The Roles of MicroRNAs in Obesity: Emphasizing Links with Chronic Kidney Disease and Cardiovascular Disorders

Round 1

Reviewer 1 Report

The authors present a good research paper. 

• The relevance of the topic: Good.
• Abstract: Can be improved.
• Keywords: Can be improved.
• Introduction: Can be improved.
• Methodology: Can be improved.
• Results: Good.
• Discussion: Good.  
• Conclusions: Can be improved.

However, RECONSIDER AFTER MAJOR REVISION. In general, the paper follows an adequate structure and correct scientific support and can be published considering some limitations. The study is interesting in the field of Obesity. However, there are a series of limitations that should be considered.

In the first place, carry out a review of the existing literature related to the subject, being essential to inquire into the MPDI – Obesities journal itself, since there are papers related to its manuscript that can help to improve it. Therefore, include those references, if any, especially from the last five years. In addition, recommend reading some papers related to the topic of Obesity:

Dowling, L., Duseja, A., Vilaca, T., Walsh, J. S., & Goljanek‐Whysall, K. (2022). MicroRNAs in obesity, sarcopenia, and commonalities for sarcopenic obesity: a systematic review. Journal of Cachexia, Sarcopenia and Muscle, 13(1), 68-85.

Gámez-Calvo, L., Hernández-Beltrán, V., Pimienta-Sánchez, L. P., Delgado-Gil, S., & Gamonales, J.M. (2022). Systematic review of intervention programmes to promote healthy physical activity and nutrition habits in Spanish school children. Archivos Latinoamericanos de Nutrición, 72(4), 294-305.

Specific comments.

Title. The title of the manuscript is correct.

Abstract. Incorporate in the summary, a more precise sentence of the methodology and the results.

Keywords. Use keywords other than those used to formulate the manuscript title

·       The document presented is a revision. However, it does not present the review article structure. Therefore, the study must be modified and placed in each of the corresponding parts.

Introduction.

Methods.

Results.

Discussion.

Conclusion.

References. They should be reviewed and updated according to the publication standards. There are many errors in the references. Therefore, correct them and adapt them to the magazine's regulations.

Author Response

Reviewer 1

The authors present a good research paper. 

• The relevance of the topic: Good.
• Abstract: Can be improved.
• Keywords: Can be improved.
• Introduction: Can be improved.
• Methodology: Can be improved.
• Results: Good.
• Discussion: Good.  
• Conclusions: Can be improved.

 However, RECONSIDER AFTER MAJOR REVISION. In general, the paper follows an adequate structure and correct scientific support and can be published considering some limitations. The study is interesting in the field of Obesity. However, there are a series of limitations that should be considered.

 Answer : We thank the reviewer for this statement.

In the first place, carry out a review of the existing literature related to the subject, being essential to inquire into the MPDI – Obesities journal itself, since there are papers related to its manuscript that can help to improve it. Therefore, include those references, if any, especially from the last five years.

 Answer : We have added three papers published in Obesities that are relevant in our review : Macedo et al (2022), Macedo et  al (2023), Souza et al (2023)

  In addition, recommend reading some papers related to the topic of Obesity:

 Dowling, L., Duseja, A., Vilaca, T., Walsh, J. S., & Goljanek‐Whysall, K. (2022). MicroRNAs in obesity, sarcopenia, and commonalities for sarcopenic obesity: a systematic review. Journal of Cachexia, Sarcopenia and Muscle, 13(1), 68-85.

 Answer : we thank reviewer for this clever remark. Accordingly we have added a new chapter 7 « MicroRNAs in sarcopenia. A direct link between CKD and obesity?” in which we discuss comprehensively the results of this interesting paper.  Line 316  and further

“7. MicroRNAs in sarcopenia. A direct link between CKD and obesity?

Sarcopenia is a common condition in CKD, with varying prevalence rates ranging from 5% to 62.5%, and higher rates are often seen in advanced stages of the disease. Sarcopenic obesity, another related condition, is reported to affect 2% to 23% of CKD patients. Sarcopenia in CKD is linked to higher risks of mortality, cardiovascular disease, and vascular calcification. (Barreto Silva et al., 2022) The factors contributing to this condition include the kidney disease itself and its impact on lifestyle, such as reduced physical activity and dietary changes.

In the early stages of CKD, when the risks associated with sarcopenia outweigh the risk of progressing to end-stage renal disease, it may be advisable to ensure sufficient calorie intake along with moderate protein intake and physical activity. However, it's important to avoid excessive protein intake, keeping it below 1.3 grams per kilogram of body weight per day. For individuals on dialysis, interventions that provide a combination of carbohydrates, protein, and fats tend to be more effective than those focusing solely on protein. It's worth noting that it may take up to 48 weeks to observe noticeable changes in muscle mass with these interventions.

