From the Plate to the Nucleus: Dietary Control of Nuclear Receptors in the Development and Prevention of Metabolic Diseases

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In this review, Tovar-Palacio C et al. describes various nuclear receptor ligands and target genes in liver, skeletal muscle, adipose, and kidney tissues regarding the function of nuclear receptors in obesity and metabolic diseases. There are numerous points to be corrected for future improvement, and I feel substantial rewriting is required for publication.

 

Major points

1. The Abstract is too long. Around 250 words is better.
2. The classification of nuclear receptors on p 3 (line 95-100) differs from standard classification. Steroid hormone receptors and thyroid hormone receptors are different classification. In general, steroid hormone receptors bind to target DNA sequences as homodimers, whereas thyroid hormone receptors bind as heterodimers with RXR, exhibiting different properties. Rewrite this section according to cited references (4-6).
3. Generally, most nuclear receptors bind DNA as dimers, so each figure should be corrected. Also, note that RXR partners form heterodimers, while steroid hormone receptors form homodimers.
4. RXR is a unique type that forms heterodimers with RAR, VDR, PPAR, LXR, FXR, PXR, etc. Thus, the description in lines 108-115 is confusing; It's better to describe them (RAR, RXR, and VDR) separately.
5. The short-chain fatty acid included in Figure 2 is not major nuclear receptor ligand. I recommend to remove this.

 

Minor points

The “8” in line 138, the “15” in line 256, the ‘21’ in line 494, and the “26” in line 687 appear unnecessary. Delete them and correct the numbers.

The English text is difficult to read, so proofreading is recommended. Additionally, it would be better to incorporate the cited references into the first sentence. For example, the sentence on lines 324-325.

Several terms are inconsistent. For example, line 491 “Nr2f6” should be NR2F6, and line 1010 ‘PPARD’ should be “PPARd (d is symbol)”. Verify all sentences.

Author Response

We sincerely thank the reviewer for the careful evaluation of our manuscript and for the constructive comments. We fully agree that substantial revisions were necessary, and we have extensively rewritten and reorganised the manuscript to improve clarity, conceptual structure, and consistency. Below, we address each point in detail.

Major points

1. The Abstract is too long. Around 250 words is better.

Response: We fully agree. The Abstract has been substantially condensed and rewritten to ~240 words, with clearer emphasis on the conceptual framework, inter-organ signalling, and translational relevance.

2. Classification of nuclear receptors (p.3, lines 95–100) differs from standard classification. Steroid hormone receptors and thyroid hormone receptors are different classes. Rewrite according to references (4–6).

Response: We thank the reviewer for pointing this out. We have rewritten this section following the standard structural and functional classification: Type I receptors (e.g., ER, AR, GR, PR, MR) that bind DNA as homodimers, Type II receptors (e.g., TR, RAR, VDR, PPAR, LXR, FXR, PXR, CAR) that bind DNA as heterodimers with RXR. The revised text explicitly reflects this distinction and aligns with the cited references.

3. Most nuclear receptors bind DNA as dimers. Figures must be corrected. RXR partners form heterodimers, while steroid hormone receptors form homodimers.

Response: We agree with the reviewer that nuclear receptor dimerisation is a fundamental mechanistic feature. In the revised figures, we now explicitly distinguish between homodimeric steroid hormone receptors and RXR-dependent heterodimeric receptors in the text and figure legends. For visual clarity and conceptual simplicity, we chose not to draw RXR explicitly in every heterodimeric complex in the main figures, as this would overcrowd the schematics and obscure inter-organ signaling pathways. Instead, RXR partnership is now clearly stated in the corresponding figure legends and main text, ensuring both accuracy and readability. This approach preserves mechanistic correctness while maintaining clear and interpretable graphical representations.

4. RXR is a unique partner forming heterodimers with RAR, VDR, PPAR, LXR, FXR, PXR, etc. The description in lines 108–115 is confusing. Separate RAR, RXR, and VDR.

Response: We agree. This section has been rewritten to clearly distinguish: RXR as an obligate heterodimeric partner, RAR and VDR as RXR-dependent Type II receptors. The revised text now avoids overlapping classifications and improves conceptual clarity.

5. Short-chain fatty acids in Figure 2 are not major nuclear receptor ligands. Remove.

Response: We agree and have removed short-chain fatty acids from Figure 2. The figure now includes only established nuclear receptor ligands.

Minor points

6. Unnecessary numbers (“8” line 138; “15” line 256; “21” line 494; “26” line 687).

Response: These have been deleted and the numbering corrected.

7. English needs proofreading; references should be incorporated into opening sentences (e.g., lines 324–325).

Response: The manuscript has undergone full language editing and restructuring for clarity and flow. We also incorporated key references into opening sentences throughout the text, including the section indicated.

8. Inconsistent terminology (e.g., “Nr2f6”, “PPARD”).

Response: We performed a systematic nomenclature audit across the manuscript. All gene and receptor symbols now follow standard conventions (e.g., NR2F6, PPARδ).

Once again, we thank the reviewer for the insightful feedback, which substantially improved the quality and rigor of our manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

Please refer to the attached peer review report for a comprehensive overview of the revisions.

