PONE-D-25-09455The olanzapine-induced metabolic syndrome appears to be partially caused by the dysfunction of the oxytocinergic system.PLOS ONE

Dear Dr. Oduor,

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Additional Editor Comments:

• Title and Abstract:
  • The title is clear but overly cautious with the phrase “appears to be partially caused.” Consider revising to a more assertive and specific title, such as: “Olanzapine-Induced Metabolic Syndrome Is Partially Mediated by Oxytocinergic System Dysfunction in Female Sprague-Dawley Rats”.
  • The abstract lacks sufficient methodological details (e.g., number of rats, doses, study duration) and specific results (e.g., effect sizes or numerical values). Revise the abstract to include these details, ensure it is concise (≤300 words), and strengthen the conclusion by linking findings to potential clinical implications or future research directions.
• Ethics and Data Availability Statements:
  • The ethics statement is incomplete, lacking details on the approving ethics committee, approval number, and adherence to animal welfare guidelines. Please provide a comprehensive statement, including the committee name and approval number.
  • The data availability statement is vague and does not meet PLOS ONE’s open data policy. Upload data to a public repository or provide a clear justification for restricted access, including contact details for data requests (e.g., “Data are available from the University of Nairobi Institutional Data Access Committee [contact email]”).
• Data Presentation:
  • The results section is repetitive and lacks structure, making it difficult to follow trends across groups. Organize results into clear subsections (e.g., induction phase outcomes, treatment phase outcomes, inter-group comparisons) and include summary tables or figures to consolidate key findings (e.g., body weight, food intake, lipid profiles).
  • Ensure figures meet PLOS ONE’s technical requirements (≥300 dpi, TIFF/EPS format) and include detailed legends explaining content and statistical significance.
• Introduction and Discussion:
  • The introduction is overly lengthy and lacks focus on the oxytocinergic system’s role. Streamline it into three sections: background on olanzapine and metabolic syndrome, oxytocin’s role in metabolism, and study objectives with a clear hypothesis.
  • The discussion is repetitive and includes excessive mechanistic detail. Shorten it, focusing on key findings, and add a subsection addressing study limitations (e.g., use of female rats, short-term treatment, animal model constraints). Strengthen clinical implications to highlight the study’s translational potential.
• Language and Style:
  • The manuscript contains numerous typographical and grammatical errors (e.g., “titd” instead of “titled,” “mctabolic syndapars” instead of “metabolic syndrome”). Engage a professional editor or use tools like Grammarly to correct these errors.
  • Replace vague terms (e.g., “notable variations”) with precise scientific language (e.g., “statistically significant differences”) and break long sentences into shorter, clearer ones to improve readability.

Additional Recommendations

References: Update references to prioritize recent studies (2015–2025) and ensure completeness in Vancouver style. Methodological Details: Clarify group allocations in the treatment phase, justify chosen doses (e.g., oxytocin, metformin), and provide detailed protocols for assays (e.g., Butler and Mailing for hepatic triglycerides). Specify statistical methods, including software and correction methods. Visualizations: Consider adding a figure (e.g., a line graph showing body weight changes over time) to enhance data clarity, as suggested in the detailed review comments.

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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?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: No

Reviewer #3: Yes

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

Reviewer #1: N/A

Reviewer #2: Yes

Reviewer #3: Yes

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The Introduction section is uncompleted and needs a key revise. The authors should explain more about the oxytocinergic system and its possible correlation with OLZ.

What is the OT? Please add its full name before mentioning the OT for the first time in the text and also in the abstract section.

Did the Metformin hydrochloride tablets weigh was 500 grams?!!

which organ was chosen for blood drawing, after the rats were anesthetized?

which section of liver tissue was chosen to determine the triglycerides? did this section of liver tissue was same for all rats?

The “O.d” in line 131 should be edited it can be “OD”

All of the figures have low resolution and should be edited. Also, they have not error bar (SEM)!!

It is suggested to perform histological studies of liver tissues.

The discussion section needs a major revise. The authors should discuss their results and the correlation between the results. This section should be re-wright briefly

Reviewer #2: 1. The method lacks strong novelty, as similar derivative blood glucose levels, oral glucose tolerance techniques have already been reported in the literature.

