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

  1. Isabell Wilming
  2. Jana Tuschewski
  3. Jessie M Osterhaus
  4. Theresa JG Bringmann
  5. Anisja Hühne-Landgraf
  6. Dominic Landgraf

  • Curated by eLife

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    eLife Assessment

    This study investigates a dietary intervention that employs a smartphone app to promote meal regularity, findings that have theoretical or practical implications for a subfield and may be clinically useful. The intervention to entice participants to adhere to specific meal times represents a restrictive diet (even though it does not ask to limit caloric intake) similar to a time-restricted feeding diet, while the control subjects are not experiencing or adhering to dietary restrictions. The authors report significant weight loss but did not rigorously assess caloric intake which remains a weakness of this study as food diaries are notoriously unreliable. While the concept is very interesting, the study is considered incomplete, and the rigor of the results should be strengthened in follow-up studies to add more stringent methods to assess caloric intake. Additionally, the study hypothesizes that the intervention resets the circadian clock. However, the study needs an objective method for assessing circadian rhythms, such as actigraphy, in addition to a subjective questionnaire.

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Abstract

Many weight loss strategies are based on the restriction of calories or certain foods. In this pilot study, we preliminary tested a weight loss intervention based solely on increasing the regularity of meals. The assumption is based on the evidence that eating at fixed times allows the circadian system to optimally prepare the food metabolism for these times.In a two-group, single center randomized-controlled single-blind pilot study (pre-registration <related-object content-type="pre-results" document-id="DRKS00021419" document-id-type="clinical-trial-number" source-id="DRKS" source-id-type="registry-name" source-type="clinical-trials-registry" xlink:href="https://drks.de/search/en/trial/DRKS00021419">DRKS00021419</related-object>) with participants aged 18-65 years and BMI ≥ 22 kg/m 2 , we used a smartphone application to identify the times at which each participant eats particularly frequently and asked participants of the experimental group to restrict their meals to only these times for six weeks. Control participants received sham treatment. Primary outcome was body weight/BMI and secondary outcome the well-being of participants.Of 148 participants taking part in the pilot study, 121 were randomized, of whom 100 (control: 33, experimental: 67) completed the study. Our results show that the more regular the meals of participants of the experimental group became, the more weight/BMI they lost, averaging 2.62 kg (0.87 kg/m 2 ); p < 0.0001 (BMI: p < 0.0001) compared to an insignificant weight loss of 0.56 kg (0.20 kg/m 2 ) in the control group; p = 0.0918 (BMI: p = 0.0658). Strikingly, weight loss was not related to self-reported changes in calories, food composition, and other food-related factors. Additionally, physical and mental well-being improved significantly.In summary, increasing the regularity of meals may cause participants to lose excess body weight and improve overall well-being. These promising results justify a larger-scale study, albeit with a more rigorous study design.Individual optimal times for meals are determined via an app-based meal diary.Generation of a structure plan for mealtimes are adjusted to individual circadian clocks.Following this plan, participants lost an average body weight of 2.6 kg over six weeks.Weight loss does not correlate with self-reported changes in food quantity or composition.Regular mealtimes contribute to the improvement of general well-being.

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  1. Version published to 10.7554/elife.96837.3 on eLife
  2. Version published to 10.7554/elife.96837 on eLife
  3. eLife

    eLife Assessment

    This study investigates a dietary intervention that employs a smartphone app to promote meal regularity, findings that have theoretical or practical implications for a subfield and may be clinically useful. The intervention to entice participants to adhere to specific meal times represents a restrictive diet (even though it does not ask to limit caloric intake) similar to a time-restricted feeding diet, while the control subjects are not experiencing or adhering to dietary restrictions. The authors report significant weight loss but did not rigorously assess caloric intake which remains a weakness of this study as food diaries are notoriously unreliable. While the concept is very interesting, the study is considered incomplete, and the rigor of the results should be strengthened in follow-up studies to add more stringent methods to assess caloric intake. Additionally, the study hypothesizes that the intervention resets the circadian clock. However, the study needs an objective method for assessing circadian rhythms, such as actigraphy, in addition to a subjective questionnaire.

  4. eLife

    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.

  5. eLife

    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.

  6. Version published to 10.1101/2024.01.30.24301983v5 on medRxiv
  7. Version published to 10.7554/elife.96837.2 on eLife
  8. eLife

    eLife Assessment

    This study investigates a dietary intervention that employs a smartphone app to promote meal regularity, which may be useful. Despite no self-reported changes in caloric intake, the authors report significant weight loss for the relatively short duration of only 6 weeks. While the concept is very interesting and deserves to be studied due to its potential clinical relevance, the study's rigor needs to be improved upon and is currently considered incomplete, notably the reliance on self-reported food intake, a highly unreliable way to assess food intake. Additionally, the study theorizes that the intervention resets the circadian clock, but the study needs more reliable methods for assessing circadian rhythms, such as actigraphy. Further, if this restrictive dietary intervention has any more promise in achieving long-term weight loss than the myriad other restrictive diets, it remains to be tested.

  9. eLife

    Reviewer #1 (Public review):

    Summary:

    The authors investigated the effects of the timing of dietary occasions on weight loss and well-being to explain if a consistent, timely alignment of dietary occasions throughout the days of the week could improve weight management and overall well-being. The authors attributed these outcomes to a timely alignment of dietary occasions with the body's circadian rhythms. This concept is rooted in understanding dietary cues as a zeitgeber for the circadian system, potentially leading to more efficient energy use and weight management. The study participants self-reported the primary outcome, body weight loss.

