in their reports was (while in reality they ate less than before).

(4) We also had the requirement for the study design that the participants could carry out the intervention in their normal everyday life and environment in order to test and ensure implementation in real life. We consider it unrealistic to be able to monitor food intake continuously and without interruption over a period of several weeks under these conditions. We therefore see no alternative to self-reporting. As the reviewers and editors did not suggest any alternative methods of data collection that would fulfil the requirements of our study, we assume that, despite criticism and reservations, they generally agree with our assessment and take this into account in their evaluation.

It is still criticized that some confounding factors are present. The reviewer makes no reference to the fact that we either eliminated these in the last version submitted (age range), identified them as unproblematic (unmatched cohorts, menstrual cycle, shift work) or even deliberately used them in order to be able to test our hypothesis more validly (inclusion of individuals with normal weight, overweight, and obesity).

Besides, the use of actimeters to determine circadian rhythms as proposed by the editors and reviewers is not valid for this study and the requirement to use them to determine a circadian reset in the eLife assessment is misleading and inappropriate. This instrument only measures physical activity, but not the physiological parameters that are relevant for an investigation in this field of research.

For the assessment of chronotype alone, the MCTQ questionnaire is a valid instrument that has been validated several times against actimetry (e.g., DOIs: 10.1080/07420528.2022.2025821, 10.1080/07420528.2023.2202246, 10.1016/j.ijpsycho.2016.07.433, 10.1155/2018/5646848). The reviewer's statement that the MCTQ questionnaire is unreliable for determining chronotype is unsupported and incorrect.

Equally unproven is the statement that any form of imposed diet appears to lead to weight loss over a period of several months.

Nevertheless, in order to prevent further misunderstandings, we have revised our text in a number of places and clarified that our statements are not irrefutable assertions, but potential interpretations of the results obtained in the pilot study, which are to be analyzed in more detail with regard to the planned more comprehensive study.