Relationships between Uncoupling Protein Genes UCP1, UCP2 and UCP3 and Irisin Levels in Residents of the Coldest Region of Siberia

Round 1

Reviewer 1 Report

The manuscript by Nikanorova et al., submitted for publication is an interesting study investigating the association between uncoupling proteins genes (UCP1, UCP2 and UCP3) and the irisin blood levels in the Yakut population. They highlighted the possible involvement of irisin and the UCP3 gene in the thermoregulation mechanism, and emphasized that the spread of allelic variants is likely related to human adaptation to a cold climate. The study is well designed and the manuscript is well-organized and well written and fairly easy for the reader to follow. Although there are several typos and the narrative is a kind of fragmentary, I just abide by scientific soundness. I would like to offer the following points for consideration by the authors towards the improvement of the manuscript:

 

1- My biggest concern is that a similar study already exists by same group ( Nikanorova, A.A.; Barashkov, N.A.; Pshennikova, V.G.; Nakhodkin, S.S.; Gotovtsev, N.N.; Romanov, G.P.; Solovyev, A.V.; Kuzmina, S.S.; Sazonov, N.N.; Fedorova, S.A. The Role of Nonshivering Thermogenesis Genes on Leptin Levels Regulation in Residents of the Coldest Region of Siberia. Int. J. Mol. Sci. 2021, 22, 4657. https://doi.org/10.3390/ijms22094657). The authors used almost the same study design,tables and figures in these two papers. Was it possible to discuss leptin and irisin in a single study?

 

2- Please add references for lines 67-70.

 

3-  You stated that the average age in the study population was 19. Please indicate why you did not include the middle or older age population.

 

4- The discussion section should be expanded by adding some recent papers discussing this topic.

 

5- Please add limitations and strengths to the discussion section

 

6- The conclusion section needs to be trimmed.  Some of the findings of the study can be moved to the discussion section

Author Response

Answer to reviewer 1

 

On behalf of the manuscript authors, I would like to thank you for your effort in reviewing the manuscript and I appreciate your comments. We addressed our responses below and revised the manuscript accordingly.

1- My biggest concern is that a similar study already exists by same group ( Nikanorova, A.A.; Barashkov, N.A.; Pshennikova, V.G.; Nakhodkin, S.S.; Gotovtsev, N.N.; Romanov, G.P.; Solovyev, A.V.; Kuzmina, S.S.; Sazonov, N.N.; Fedorova, S.A. The Role of Nonshivering Thermogenesis Genes on Leptin Levels Regulation in Residents of the Coldest Region of Siberia. Int. J. Mol. Sci. 2021, 22, 4657. https://doi.org/10.3390/ijms22094657). The authors used almost the same study design,tables and figures in these two papers. Was it possible to discuss leptin and irisin in a single study?

 

Answer to reviewer 1

 

• Thank you very much for this comments. We believe which is obvious that the presented paper about association between uncoupling proteins genes (UCP1, UCP2 and UCP3) and the irisin blood levels in the Yakut population is self-sufficient since it contains completely new data and that differs from the previous work - devoted to another hormone (leptin). However we are very grateful for this for this comment, and we will think about your proposal to present a generalized work on several hormones in future papers.

2- Please add references for lines 67-70.

- Done.

 

3. You stated that the average age in the study population was 19. Please indicate why you did not include the middle or older age population.

• Thank you very much for this comment. Since hormone levels can be affected by chronic diseases, which are more common in individual’s middle or older age, in our study we included only young people.

 

4. The discussion section should be expanded by adding some recent papers discussing this topic.

Done

 

5- Please add limitations and strengths to the discussion section

 

Thank you very much for this addition. We added the limitations and strengths to the discussion section.

 

6- The conclusion section needs to be trimmed. Some of the findings of the study can be moved to the discussion section

Thank you very much for this comment. We believe that all parts of our conclusion have an important for readers. Since each conclusion can be used in different areas of research devoted to this problem.

Author Response File: Author Response.docx

Reviewer 2 Report

23 August 2022 

The review on the manuscript titled ‘The Role of Uncoupling Proteins Genes UCP1, UCP2 and UCP3 on Irisin Levels regulation in Residents of the Coldest Region of Siberia’ by Nikanorova AA et al., submitted to Genes

Manuscript ID: genes-1894825 

Dear Authors, 

Irisin is a thermogenic protein which activates uncoupling protein (UCP) 1. In the present study entitled ‘The Role of Uncoupling Proteins Genes UCP1, UCP2 and UCP3 on Irisin Levels regulation in Residents of the Coldest Region of Siberia’, Nikanorova and colleagues investigated the relationship between the UPC1-3 and the irisin of people residing in a cold region.

The main strength of this manuscript is that it addresses an interesting and innovative question, revealing a single nucleotide polymorphism (SNP) of the UCP3 gene is associated with higher levels of irisin, with lower weight and height, and higher prevalence in the northern Asia.  