    Strengths:

    The innovative focus of the study on the timing of dietary occasions rather than daily energy intake or diet composition presents a fresh perspective in dietary intervention research. The feasibility of the diet plan, developed based on individual profiles of the timing of dietary occasions identified before the intervention, marks a significant step towards personalised nutrition.

    Weaknesses:

    The methodology lacks some measurements that are emerging as very relevant in the field of nutritional science, such as data on body composition, and potential confounders not accounted for (e.g., age range, menstrual cycle, shift work, unmatched cohorts, inclusion of individuals with normal weight, overweight, and obesity). The primary outcome's reliance on self-reported body weight and subsequent measurement biases undermines the reliability of the findings.

    Achievement of Objectives and Support for Conclusions:

    The study's objectives were partially met; however, the interpretation of the effects of meal timing on weight loss is compromised by the aforementioned weaknesses. The evidence does not fully support most of the claims due to methodological limitations caused partially by the COVID-19 pandemic.

    Impact and Utility:

    Despite its innovative approach, the study's utility for practical application is limited by methodological and analytical shortcomings. Nevertheless, it represents a good basis for further research. If these findings were further investigated, they could have meaningful implications for dietary interventions and metabolic research. The concept of timing of dietary occasions in sync with circadian rhythms holds promise but requires further rigorous investigation.

  10. eLife

    Reviewer #2 (Public review):

    The authors tested a dietary intervention focused on improving meal regularity. Participants first utilized a smartphone application to track participants' meal frequencies, participants were then asked to restrict their meal intake to times when they most often eat to enhance meal regularity for six weeks, resulting in significant weight loss despite supposedly no changes in caloric intake.

    While the concept is appealing, and the use of a smartphone app in participants' typical everyday environment to regularize food intake is interesting, significant weaknesses severely limit the value of the study due to a lack of rigor, such as the reliance on self-reported food intake which has been discredited in the field. The study's major conclusions are insufficiently supported, particularly that weight loss occurred even though food intake supposedly is not altered. This intervention may merely represent another restrictive diet among countless others that all seem to work for a few weeks to months resulting in a few pounds of weight loss

    (1) Unreliable method of caloric intake

    The trial's reliance on self-reported caloric intake is problematic, as participants tend to underreport intake. For example, as 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. More rigorous methods for assessing food intake should have been utilized. Further, the control group was not asked to restrict their diet in any way, and hence, to do that in the treatment group may be sufficient to reduce caloric intake and weight loss. Merely acknowledging the unreliability of self-reported caloric intake is insufficient, as it still leaves the reader with the impression that there is no change in food intake when, in reality, we actually have no idea if food intake was altered. 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 that 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.

    (2) Lack of objective data regarding circadian rhythm

    The assessment of circadian rhythm using the MCTQ, a self-reported measure of chronotype, is unreliable, and it is unclear why more objective methods like actigraphy was not used.

    In the revised version, the authors emphasize these limitations in the manuscript. The study's major conclusions are insufficiently supported, in particular, that weight loss occurred even though food intake supposedly is not altered and that circadian rhythm was improved.

  11. eLife

    Author response:

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

    eLife Assessment

    This study investigates a dietary intervention that employs a smartphone app to promote meal regularity, which may be useful. Despite no observed changes in caloric intake, the authors report significant weight loss. While the concept is very interesting and deserves to be studied due to its potential clinical relevance, the study's rigor needs to be revised, notably for its reliance on self-reported food intake, a highly unreliable way to assess food intake. Additionally, the study theorizes that the intervention resets the circadian clock, but the study needs more reliable methods for assessing circadian rhythms, such as actigraphy.

    Thank you for the positive yet critical feedback on our manuscript. We are pleased with the assessment that our study is very interesting and deserves to be continued. We have addressed the points of criticism mentioned and discussed the limitations of the study in more detail in the revised version than before.

    Nevertheless, we would like to note that one condition for our study design was that the participants were able to carry out the study in their normal everyday environment. This means that it is not possible to fully objectively record food intake - especially not over a period of eight weeks. In our view, self-reporting of food intake is therefore unavoidable and also forms the basis of comparable studies on chrononutrition. We believe that recording data with a smartphone application at the moment of eating is a reliable means of recording food consumption and is better suited than questionnaires, for example, which have to be completed retrospectively. Objectivity could be optimized by transferring photographs of the food consumed. However, even this only provides limited protection against underreporting, as photos of individual meals, snacks, or second servings could be omitted by the participants. Sporadic indirect calorimetric measurements can help to identify under-reporting, but this cannot replace real-time self-reporting via smartphone application.

    Our data show that at the behavioral level, the rhythms of food intake are significantly less variable during the intervention. Our assumption that precise mealtimes influence the circadian rhythms of the digestive system is not new and has been confirmed many times in animal and human studies. It can therefore be assumed that comparable effects also apply to the participants in our study. Of course, a measurement of physiological rhythms is also desirable for a continuation of the study. However, we suspect that cellular rhythms in tissues of the digestive tract in particular are decisive for the changes in body weight. The characterization of these rhythms in humans is at best indirectly possible via blood factors. Reduced variability of the sleep-wake rhythm, which is measured by actigraphy, may result from our intervention, but in our view is not the decisive factor for the optimization of metabolic processes.