Overall Recommendation: Major Revision

In its current form, the manuscript is informative but overly long, insufficiently synthesised, and unevenly focused. With substantial restructuring, condensation, and a stronger emphasis on critical integration and translational relevance, this review has the potential to become a valuable and authoritative contribution to the field of nuclear receptor biology and nutritional metabolism.

The manuscript would substantially benefit from the addition of targeted integrative sections addressing conceptual framing, inter-organ crosstalk, translational limitations, and future directions. These additions, combined with selective condensation of existing material, would enhance coherence, readability, and impact, positioning the review as a truly integrative and authoritative contribution to the field. Overall, selective use of summary tables, alongside targeted integrative sections, would substantially improve clarity, synthesis, and accessibility without diluting scientific depth.

Comments for author File: Comments.pdf

Author Response

We sincerely thank the reviewer for their thorough, thoughtful, and constructive evaluation of our manuscript, “From the plate to the nucleus: The interaction of nutrition with nuclear receptors in obesity and metabolic diseases.” We greatly appreciate the recognition of the relevance and potential impact of our work, as well as the detailed suggestions to strengthen its conceptual clarity, balance, and translational value.

We have carefully revised the manuscript in response to all major and minor comments. Below, we provide a point-by-point response describing how each issue has been addressed.

Major Issues

1. Front matter
2. Title precision

Comment: The title is engaging but overly broad; “nutrition” does not interact directly with nuclear receptors.

Response: We agree and have refined the title to more accurately reflect the mechanistic focus. The revised title now emphasises dietary ligands and metabolites as the active signals interacting with NSNRs, rather than “nutrition” in general.

1. Abstract length and focus

Comment: The abstract is too long and overly dense; it should foreground a conceptual framework, cross-organ integration, and translational relevance.

Response: We have fully rewritten and shortened the abstract to meet journal guidelines (~250 words). The new version is structured around: A unifying conceptual framework (NSNRs as integrative metabolic nodes), Cross-organ signalling and crosstalk, and Translational implications, while reducing mechanistic detail.

1. Keywords

Comment: Additional keywords such as “nuclear receptor crosstalk” and “dietary ligands” would improve discoverability.

Response: We have expanded the keyword list to include: Nuclear receptor crosstalk; Metabolic flexibility; Dietary ligands; Nutrigenomics

2. Lack of a clear conceptual scaffold

Comment: The manuscript reads as encyclopedic; NSNRs as integrative nodes are not consistently used as an organising framework.

Response: We fully agree and have restructured the manuscript around a unifying conceptual model, in which: Diet functions as a ligand-providing endocrine organ, and liver, adipose tissue, skeletal muscle, and kidney act as secondary signal generators and integrators via NSNR networks. This framework is now introduced explicitly in the Introduction and revisited throughout the manuscript to guide interpretation.

2a–b. Redundancy and repeated organ structure

Comment: The repeated physiology → receptors → ligands → disease structure is redundant.

Response: We have condensed shared mechanisms (e.g., oxidative stress, lipotoxicity, PPAR signalling) into integrative sections, and shifted organ sections toward what is unique or context-specific rather than reiterating the same pathways. We also introduced multiple summary and comparative tables to replace repetitive narrative.

2c. Early integrative framework

Comment: A short integrative section should appear early.

Response: We added a new conceptual section at the end of the Introduction, defining NSNRs as a distributed metabolic signalling network that integrates Dietary ligands, Gut-derived metabolites, Endocrine cues, and Circadian signals. This section now functions as the conceptual “map” for the rest of the review.

3. Inter-organ crosstalk is fragmented

Comment: Crosstalk is mentioned but never synthesized.

Response: We have established a dedicated section titled: “NSNR-Mediated Inter-Organ Crosstalk in Metabolic Homeostasis and Disease”. This section encompasses liver–adipose–muscle–kidney signalling, gut–liver and gut–muscle axes, as well as endocrine and paracrine feedback loops. Additionally, we introduced a comprehensive table illustrating Ligands, Receptors, Source tissues, and Target organs. This directly addresses the reviewer’s recommendation.

4. Translational rigor and evidence balance

Comment: In vitro, animal, and human data are not clearly distinguished.

Response: We added a new “Translational Relevance and Current Limitations” section and a level-of-evidence matrix distinguishing: In vitro, animal, observational human, and interventional human studies. This clarifies translational confidence and prevents overinterpretation of preclinical findings.

5. Organ section imbalance

Comment: Liver and muscle dominate; kidney is underdeveloped.

Response: We have condensed the liver and muscle sections, moved shared content into tables, and strengthened the kidney section by emphasising: unique receptor profiles, mineral–metabolic crosstalk, underexplored NSNR roles, and cross-referencing to the crosstalk section to reduce redundancy and reinforce systemic integration.

6. Dietary bioactives: overly affirmative tone

Comment: Polyphenols and functional foods are discussed too positively; variability and context must be acknowledged.