In general, I think the idea of this observational study is really interesting and the authors’ fascinating observations on this timely topic may be of interest to the readers of Cells. However, some comments, as well as some crucial evidence that should be included to support the authors’ argumentation, needed to be addressed to improve the quality of the manuscript, its adequacy, and its readability prior to the publication in the present form. My overall judgment is to publish this research article after the authors have carefully considered my suggestions below, particularly reshaping the manuscript by adding more evidence.

Please consider the following comments:

1.      Title: I suggest presenting a more relevant title based on this study and results, as ‘The role’ is not main topic of this manuscript.

2.      Abstract: The abstract is nicely presented. But I recommend the authors shortly present the background including general information and the rationale leading to the objectives. Also, the word number should be reduced to 200.

3.      Keywords: Please reduce the number of keywords to ten and use as many keywords as possible in the first two sentences of the abstract.

4.      A Graphical Abstract is highly recommended.

5.      Introduction: The ‘Introduction’ section is generally well-written and nicely presented, with a good balance of descriptive text and information. I recommend that the authors present UCPs in a single paragraph and irisin in another, briefly summarize UCP1-3, expand the description of other functions of irisin shortly, and refer to the involvement of tryptophan-kynurenine metabolic system in mitochondrial bioenergetics (https://doi.org/10.3390/ijms23147596; https://doi.org/10.3390/cells11162607).

6.      Materials and Methods: I suggest presenting demographic data and SNPs in the tables.

7.      Results 3.3: I suggest summarizing the results in the table.

8.      Discussion: Here, the authors present their expert opinion by developing argument based on the previous sections. Furthermore, I recommend that the authors develop this section with significance of the current study, the weaknesses or the limitation in the present review, the potentials, the ultimate goal, research or knowledge needed to achieve, the biggest challenge in this goal, and future research direction, among others.

9.      I believe that a ‘Conclusion’ paragraph would benefit from some thoughtful as well as in-depth considerations by the author, because as it stands, it is very descriptive but not enough theoretical to adequately convey what the authors believe is the take-home message of their study. Therefore, please provide a synthesis of the data presented in the paper as well as possible keys to advancing research and understanding the relationship between UCPs and irisin in cold tolerance.

Overall, the manuscript contains four figures, one table, and 77 references. I believe that this manuscript might carry important value presenting the relationship between the UPC1-3 and the irisin of people residing in a cold region. I hope that, after these careful revisions, the manuscript can meet the Journal’s high standards for publication. I am available for a new round of revision of this article.

I declare no conflict of interest regarding this manuscript.

 

Best regards,

 

 

Reviewer

Author Response

Answer to reviewer 2

 

On behalf of the manuscript authors, I would like to thank you for your effort in reviewing the manuscript and I appreciate your comments. We addressed our responses below and revised the manuscript accordingly. We have carefully considered all comments and we believe that our evidence presented in this study correspond to original association studies of Genetics and Hereditary area, which indeed in this case are forced to be very descriptive characters limited by applied design and methods (the overall design of the article was prepared for the journal Genes). In this case we cannot be present more evidence. However, we believe that this evidence will be finding in other experimental or theoretical works, and we hope that our original associative study will be helpful in this.

1. Title: I suggest presenting a more relevant title based on this study and results, as ‘The role’ is not main topic of this manuscript.

- Thank you very much, we changed the title on “Relationships between Uncoupling Proteins Genes UCP1, UCP2 and UCP3 and Irisin Levels in Residents of the Coldest Region of Siberia”

2. Abstract: The abstract is nicely presented. But I recommend the authors shortly present the background including general information and the rationale leading to the objectives. Also, the word number should be reduced to 200.

- Thank you very much for this recommendation, we believe that our abstract have a necessary background information. However we have reduced the abstract as much as possible.

3.Keywords: Please reduced the number of keywords to ten and use as many keywords as possible in the first two sentences of the abstract.

 

- We reduced of our keywords and included in update keywords words used in first two sentences of the abstract.

 

4. A Graphical Abstract is highly recommended

- Its good idea. A graphical abstract has been added. We all hope that it helps the reader grasp the essence of this manuscript.

5. Introduction: The ‘Introduction’ section is generally well-written and nicely presented, with a good balance of descriptive text and information. I recommend that the authors present UCPs in a single paragraph and irisin in another, briefly summarize UCP1-3, expand the description of other functions of irisin shortly, and refer to the involvement of tryptophan-kynurenine metabolic system in mitochondrial bioenergetics (https://doi.org/10.3390/ijms23147596; https://doi.org/10.3390/cells11162607).

 

- Thank you for your this comment. We divided our paragraphs about Irisin and UCPs. We added briefly disruption of UCPs in single paragraph. However, we are afraid that more information about other functions of irisin will be superfluous and lead away from the main problem. However we cited the involvement of tryptophan-kynurenine metabolic system in mitochondrial bioenergetics (https://doi.org/10.3390/ijms23147596; https://doi.org/10.3390/cells11162607) in discussion section.