    We have addressed the specific comments and made changes to the manuscript as indicated below.

    Reviewer #1 (Public Review):

    The authors Wilming and colleagues set out to determine the impact of regularity of feeding per se on the efficiency of weight loss. The idea was to determine if individuals who consume 2-3 meals within individualized time frames, as opposed to those who exhibit stochastic feeding patterns throughout the circadian period, will cause weight loss.

    The methods are rigorous, and the research is conducted using a two-group, single-center, randomized-controlled, single-blinded study design. The participants were aged between 18 and 65 years old, and a smartphone application was used to determine preferred feeding times, which were then used as defined feeding times for the experimental group. This adds strength to the study since restricting feeding within preferred/personalized feeding windows will improve compliance and study completion. Following a 14-day exploration phase and a 6-week intervention period in a cohort of 100 participants (inclusive of both the controls and the experimental group that completed the study), the authors conclude that when meals are restricted to 45min or less durations (MTVS of 3 or less), this leads to efficient weight loss. Surprisingly, the study excludes the impact of self-reported meal composition on the efficiency of weight loss in the experimental group. In light of this, it is important to follow up on this observation and develop rigorous study designs that will comprehensively assess the impact of changes (sustained) in dietary composition on weight loss. The study also reports interesting effects of regularity of feeding on eating behavior, which appears to be independent of weight loss. Perhaps the most important observation is that personalized interventions that cater to individual circadian needs will likely result in more significant weight loss than when interventions are mismatched with personal circadian structures.

    We would like to thank the reviewer for the positive assessment of our study.

    (1) One concern for the study is its two-group design; however, single-group cross-over designs are tedious to develop, and an adequate 'wash-out' period may be difficult to predict.

    A cross-over design would of course be highly desirable and, if feasible, would be able to provide more robust data than a two-group design. However, we have strong doubts about the feasibility of a cross-over design. Not only does the determination of the length of the washout period to avoid carry-over effects of metabolic changes pose a difficulty, but also the assumption that those participants who start with the TTE intervention will consciously or unconsciously pay attention to adherence to certain eating times in the next phase, when they are asked to eat at times like before the study.

    In a certain way, however, our study fulfills at least one arm of the cross-over design. During the follow-up period of our study, there were some participants who, by their own admission, started eating at more irregular times again, which is comparable to the mock treatment of the control subjects. And these participants gained weight again.

    (2) A second weakness is not considering the different biological variables and racial and ethnic diversity and how that might impact outcomes. In sum, the authors have achieved the aims of the study, which will likely help move the field forward.

    In the meantime, we have at least added analyses regarding the age and gender of the participants and found no correlations with weight loss. The sample size of this pilot study was too small for a reliable analysis of the influence of ethnic diversity. If the study is continued with a larger sample size, this type of analysis will certainly come into play.

    We are pleased with the assessment that we have achieved our goals and are helping to advance the field.

    Reviewer #2 (Public Review):

    Summary:

    The authors investigated the effects of the timing of dietary occasions on weight loss and well-being with the aim of explaining if a consistent, timely alignment of dietary occasions throughout the days of the week could improve weight management and overall well-being. The authors attributed these outcomes to a timely alignment of dietary occasions with the body's own circadian rhythms. However, the only evidence the authors provided for this hypothesis is the assumption that the individual timing of dietary occasions of the study participants identified before the intervention reflects the body's own circadian rhythms. This concept is rooted in understanding of dietary cues as a zeitgeber for the circadian system, potentially leading to more efficient energy use and weight management. Furthermore, the primary outcome, body weight loss, was self-reported by the study participants.

    Strengths:

    The innovative focus of the study on the timing of dietary occasions rather than daily energy intake or diet composition presents a fresh perspective in dietary intervention research. The feasibility of the diet plan, developed based on individual profiles of the timing of dietary occasions identified before the intervention, marks a significant step towards personalised nutrition.

    We thank the reviewer for the generally positive assessment of our study and for sharing the view that our personalized approach represents an innovative step in chrononutrion.

    Weaknesses:

    (1) Several methodological issues detract from the study's credibility, including unclear definitions not widely recognized in nutrition or dietetics (e.g., "caloric event"), lack of comprehensive data on body composition, and potential confounders not accounted for (e.g., age range, menstrual cycle, shift work, unmatched cohorts, inclusion of individuals with normal weight, overweight, and obesity).

    We have replaced the term "caloric event" with "calorie intake occasion" and otherwise revised our manuscript with regard to other terminology in order to avoid ambiguity.

    We agree with the reviewer that the determination of body composition is a very important parameter to be investigated. Such investigations will definitely be part of the future continuation of the study. In this pilot study, we aimed to clarify in principle whether our intervention approach shows effects. Since we believe that this is certainly the case, we would like to address the question of what exactly the physiological mechanisms are that explain the observed weight loss in the future.

    Part of these future studies will also include other parameters in the analyses. However, in response to the reviewer's suggestions, we have already completed analyses regarding age and gender of the participants, which show that both variables have no influence on weight loss.

    In our view, the menstrual cycle should not have a major influence on the effectiveness of a 6-week intervention.