2. The abstract contains detail and should be more concise, focusing on key outcomes and significance.

3. The introduction provides adequate background but does not clearly justify the need for this method over existing Oxytocin, on the other hand, is known to have roles in regulation of feeding behavior, as well as lipid and

26 glucose metabolism.

4. Experimental methodology is detailed, but some steps—such as wavelength selection and validation criteria—need clearer justification.

5. Figures and tables are numerous but not well integrated into the discussion, causing redundancy.

6. The discussion lacks comparison with alternative established methods, particularly in terms of sensitivity, accuracy, and practical advantages In contrast, central OT has been shown to exert anorexigenic effects with direct oxytocinergic neural .

8. The greenness evaluation (NPY/AgRP) is a strong point but lacks a deep critical analysis and clear benchmarking against literature.

9. Language and grammar issues are frequent; the manuscript needs professional editing for clarity and consistency.

10. The conclusion is somewhat overstated and should be more balanced, acknowledging limitations and potential improvements.

11. The references include some outdated or low-impact sources and suffer from inconsistent formatting and integration into the main text.

Reviewer #3: This study looks at whether oxytocin can reduce the negative side effects of olanzapine, a drug used to treat mental illness. Olanzapine can cause weight gain, high blood sugar, and high fat levels, which can lead to metabolic syndrome. The authors tested their idea on female rats. They found that giving oxytocin with olanzapine helped lower food intake, body weight, blood sugar, and fat buildup. The results were compared to both untreated rats and rats given metformin.

Major Strengths

1. Important Topic

Olanzapine is widely used, but its side effects are a real concern. This study tackles a serious problem and explores a possible solution.

2. Clear Design

The groups and treatments are well organized. The study covers many important health markers like body weight, blood sugar, and liver fat.

3. Good Comparisons

Including a metformin group makes the study stronger, since metformin is already known to help with metabolic issues.

4. Logical Discussion

The authors give reasonable explanations for how oxytocin might work in the brain and body to reduce these side effects.

What Needs to Be Improved

1. No Lab Tests for Molecules

The study talks a lot about how oxytocin and olanzapine affect certain pathways in the body. But the absence of molecular analyses (e.g., Western blot for AMPK, SREBP, GLUT4, OXTR expression) limits mechanistic conclusions. The authors should mention this as a limitation.

2. Sex-Specific Limitations

Using only female rats limits the study. The authors say why they chose them, but they should also clearly say that results might differ in males or in humans.

3. Oxytocin Dosage Info Missing

The paper doesn’t explain how long oxytocin stays in the body after injection or how much actually reaches the brain. This should be briefly mentioned.

4. Figures Could Be Better

Make sure all graphs and figure legends are clear and easy to read on their own.

5. Writing Style

Some parts are too formal. A few short edits could make it easier to read.

Minor Suggestions

1. Say whether food intake was measured per rat or per cage.

2. Use the same units throughout the paper (e.g., mmol/L or mg/dL—don’t switch between them).

3. Add a short list of abbreviations.

This study is well done and has practical value. It shows that oxytocin might help reduce side effects caused by olanzapine. With a few edits to add clarity and improve the figures, the paper will be ready for publication. It’s a solid step forward in a field that needs new ideas.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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The olanzapine-induced metabolic syndrome appears to be partially caused by the dysfunction of the oxytocinergic system.

PONE-D-25-09455R1

Dear Dr. Oduor,

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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Kind regards,

Jianhong Zhou

Staff Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: (No Response)

Reviewer #3: All comments have been addressed

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

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: (No Response)

Reviewer #3: Yes

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

Reviewer #2: I Don't Know

Reviewer #3: Yes

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: No

Reviewer #3: Yes

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

Reviewer #3: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: Overall Recommendation I recommend the acceptance of this manuscript, contingent upon addressing the revisions suggested above.

Reviewer #3: The study tests whether oxytocin can reduce the harmful metabolic effects of olanzapine in female rats. The revised version provides a lot of detail on the design, results, and possible mechanisms. Overall, the manuscript is stronger and clearer than the first version and the results are convincing.

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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 #2: No

Reviewer #3: No

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