 

 

6. Materials and Methods: I suggest presenting demographic data and SNPs in the tables.

- Done. All the data described in the study are provided in the Supplementary Table S2.

7. Results 3.3: I suggest summarizing the results in the table.

- Done. Comparative analysis of the prevalence of the polymorphisms in twelve East Asian populations living in different climatic zones are presented in Supplementary Table S6.

 

8. Discussion: Here, the authors present their expert opinion by developing argument based on the previous sections. Furthermore, I recommend that the authors develop this section with significance of the current study, the weaknesses or the limitation in the present review, the potentials, the ultimate goal, research or knowledge needed to achieve, the biggest challenge in this goal, and future research direction, among others.

- Thank you very much for this comment. We added the limitations of our study in discussion section. We all understand the reviewer’s messages regarding very basic discuss. However our study limited by applied design and methods and in this case we cannot be present more evidence of role of UCP3, included theoretical evidence for some reasons. Basic reason it’s that possible keys to advancing research and understanding the relationship between UCPs and irisin in cold tolerance in present time is unknown. However, we believe that this will be possible after elucidating the role of UCP3 in thermogenesis what can such associative studies is contributed.

 

9. I believe that a ‘Conclusion’ paragraph would benefit from some thoughtful as well as in-depth considerations by the author, because as it stands, it is very descriptive but not enough theoretical to adequately convey what the authors believe is the take-home message of their study. Therefore, please provide a synthesis of the data presented in the paper as well as possible keys to advancing research and understanding the relationship between UCPs and irisin in cold tolerance.

- Thank you very much for this comment. We added the final theoretical conclusion about relationships between UCP3 and irisin levels. However we did not delete other parts of our conclusion despite their descriptive character. We hope that our conclusion have an certain significant for readers, since each conclusion can be used in different areas of clinical or population genetics and biochemical research devoted to this problem.

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

I am satisfied that the authors have addressed all of my previous concerns about the article. It is now much improved and I feel that it is now suitable for publication.

Author Response

Answer to reviewer 1

 

Thank you very much! We appreciate the time and effort that you have dedicated to providing valuable feedback on our manuscript.

Author Response File: Author Response.docx

Reviewer 2 Report

1 September 2022 

The 2^nd review on the manuscript titled ‘The Role of Uncoupling Proteins Genes UCP1, UCP2 and UCP3 on Irisin Levels regulation in Residents of the Coldest Region of Siberia’ by Nikanorova AA et al., submitted to Genes

Manuscript ID: genes-1894825 

Dear Authors, 

I am pleased to see that the authors did an excellent work clarifying most of the comments I have raised in the previous round of the review session. Currently, this paper is a well-written, timely piece of research and revealing that a single nucleotide polymorphism of the uncoupling protein (UCP) 3 gene is associated with higher levels of irisin, with lower weight and height, and higher prevalence in the northern Asia. That said, I just suggest some minor points below, I believe, for the betterment of this manuscript to finalize my review session.

Comments:

1.      Abstract: It is corrected in the revised abstract, but the abbreviation UCP should be expanded in the first appearance.

2.      Keywords: Again, it is corrected. But the inclusion of “uncoupling protein gene” or “uncoupling protein” is better than that of only abbreviations and including mitochondria makes all together ten keywords.

3.      Discussion, References: The reference (https://doi.org/10.3390/ijms23147596) is missing.

Overall, the manuscript contains four figures, one table, and 82 references. This is a timely and needed work, thus I believe that manuscript now meets the Journal’s standards for publication. I am always available for other reviews of such interesting and important articles. I look forward to seeing further study on this issue by these authors in the future. 

I declare no conflict of interest regarding this manuscript.

 

Best regards, 

 

Reviewer

Author Response

Answer to reviewer 2

 

Dear, reviewer! We appreciate the time and effort that you have dedicated to providing valuable feedback on our manuscript. We addressed our responses below and revised the manuscript accordingly. Thank you very much for your interest of our work.

1. Abstract: It is corrected in the revised abstract, but the abbreviation UCP should be expanded in the first appearance.

- Thank you very much for this comment, we expanded the abbreviation UCP in the first appearance in the abstract text.

2. Keywords: Again, it is corrected. But the inclusion of “uncoupling protein gene” or “uncoupling protein” is better than that of only abbreviations and including mitochondria makes all together ten keywords.

- Thank you very much for this recommendation, we added in our keywords “uncoupling protein gene”

3. Discussion, References: The reference (https://doi.org/10.3390/ijms23147596) is missing.

- Thank you very much for this link is a very interesting work, we will be happy to cite this article in the future, in other more relevant to this topic work.

 

Author Response File: Author Response.docx