PONE-D-26-01746Impact of the FTO rs9939609 risk allele on subcutaneous adipose tissue fatty acid composition in adults with obesityPLOS One

Dear Dr. Ingrid Løvold Mostad,

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ACADEMIC EDITOR: Major revision

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Marwan Salih Al-Nimer, MD, PhD

Academic Editor

PLOS One

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Reviewers' comments:

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Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: No

Reviewer #2: No

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: The study involves a very large number of statistical comparisons across genotypes, sexes, depots, individual fatty acids, and grouped fatty acids, which substantially increases the risk of false-positive findings. Although Bonferroni correction is applied in selected analyses, the overall analytical strategy remains highly exploratory. This concern is particularly relevant for the male subgroup analyses, where sample sizes are very small (e.g., n = 6 in the TT genotype group). While the authors appropriately express caution in the Discussion, this exploratory nature should be emphasized more explicitly in the Results, Abstract, and Conclusions to avoid overinterpretation by readers.

The numerous tables and highly detailed reporting of each fatty acid may obscure the main findings. The authors should simplify the Results section by focusing on key biological patterns and adding brief summaries to help readers navigate the data. Despite these concerns, the manuscript makes a valuable contribution.

Reviewer #2: The study titled “Impact of the FTO rs9939609 risk allele on subcutaneous adipose tissue fatty acid composition in adults with obesity” by Mostad et al addresses an important and relevant topic; however, several revisions are needed to improve the clarity and rigor of the manuscript.

1. Pages 9-10: The introduction would benefit from a clearer and more explicitly defined research gap early in the section. While the authors reference several potential gaps, including non-satiety mechanisms, fatty acid metabolism, and depot-specific effects, the primary unanswered question is not clearly articulated. A more focused statement outlining exactly what remains unknown and how the present study addresses this gap would improve clarity and strengthen the framing of the manuscript.

2. Pages 9-10: A substantial portion of the introduction summarizes the authors’ prior studies (refs 6–10). While this work is relevant, the emphasis creates a somewhat self-referential tone and limits broader contextualization within the existing literature. Expanding the discussion to more comprehensively synthesize findings from independent groups would provide a more balanced and field-wide perspective.

3. Pages 9-10: The biological rationale underlying the study requires further development. Specifically, the proposed link between FTO, fatty acid metabolism, and adipose tissue fatty acid composition is introduced but not convincingly explained. Additionally, the rationale for examining fatty acid composition rather than adiposity measures themselves should be more clearly justified.

4. Line 69: The inclusion criteria specify participants aged ≥20 years, but no upper age limit is reported. Please clarify whether an upper age cutoff was applied, as advanced age can substantially influence adipose tissue biology and fatty acid composition and may confound the interpretation of obesity-related metabolic findings.

5. Line 69: The study includes participants with BMI ≥35 kg/m², whereas standard definitions classify obesity at BMI ≥30 kg/m². Please clarify the rationale for using this higher threshold.

6. Page 33: The analysis focuses on a single FTO locus (rs9939609). However, other FTO variants may have distinct or even divergent effects on adiposity and body composition. Please acknowledge this limitation and discuss how restricting the analysis to one locus may influence the interpretation of the genetic findings.

7. Page 33: The study does not evaluate mRNA expression levels across FTO rs9939609 genotypes or assess appetite- and hormone-related markers. Given that variation in FTO expression and associated hormonal pathways may influence body composition, the absence of these functional correlates should be acknowledged.

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Reviewer #1: Yes:  Aisha Al Khinji

Reviewer #2: No

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Impact of the FTO rs9939609 risk allele on subcutaneous adipose tissue fatty acid composition in adults with obesity class 2 and 3

PONE-D-26-01746R1

Dear Dr. Ingrid Løvold Mostad,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Marwan Salih Al-Nimer, MD, PhD

Academic Editor

PLOS One

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