Dear Dr. Kiliaan,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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We look forward to receiving your revised manuscript.

Kind regards,

Peng Gao, Ph.D.

Academic Editor

PLOS ONE

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Before we proceed with your manuscript, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., a Research Ethics Committee or Institutional Review Board, etc.). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of recommended repositories, please see

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We will update your Data Availability statement on your behalf to reflect the information you provide.

3. In the online submission form, you indicated that Datasets are available upon request and hippocampal RNAseq data will be available in the Gene Expression Omnibus (GEO) repository (https://www.ncbi.nlm.nih.gov/gds) after acceptance.

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Additional Editor Comments :

The evidence supporting improved hippocampal vasoreactivity and cortico-hippocampal connectivity post-lipectomy is compelling, backed by robust MRI and behavioral data. However, the cognitive outcomes are mixed, with no clear improvement in learning tasks despite enhanced connectivity. This discrepancy suggests that other factors (e.g., aging, additional comorbidities) may modulate cognitive outcomes. The histological absence of neuroinflammation contrasts with RNAseq findings, highlighting the need for complementary techniques (e.g., multiplex cytokine assays) to resolve this inconsistency.

1. Discuss how eWAT findings might extrapolate to human visceral fat, addressing anatomical/functional differences and potential compensatory mechanisms in humans.

2. Perform additional cognitive tests (e.g., fear conditioning) to reconcile behavioral findings with imaging results. Consider longer post-surgery follow-ups to capture delayed cognitive effects.

3. Measure arteriovenous differences in adipokines/cytokines or use kinetic labeling to better quantify WAT-derived systemic contributions.

4. Reanalyze CBF data to explicitly compare pre- vs. post-surgery trends within groups, as the current interpretation of “masked aging effects” is speculative without direct statistical support.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

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

Reviewer #1: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

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Reviewer #1: This paper mainly studied the Partial removal of visceral epididymal white adipose tissue in obese Ldlr-/-.Leiden mice alters adipokine secretion and improves cerebrovascular health. There are some problems that need to be modified.

The main problem:

1. Please combine Figure 1 and Figure 2 in a picture and mark the words Ldlr-/- mice in Figure 1.

2. In Figure S1, only statistical diagrams are available. Please add representative histological pictures.

3. What is the control group for these values in Table 1? Please explain the result.

4. There are Figure1-9 in this article.Please modify no more than 6 Figures, for example, Figure 4 and 9 can be placed in the supplementary data.

5. In Figure 9, only sequencing results were analyzed, and no validation experiments were conducted on USP22. the conclusion "Partial eWAT lipectomy specifically inactivates USP22 in the hippocampus" lacks rigor.

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what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy

Reviewer #1: No

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While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org . Please note that Supporting Information files do not need this step.

Partial removal of visceral epididymal white adipose tissue in obese Ldlr-/-.Leiden mice impacts adipokine secretion, plasma free fatty acids, and improves cerebrovascular health

PONE-D-25-13042R1

Dear Dr. Kiliaan,

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.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Peng Gao, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewer #1:

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

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Reviewer #1: This article has undergone numerous revisions based on the specific review comments. Each review comment has been responded to rigorously, and the quality of the images is high. Therefore, I agree to accept this article.

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what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy

Reviewer #1: No

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