Response: We revised this section to explicitly address bioavailability, hormesis, dose-response, and inter-individual variability, distinguish dietary patterns from isolated compounds, and conclude with a “Future Directions” subsection highlighting unanswered questions and the need for personalised approaches.

 

Minor Issues

We corrected:

Typographical inconsistencies

Abbreviation errors

Receptor nomenclature

Paragraph length and flow

Figures are now explicitly integrated into the narrative and cross-referenced.

Closing statement

We are grateful to the reviewer for their insightful critique, which substantially strengthened the manuscript. The revised version now presents a coherent, integrative paradigm in which NSNRs serve as systemic metabolic sensors and coordinators, with diet acting as an external endocrine organ. We believe this reframing enhances clarity, translational relevance, and conceptual impact.

Thank you for helping us elevate the scientific and narrative quality of this work.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Manuscript is well improved and I think it suitable for publication after correcting several points.

1. In page 5, the number "1" is duplicated in line 116 and 123. Correct them including "2" in line 130 and "3" in line 136.

2. In this review, "RAAS" in line 445 and 625 may be not familiar for readers. Please write out the full form of the abbreviation as "Renin-Angiotensin-Aldosterone System".

3. In line 624, reference paper 43 is related to only PPARd, not FXR and LXR. Change line 623 as "PPARd loss increases vulnerability to ischemic stress [43], " and add references related to FXR and LXR.

4. In line, is "Figure 6" not "Figure 5" ? Because Figure 6 is listed before Figure 5, I felt strange. Please check and correct it.

5. In line 678, "PPARD" is "PPARd (d is symbol)" as other sentences. Please correct it.

6.  There is not Figure 7 described in line 689. Please correct it.

7. Table 4 is consists of two different Tables. Lower Table shows NRs expression in tissue. I think it's better to have two tables as Table 4 and 5. And about PPARa/g/d, expressing tissues are different. PPARa is highly expressed in liver and PPARg shows high expression in adipose. So, I recommend to describe "High (a)" in liver and "High (g)" in adipose. "a" and "g" are symbol.

Author Response

Thank you very much for your precise and valuable observations. Here are the responses to each comment.

1. In page 5, the number "1" is duplicated in line 116 and 123. Correct them including "2" in line 130 and "3" in line 136.

R= Done

2. In this review, "RAAS" in line 445 and 625 may be not familiar for readers. Please write out the full form of the abbreviation as "Renin-Angiotensin-Aldosterone System".

R= Done

3. In line 624, reference paper 43 is related to only PPARd, not FXR and LXR. Change line 623 as "PPARd loss increases vulnerability to ischemic stress [43], " and add references related to FXR and LXR.

R= Done

4. In line, is "Figure 6" not "Figure 5" ? Because Figure 6 is listed before Figure 5, I felt strange. Please check and correct it.

R= Yes, it has been corrected to Figure 5.

5. In line 678, "PPARD" is "PPARd (d is symbol)" as other sentences. Please correct it.

R= Done

6.  There is not Figure 7 described in line 689. Please correct it.

R= Done, it has been corrected to Figure 5.

7. Table 4 is consists of two different Tables. Lower Table shows NRs expression in tissue. I think it's better to have two tables as Table 4 and 5. And about PPARa/g/d, expressing tissues are different. PPARa is highly expressed in liver and PPARg shows high expression in adipose. So, I recommend to describe "High (a)" in liver and "High (g)" in adipose. "a" and "g" are symbol.

R= Done, thank you for the suggestion; it looks much better now.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have comprehensively addressed all major concerns I raised in the first review. The revised manuscript shows now a substantial improvement in conceptual clarity, organisation, and balance. The review is now structured around a clear integrative framework in which nutrient-sensing nuclear receptors (NSNRs) function as systemic metabolic signalling nodes. Redundancy across organ sections has been reduced, a dedicated section on NSNR-mediated inter-organ crosstalk has been added, and the distinction between preclinical and human evidence is clearer. The discussion of dietary bioactives is now more balanced and appropriately cautious.

I am pleased to recommend the manuscript for publication on Receptors pending these minor editorial revisions:

1. Further harmonisation of terminology to make it consistent throughout the manuscript;

2. Minor streamlining of a few lengthy paragraphs to improve readability;

3. Captions of Figure 1, 3, 5 and 6 comprise just the figure title. More information should be added to the caption (besides the description, which is lacking). In this regard, this is a good place for recycling textbook text from the manuscript also to both streamline and tighten the article itself.

Author Response

We are very grateful for the reviewers' suggestions, and as the reviewer indicates, we also believe that the revised manuscript now shows a substantial improvement in conceptual clarity, organisation, and balance. Here are our responses to each comment.

1 and 2 Further harmonisation of terminology to make it consistent throughout the manuscript and minor streamlining of a few lengthy paragraphs to improve readability

R= We revised the manuscript and made an effort to address these suggestions.

3 Captions of Figure 1, 3, 5 and 6 comprise just the figure title. More information should be added to the caption (besides the description, which is lacking). In this regard, this is a good place for recycling textbook text from the manuscript also to both streamline and tighten the article itself.

R= We included the necessary information in the figure legends.