    The inclusion of shift workers is not a problem from our point of view. If their work shifts allow them to follow their personal eating schedule, we see no violation of our hypothesis. If this is not the case, as our data in Fig. 1G show, we do not expect any weight loss. Nevertheless, the reviewer is of course right that shift work can generally be a confounding factor and have an influence on weight loss success. To our knowledge, none of the 100 participants evaluated were shift workers. In a continuation of the study, however, shift work should be an exclusion criterion. Yet, our intervention approach could be of great interest for shift workers in particular, as they may be at a particularly high risk of obesity due to irregular eating times. A separate study with shift workers alone could therefore be of particular interest.

    The fact that it turned out that the baseline BMI of the remaining 67 EG and 33 CG participants did not match is discussed in detail in the section "3.1 Limitations". Although this is a limitation, it does not raise much doubt about the effectiveness of the intervention, as a subgroup analysis shows that intervention subjects lose more weight than control subjects of the same BMI.

    The inclusion of a wide BMI range was intentional. Our hypothesis is that reduced temporal variability in eating times optimizes metabolism and therefore excess body weight is lost (which we would like to investigate specifically in future studies). We hypothesize that people living with a high BMI will experience greater optimization than people with a lower BMI. Our data in Figs. 1H and S2I suggest that this assumption is correct.

    (2) The primary outcome's reliance on self-reported body weight and subsequent measurement biases further undermines the reliability of the findings.

    Self-reported data is always more prone to errors than objectively measured data. With regard to the collection of body weight, we were severely restricted in terms of direct contact with the participants during the conduct of the study due to the Covid-19 pandemic. At least the measurement of the initial body weight (at T0), the body weight after the end of the exploration phase (at T1) and the final body weight (at T2) were measured in video calls in the (virtual) presence of the study staff. These are the measurement points that were decisive for our analyses. Intermediate self-reported measurement points were not considered for analyses. We have added in the Materials & Methods section that video calls were undertaken to minimize the risk of misreporting.

    (3) Additionally, the absence of registration in clinical trial registries, such as the EU Clinical Trials Register or clinicaltrials.gov, and the multiple testing of hypotheses which were not listed a priori in the research protocol published on the German Register of Clinical Trials impede the study's transparency and reproducibility.

    Our study was registered in the DRKS - German Clinical Trials Register in accordance with international requirements. The DRKS fulfills the same important criteria as the EU Clinical Trial Register and clinicaltrials.gov.

    We quote from the homepage of the DRKS: „The DRKS is the approved WHO Primary Register in Germany and thus meets the requirements of the International Committee of Medical Journal Editors (ICMJE). […] The WHO brings together the worldwide activities for the registration of clinical trials on the International Clinical Trials Registry Platform (ICTRP). […] As a Primary Register, the DRKS is a member of the ICTRP network.”

    We are therefore convinced that we registered our study in the correct place.

    Furthermore, in our view, we did not provide less information on planned analyses than is usual and all our analyses were covered by the information in the study registry. We have stated the hypothesis in the study register that „strict adherence to [personalized] mealtimes will lead to a strengthening of the circadian system in the digestive tract and thus to an optimization of the utilization of nutrients and ultimately to the adjustment of body weight to an individual ideal value.“

    In our view, numerous analyses are necessary to test this hypothesis. We investigated whether it is the adherence to eating times that is related to the observed weight loss (Fig. 1), or possibly other variables resulting from adherence to the meal schedule (Fig. 3). In addition, we analyzed whether the intervention optimized the utilization of nutrients, which we did based on the food composition and number of calories during the exploration and intervention phases (Fig. 2). We investigated whether the personalization of meal schedules plays a role (Fig. 3). And we attempted to analyze whether the adjustment of body weight to an individual ideal value occurs by correlating the influence of the original BMI with weight loss. Only the hypothesis that the circadian system in the digestive tract is strengthened has not yet been directly investigated, a fact that is listed as a limitation. Although it can be assumed that this has happened, as the Zeitgeber “food” has lost significant variability as a result of the intervention. The analyses on general well-being are covered in the study protocol by the listing of secondary endpoints.

    Beyond that, we did not analyze any hypotheses that were not formulated a priori.

    For these reasons, we see no restriction in transparency, reproducibility or requirements and regulations.

    Achievement of Objectives and Support for Conclusions:

    (4) The study's objectives were partially met; however, the interpretation of the effects of meal timing on weight loss is compromised by the weaknesses mentioned above. The evidence only partially supports some of the claims due to methodological flaws and unstructured data analysis.

    We hope that we have been able to dispel uncertainties regarding some interpretations through supplementary analyses and the addition of some methodological details.

    Impact and Utility:

    (5) Despite its innovative approach, significant methodological and analytical shortcomings limit the study's utility. If these issues were addressed, the research could have meaningful implications for dietary interventions and metabolic research. The concept of timing of dietary occasions in sync with circadian rhythms holds promise but requires further rigorous investigation.

    We are pleased with the assessment that our data to date is promising. We hope that the revised version will already clarify some of the doubts about the data available so far. Furthermore, we absolutely agree with the reviewer: the present study serves to verify whether our intervention approach is potentially effective for weight loss - which we believe is the case. In the next steps, we plan to include extensive metabolic studies and to adjust the limitations of the present study.

    Reviewer #3 (Public Review):

    The authors tested a dietary intervention focused on improving meal regularity in this interesting paper. The study, a two-group, single-center, randomized, controlled, single-blind trial, utilized a smartphone application to track participants' meal frequencies and instructed the experimental group to confine their eating to these times for six weeks. The authors concluded that improving meal regularity reduced excess body weight despite food intake not being altered and contributed to overall improvements in well-being.

