Reviewer 1

Subject Appropriateness of the Manuscript

The topic of this manuscript falls within the scope of Journal of Obesity

Recommendation

Reject (Paper is not of sufficient quality or novelty to be published in this Journal)

Comments

The aim of this study was to examine factors predicting weight gain on chow, a synthetic control diet, and a synthetic HFD in C57BL6/J mice. The authors report larger variation in weight gain in mice on HFD that was not present in leptin deficit models, that was unrelated to animal dominance. Weight gain was inversely related to pre-diet weight loss in response to a 16hour fast, please rationale why this was tested as a predictive factor in the introduction. Weight gain was not related to the measured appetite and glucoregulatory hormonal factors. There are a lot of small errors and omissions in this work throughout that require attention. I found some of the figures a bit confusing and don’t understand why some figures are supplementary and others are not.

Comments

Table 1 - the percentages given as fat, CHO and protein do not add up to 100% (67% for chow, 89 and 91% for CD and HFD so this leads me to believe that it is by weight with fibre missing from the calculation? But I cannot compute how a 45% fat by weight diet is only 0.7kcals/g less than the 5% by weight fat diet. Please check.
I disagree that a high fat content specifically causes weight gain, even if the calculations from table 1 are correct and there was no difference in energy intakes. Activity levels of mice were not assessed and so this claim should be removed.
Why was a 16h fast chosen? This should be discussed, this is prolonged and likely induces some stress, could stress susceptibility be a factor related to weight gain? Can cortisol be assessed?
Do the investigators consider that fasting levels of gut related peptides and one refed timpoint is sufficient for proper assessment of appetite related factors? Please discuss. Please clarify the re-fed time taken in the methodology.
I am confused between cohorts 3-6 given in Figure S1 and Cohorts 1-4 in the text please reconcile. Since HFD animals gained more at one location than the other, I do not think it is appropriate to combine these. Do the results hold when HFD groups are separated into cohorts by location? Could this be reason for variability in weight gain on HFD? I am not sure what is meant by “minimal variation across cohorts”? From the figure to me it looks as if there is considerable variation across the HFD cohorts, but within the same cohort is smaller variation?
Please also provide data as to all relationships between WL by fasting when given in grams rather than as % in Figure 3, do these results hold? Why were there 3 fasting weight loss periods reported in Figure 3A? This was only done twice 12 weeks apart? There were also 2 outliers, did results include these individuals? Figure 3B can be deleted.
The last 3 paragraphs of the results section could be shortened to one. Please clarify the relative contribution of fasting response and diet to weight gain.
Please be consistent with terminology utilising NCD or “chow”
Why use “trend” to described the reduction in food intake, this P was <0.05?
Figure 3B doesn’t match the listed figure should be 1C and 1D? Figures 2 is not significant and could be removed. Why were NCD not included on Figure 4? Data is not split in SFig2 for hormone/diet differences but is stated in the results section. Please include or remove entirely.

Reviewer 2

Subject Appropriateness of the Manuscript

The topic of this manuscript falls within the scope of Journal of Obesity

Recommendation

Reject (Paper is seriously flawed; do not encourage resubmission.)

Comments

In this manuscript the authors have described the physiological effects of dietary manipulation in a common inbred strain of laboratory mice. The aim of this study was to control the genetic background, environment and diet of these laboratory animals as closely as possible in order to assess the amount of variability that is not due to genetic differences. Although this work is compare different genetic mouse, the data presented are not novel and some results are not consistent with the conclusive statements of the Authors.

I saw this paper published on biorxiv already. http://biorxiv.org/content/early/2014/04/23/004283