    The concept is interesting, but the need for more rigor is of concern.

    We would like to thank the reviewer for the interest in our study.

    (1) A notable limitation is the reliance on self-reported food intake, with the primary outcome being self-reported body weight/BMI, indicating an average weight loss of 2.62 kg. Despite no observed change in caloric intake, the authors assert weight loss among participants.

    As already described above in the responses to the reviewer 2, the body weight assessment took place in video calls in the (virtual) presence of study staff, so that the risk of misreporting is minimized. We have added this information to the manuscript.

    When recording food intake, we had to weigh up the risk of misreporting against the risk of a lack of validity in a permanently monitored setting. It was important to us to investigate the effectiveness of the intervention in the participants' everyday environment and not in a laboratory setting in order to be able to convincingly demonstrate its applicability in everyday life. The restriction of self-reporting is therefore unavoidable in our view and must be accepted. It can possibly be reduced by photographing the food, but even this is not a complete protection against underreporting, as there is no guarantee that everything that is ingested is actually photographed.

    However, our analyses show that the reporting behavior of individual participants did not change significantly between the exploration and intervention phases. We do not assume that participants who underreported only did so during the exploration phase (and only ate more than reported in this study phase) and reported correctly in the intervention phase (and then indeed consumed fewer calories). We discuss this point in the section "3.1 Limitations".

    (2) The trial's reliance on self-reported caloric intake is problematic, as participants tend to underreport intake; for example, in the NEJM paper (DOI: 10.1056/NEJM199212313272701), some participants underreported caloric intake by approximately 50%, rendering such data unreliable and hence misleading. More rigorous methods for assessing food intake are available and should have been utilized. Merely acknowledging the unreliability of self-reported caloric intake is insufficient as it would still leave the reader with the impression that there is no change in food intake when we actually have no idea if food intake was altered. 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 short-term diet among countless others that show that one may lose weight by going on a diet, principally due to heightened dietary awareness.

    The risks of self-reporting, our considerations, and our analysis of participants' reporting behavior and caloric intake over the course of the study are discussed in detail both in our responses above and in the manuscript.

    With regard to the reviewer's second argument, we have largely adapted the study protocol of the control group to that of the experimental group. Apart from the fact that the control subjects were not given guidelines on eating times and were instead only given a very rough time window of 18 hours for food intake, the content of the sessions and the measurement methods were the same in both groups. This means that the possibility of increased nutritional awareness was equally present in both groups, but only the participants in the experimental group lost a significant amount of body weight.

    In future continuations of the study, further follow-up after an even longer period than four weeks (e.g. after 6 months) can be included in the protocol in order to examine whether the effects can be sustained over a longer period.

    (3) Furthermore, the assessment of circadian rhythm using the MCTQ, a self-reported measure of chronotype, may not be as reliable as more objective methods like actigraphy.

    The MCTQ is a validated means of determining chronotype and its results are significantly associated with the results of actigraphic measurements. In our view, the MCTQ is sufficient to test our hypothesis that matching the chronobiological characteristics of participants is beneficial. Nevertheless, measurements using actigraphy could be of interest, for example to correlate the success of weight loss with parameters of the sleep-wake rhythm.

    (4) Given the potential limitations associated with self-reported data in both dietary intake and circadian rhythm assessment, the overall impact of this manuscript is low. Increasing rigor by incorporating more objective and reliable measurement techniques in future studies could strengthen the validity and impact of the findings.

    The body weight data was not self-reported, but the measurements were taken in the presence of study staff. Although optimization might be possible (see above), we do not currently see any other way of recording all calorie intake occasions in the natural environment of the participants over a period of several weeks (or possibly longer, as noted by the reviewer) other than self-report and, in our opinion, it would not be feasible. For the future continuation of the study, we are planning occasional indirect calorimetry measurements that can provide information about the actual amount of food consumed in different phases of the study. These can reveal errors in the self-report but will not be able to replace daily data collection by means of self-report.

    Reviewer #1 (Recommendations For The Authors):

    Summary:

    This interesting and timely study by Wilming and colleagues examines the effect of regularity vs. irregularity of feeding on body weight dynamics and BMI. A rigorous assessment of the same in humans needs to be improved, which this study provides. The study is well-designed, with a 14-day exploration phase followed by 6 weeks of intervention, and it is commendable to see the number of participants (100) who completed the study. Incorporation of a follow-up assessment 4 weeks after the conclusion of the study shows maintained weight loss in a subset of Experimental Group (EG) participants who continue with regular meals. There are several key observations, including particular meal times (lunch and dinner), which, when restricted to 45min or less in duration (MTVS of 3 or less), will lead to efficient weight loss, as well as correlations between baseline BMI and weight loss. The authors also exclude the impact of self-reported meal composition on the efficiency of weight loss in the EG group in the context of this study. The study reports interesting effects of regularity of feeding on eating behavior, which appears to be independent of weight loss. Finally, the authors highlight an important point: to provide attention to personalized feeding and circadian windows and that personalized interventions that cater to individual circadian structures will result in more significant weight loss. This is an important concept that needs to be brought to light. There are only a few minor comments listed below:

    Minor comments:

    (1) The authors may provide explanations for the reduction in the MTVS in the EG and the increase in the same for the Control Group (CG). The increases in MTVS in CG are surprising (lines 105-106) because it is assumed that there is no difference in CG eating patterns prior to and during the study.

    As the reviewer correctly states, our assumption was that there should be no change in the MTVS before and during the study - but we could not rule this out, as the subjects were not given any indication of the regularity of food intake in the fixed time window in the meetings with the study staff, i.e. they were not instructed to continue eating exactly as before. This would possibly have led to an effort on the part of the participants to adhere to a schedule as precisely as possible. As a result, there was a statistically significant worsening of the MTVS in the CG, which was less than 0.6 MTVS, i.e. a time span of only approx. ± 7.5 min, and remained within the MTVS 3. Since there were no correlations between the measured MTVS and the weight of the subjects in the CG and a change of about half an MTVS value has only a rather minor effect on weight, we do not attribute great significance to the observed deterioration in the MTVS.

    (2) There would be greater clarity for the readers if the authors clearly defined the study design in detail at the outset of the study, e.g., in section 2.1.

    We have included a brief summary of the study design at the end of the introduction so that the reader is already familiar with it at the beginning of the manuscript without having to switch to the material and methods section.

    (3) The data in Fig S2H is important and informs readers that the regularity of lunch and dinner is more related to body weight changes than breakfast. These data should be incorporated in the Main Figure. In addition, analyses of Table S7 data indicate that MTVS of no greater than 3 or -/+45mins of the meal-timing window is associated with efficient weight loss) should be represented in a figure panel in the Main Figures.

    As suggested by the reviewer, we have moved Fig. S2H to the main Fig. 1. In addition, Table S7 is now no longer inserted as a supplementary table but as main Table 1 in the manuscript.

    (4) The authors state in lines 222-223 that "weight changes of participants were not related to one of these changes in eating characteristics (Fig. 3B-D, Tab. S6)", referring to the shortening of feeding windows as noted in the EG group. This is a rather simplistic statement, which should be amended to include that weight changes may not relate to changes in eating characteristics per se but likely relate to changes in metabolic programming, for instance, energy expenditure increases, which have been shown to associate with these changes in eating characteristics. This is important to note.

    We have changed the wording at this point so that it is clear that we are only referring here in the results section to the results of the mathematical analysis, which showed no correlation between the eating time window and weight loss in our sample. However, we have now explicitly mentioned the change in metabolic programming correctly noted by the reviewer in the discussion at the end of section 3.

    (5) Please provide more background and details on the attributes that define individual participant chronotypes in the manuscript before discussing datasets, e.g., mSP and mEP. This is relation to narratives between 228-230: "Indeed, our data show that the later the chronotype of participants (measured by the MCTQ mid-sleep phase, mSP [24]), the later their mid-eat phase (mEP) on weekends (Fig. 3E, Tab. S6), with the mSP and mEP being almost antiphasic on average (Fig. 3F, Tab. S10)." This will help readers unfamiliar with circadian biology/chronobiology research understand the contents of this manuscript, particularly Fig 3.

    We have explained the new chronobiology terms that appear in the chapter better in the revised version so that they are easier to understand.

    Reviewer #2 (Recommendations For The Authors):

    (1) Clarify Terminology: Define or avoid using ambiguous terms such as "caloric event" to prevent confusion, especially for readers less familiar with chronobiology. Consider providing clear explanations or opting for more widely understood terms.

    We have replaced "caloric event" with “calorie intake occasion” and explain various chronobiology terms better, so that hopefully readers from other disciplines can now follow the text more easily.

    (2) Detailed Methodological Descriptions: Improve the transparency of your methods, especially concerning the measurement of primary and secondary outcomes. Address the concerns raised about the reliability of self-reported weight and the potential biases in measurement methods.

    In the section "3.1 Limitations", we have examined the aspect of the reliability of self-reported data and our measures to reduce this uncertainty in more detail. We have also added further details on the measurement of outcomes in the materials and methods section.

    (3) Address Participant Selection Criteria: Reevaluate the inclusion criteria and consider discussing the implications on the study's findings of the broad age range, the inclusion of shift work, unmatched cohorts, and inclusion of individuals with normal weight, overweight, and obesity. Provide a subgroup analysis or discuss how BMI might have influenced the results. Even though this is an additional post-hoc analysis, it would directly address one of the major weaknesses of the study design.

    We have supplemented the analyses and now show in Fig. S2G that neither age nor gender had any influence on weight loss as a result of the intervention. To our knowledge, none of the 100 participants evaluated were shift workers. Even if shift workers were part of the study without our knowledge, we do not consider this to be a problem as long as their shifts allow them to keep to certain eating times. The fact that it turned out that the baseline BMI of the remaining 67 EG and 33 CG participants did not match is discussed in detail in the section "3.1 Limitations". Our previous analysis in Fig. S2I already showed that there is a negative correlation between baseline BMI and weight loss - an interesting result, as it shows that people with a high BMI particularly benefit from the intervention. In addition, we already showed in Fig. S2J in a subgroup analysis that in all strata the BMI of EG subjects decreased more than that of CG subjects, even if they had the same initial BMI. We do not consider the wide dispersion of the BMIs of the included participants to be a weakness of the study design. On the contrary, it allows us to make a statement about which target group the intervention is particularly suitable for.

    (4) Improve Statistical Analysis: If not already done, involve a biostatistician to review the statistical analyses, particularly concerning post-hoc tests, correlation analyses, and the handling of measurement biases. Ensure that deviations from the original study protocol are clearly documented and justified.

    All analyses have already been checked by a statistician, decided together with him and approved by him.

    (5) Data Interpretation and Speculation: Limit speculation and clearly distinguish between findings supported by your data from hypotheses and future directions. Ensure that discussions about the implications of meal timing on metabolism are supported by evidence with adequate references and clearly state where further research is needed.

    We have revised the discussion and, especially through the detailed discussions of the limitations, we have emphasized more clearly what has been achieved and what still needs to be proven in future studies.

    (6) Clinical Trial Registration: Address the lack of registration in the EU Clinical Trials Register and clinicaltrials.gov. Discuss its potential implications on the study's transparency and how it aligns with current requirements and regulations.

    Our study was registered in the DRKS - German Clinical Trials Register in accordance with international requirements. The DRKS fulfills the same important criteria as the EU Clinical Trial Register and clinicaltrials.gov.

    We quote from the homepage of the DRKS: „The DRKS is the approved WHO Primary Register in Germany and thus meets the requirements of the International Committee of Medical Journal Editors (ICMJE).[…] The WHO brings together the worldwide activities for the registration of clinical trials on the International Clinical Trials Registry Platform (ICTRP). […] As a Primary Register, the DRKS is a member of the ICTRP network.”

    We are therefore convinced that we registered our study in the correct place before it began and see no restriction in transparency or requirements and regulations.

    (7) Use of Sensitive and Current Terminology: Update the manuscript to reflect the latest recommendations regarding the language used to describe obesity and patients living with obesity. This ensures respect and accuracy in reporting and aligns with contemporary standards in the field.

    We updated the manuscript accordingly.

    (8) Strengthen the Introduction: Expand the literature review to include more recent and relevant studies that contextualise your work within the broader field of chrononutrition. This could help clarify how your study builds upon or diverges from existing research.

    We have included further studies in the introduction that aim to reduce body weight by restricting food intake to certain time periods. We have also more clearly contrasted the designs of these studies with the design of our study.

    (9) Clarify Discrepancies and Errors: Address any inconsistencies, such as the discrepancy in meal timing instructions (90 minutes reported in the conclusion vs. 60 minutes reported in the methods), and ensure all figures, tables, and statistical analyses are correctly referenced and described.

    The first point mentioned by the reviewer is not an inconsistency. To ensure the feasibility of the intervention, each participant was initially given a time window of +/- 30 minutes (60 min) from the specified eating time. Our later analyses show that even a time window of +/- 45 minutes (90 min) around the specified eating time is sufficient to lose weight efficiently (see results in Table 1).

    We have checked all references to figures, tables and statistical analyses and updated them if necessary.

    (10) Discuss Limitations and Bias: More thoroughly discuss the limitations of your study, including the potential impacts of biases and how they were mitigated. Additionally, consider the effects of including shift workers and how this choice impacts the applicability of your findings.

    Section “3.1 Limitations” has now been supplemented by a number of points and discussions. As described above, we do not consider the inclusion of shift workers to be a limitation as long as they are able to adhere to the specifications of the eating time plan. We cannot derive any indications to the contrary from our data.

    (11) Consider Publishing Separate Manuscripts: If the study encompasses a wide range of outcomes or post-hoc analyses, consider separating these into distinct publications to allow for a more focused and detailed exploration of each set of findings.

    We will take this advice into consideration for future publications on the continuation of the study. As this is a pilot study that is intended to clarify whether and to what extent the intervention is effective, we believe it makes sense to report all the data in a publication.

    (12) By addressing these recommendations, the authors can significantly improve their manuscript's clarity, reliability, and impact. This would not only support the dissemination of their findings but also would contribute valuable insights into the growing field of chrononutrition.

    We hope that we have satisfactorily answered, discussed and implemented the points mentioned by the reviewer in the manuscript, so that clarity, reliability, and impact have been increased and it can offer a valuable contribution to the named field.

  12. Version published to 10.1101/2024.01.30.24301983v4 on medRxiv
  13. Version published to 10.7554/elife.96837.1 on eLife
  14. eLife

    eLife assessment

    This study investigates a dietary intervention that employs a smartphone app to promote meal regularity, which may be useful. Despite no observed changes in caloric intake, the authors report significant weight loss. While the concept is very interesting and deserves to be studied due to its potential clinical relevance, the study's rigor needs to be improved, and is currently considered inadequate, notably for its reliance on self-reported food intake, a highly unreliable way to assess food intake. Additionally, the study theorizes that the intervention resets the circadian clock, but the study needs more reliable methods for assessing circadian rhythms, such as actigraphy.

  15. eLife

    Reviewer #1 (Public Review):

    The authors Wilming and colleagues set out to determine the impact of regularity of feeding per se on the efficiency of weight loss. The idea was to determine if individuals who consume 2-3 meals within individualized time frames, as opposed to those who exhibit stochastic feeding patterns throughout the circadian period, will cause weight loss.

    The methods are rigorous, and the research is conducted using a two-group, single-center, randomized-controlled, single-blinded study design. The participants were aged between 18 and 65 years old, and a smartphone application was used to determine preferred feeding times, which were then used as defined feeding times for the experimental group. This adds strength to the study since restricting feeding within preferred/personalized feeding windows will improve compliance and study completion. Following a 14-day exploration phase and a 6-week intervention period in a cohort of 100 participants (inclusive of both the controls and the experimental group that completed the study), the authors conclude that when meals are restricted to 45min or less durations (MTVS of 3 or less), this leads to efficient weight loss. Surprisingly, the study excludes the impact of self-reported meal composition on the efficiency of weight loss in the experimental group. In light of this, it is important to follow up on this observation and develop rigorous study designs that will comprehensively assess the impact of changes (sustained) in dietary composition on weight loss. The study also reports interesting effects of regularity of feeding on eating behavior, which appears to be independent of weight loss. Perhaps the most important observation is that personalized interventions that cater to individual circadian needs will likely result in more significant weight loss than when interventions are mismatched with personal circadian structures. One are of concern for the study is its two-group design; however, single-group cross-over designs are tedious to develop, and an adequate 'wash-out' period may be difficult to predict. A second weakness is not considering the different biological variables and racial and ethnic diversity and how that might impact outcomes. In sum, the authors have achieved the aims of the study, which will likely help move the field forward.

  16. eLife

    Reviewer #2 (Public Review):

    Summary:

    The authors investigated the effects of the timing of dietary occasions on weight loss and well-being with the aim of explaining if a consistent, timely alignment of dietary occasions throughout the days of the week could improve weight management and overall well-being. The authors attributed these outcomes to a timely alignment of dietary occasions with the body's own circadian rhythms. However, the only evidence the authors provided for this hypothesis is the assumption that the individual timing of dietary occasions of the study participants identified before the intervention reflects the body's own circadian rhythms. This concept is rooted in understanding of dietary cues as a zeitgeber for the circadian system, potentially leading to more efficient energy use and weight management. Furthermore, the primary outcome, body weight loss, was self-reported by the study participants.

    Strengths:

    The innovative focus of the study on the timing of dietary occasions rather than daily energy intake or diet composition presents a fresh perspective in dietary intervention research. The feasibility of the diet plan, developed based on individual profiles of the timing of dietary occasions identified before the intervention, marks a significant step towards personalised nutrition.

    Weaknesses:

    Several methodological issues detract from the study's credibility, including unclear definitions not widely recognized in nutrition or dietetics (e.g., "caloric event"), lack of comprehensive data on body composition, and potential confounders not accounted for (e.g., age range, menstrual cycle, shift work, unmatched cohorts, inclusion of individuals with normal weight, overweight, and obesity). The primary outcome's reliance on self-reported body weight and subsequent measurement biases further undermines the reliability of the findings. Additionally, the absence of registration in clinical trial registries, such as the EU Clinical Trials Register or clinicaltrials.gov, and the multiple testing of hypotheses which were not listed a priori in the research protocol published on the German Register of Clinical Trials impede the study's transparency and reproducibility.

    Achievement of Objectives and Support for Conclusions:

    The study's objectives were partially met; however, the interpretation of the effects of meal timing on weight loss is compromised by the weaknesses mentioned above. The evidence only partially supports some of the claims due to methodological flaws and unstructured data analysis.

    Impact and Utility:

    Despite its innovative approach, significant methodological and analytical shortcomings limit the study's utility. If these issues were addressed, the research could have meaningful implications for dietary interventions and metabolic research. The concept of timing of dietary occasions in sync with circadian rhythms holds promise but requires further rigorous investigation.

  17. eLife

    Reviewer #3 (Public Review):

    The authors tested a dietary intervention focused on improving meal regularity in this interesting paper. The study, a two-group, single-center, randomized, controlled, single-blind trial, utilized a smartphone application to track participants' meal frequencies and instructed the experimental group to confine their eating to these times for six weeks. The authors concluded that improving meal regularity reduced excess body weight despite food intake not being altered and contributed to overall improvements in well-being.

    The concept is interesting, but the need for more rigor is of concern.

    A notable limitation is the reliance on self-reported food intake, with the primary outcome being self-reported body weight/BMI, indicating an average weight loss of 2.62 kg. Despite no observed change in caloric intake, the authors assert weight loss among participants.

    The trial's reliance on self-reported caloric intake is problematic, as participants tend to underreport intake; for example, in the NEJM paper (DOI: 10.1056/NEJM199212313272701), some participants underreported caloric intake by approximately 50%, rendering such data unreliable and hence misleading. More rigorous methods for assessing food intake are available and should have been utilized. Merely acknowledging the unreliability of self-reported caloric intake is insufficient as it would still leave the reader with the impression that there is no change in food intake when we actually have no idea if food intake was altered. 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 short-term diet among countless others that show that one may lose weight by going on a diet, principally due to heightened dietary awareness.

    Furthermore, the assessment of circadian rhythm using the MCTQ, a self-reported measure of chronotype, may not be as reliable as more objective methods like actigraphy.

    Given the potential limitations associated with self-reported data in both dietary intake and circadian rhythm assessment, the overall impact of this manuscript is low. Increasing rigor by incorporating more objective and reliable measurement techniques in future studies could strengthen the validity and impact of the findings.

  18. Version published to 10.1101/2024.01.30.24301983v3 on medRxiv
  19. Version published to 10.1101/2024.01.30.24301983v2 on medRxiv
  20. Version published to 10.1101/2024.01.30.24301983v1 on medRxiv