In summary, sarcopenia is a prevalent concern in CKD due to its impact on muscle mass and function. Nutritional interventions, emphasizing adequate energy and protein intake, can help address various aspects of sarcopenia in CKD patients. In a recent study,(Barreto Silva et al., 2022) 24 miRNAs functioned in relation to muscle and sarcopenia as well as adiposity and obesity. Some miRNAs had limited or no studies related to obesity or sarcopenia, making their relevance in the context of sarcopenic obesity uncertain in the present conditions (such as miR-29b-2-5p, miR-378c, miR-4732-5p, miR-487a-3p, miR-550a-3p, miR-576-5p, and miR-589-5p). On the other hand, other miRNAs have been shown to be differentially regulated in related diseases or metabolic responses, such as chronic obstructive pulmonary disease or amyotrophic lateral sclerosis (miR-1246), in response to a high-fat meal (miR-145-5p), or during exercise (miR-766-3p). However, the majority of these commonly expressed miRNAs were involved in critical processes like protein homeostasis, mitochondrial dynamics, muscle fiber type determination, insulin resistance, and adipogenesis—all of which were implicated in the development of sarcopenic obesity. Furthermore, these miRNAs predominantly targeted genes within the PI3K/AKT and TGF-β pathways. »

Gámez-Calvo, L., Hernández-Beltrán, V., Pimienta-Sánchez, L. P., Delgado-Gil, S., & Gamonales, J.M. (2022). Systematic review of intervention programmes to promote healthy physical activity and nutrition habits in Spanish school children. Archivos Latinoamericanos de Nutrición, 72(4), 294-305.

             Answer : as this publication is not referenced in pubmed and not excedingly relevant to the paper , we choose not to reference it, and replaced it with ref  Souza et al, obesities 2023 that is on the same topic.

Specific comments.

Title. The title of the manuscript is correct.

Abstract. Incorporate in the summary, a more precise sentence of the methodology and the results.

Answer : there is no methodology and results, as this is a review.

Keywords. Use keywords other than those used to formulate the manuscript title

A list of relevant keywords has been added.

References. They should be reviewed and updated according to the publication standards. There are many errors in the references. Therefore, correct them and adapt them to the magazine's regulations.

Answer : Done. In authors instructions it is stated that references may be in any style, provided that you use the consistent formatting throughout. We used Zotero

Reviewer 2 Report

1.How to regulate miRNA expression level to improve pathological cardiac changes?

2.How high-throughput technologies such as next-generation sequencing can identify a panel of miRNAs that exhibit differential expression patterns in obesity-related diseases?

3.How loss of miR-192/194 affects diet-induced fatty liver?

4.Role of miRNAs in CKD and why obesity and CKD are linked?

5.How microRNA regulates the role of vascular smooth muscle cells in atherosclerosis?

Author Response

Reviewer 2

1.How to regulate miRNA expression level to improve pathological cardiac changes?

Answer : We have described in other reviews miRNA involved in pathological cardiac changes and how they could be modulated to improve cardiac function in Maitrias et al ATVB. We thus added in the present paper the following sentence line 368. « miRNAs are involved in pathological cardiac changes, frequent in obesity and CKD, and could be modulated to improve cardiac function via several techniques that we already described elsewhere. (Maitrias et al, 2017) »

These technological means are also summarized in the figure of the present paper.

2.How high-throughput technologies such as next-generation sequencing can identify a panel of miRNAs that exhibit differential expression patterns in obesity-related diseases?

Answer : For this one would need to compare for example obesity patients afflicted with CKD to obesity patients with no renal disorder, and detect the most deregulated miRNAs.  This statement has been added to the manuscript line 305.

« For this one would need to compare for example obesity patients afflicted with CKD to obesity patients with no renal disorder, and detect the most deregulated miRNAs.»

3.How loss of miR-192/194 affects diet-induced fatty liver?

Answer We thank the reviewer for this interesting suggestion. Consequently we discussed the findings of Nie et al (2017) in subsection « MicroRNAs in Energy Homeostasis and Metabolic Pathways » starting line 129

Non-alcoholic fatty liver disease (NAFLD) impacts the metabolic syndrome associated with obesity. A group investigated the pathophysiological role of miR-194 in metabolic dysfunction brought on by obesity and found that the consumption of a high-fat diet or exposure to palmitic acid significantly elevates the levels of miR-194 in the liver, both in living organisms and in cell cultures.(Nie et al, 2017) Inhibiting miR-194 expression shielded cultured liver cells from the inflammatory response induced by palmitic acid. miR-194 directly binded to the 3'-UTR of FXR/Nr1h4, leading to the suppression of FXR/Nr1h4 gene expression. Conversely, silencing FXR/Nr1h4 eliminates the hepatic benefits observed in obese mice treated with a miR-194 inhibitor. These findings suggest that miR-194 and FXR/Nr1h4 could serve as potential diagnostic markers and therapeutic targets for NAFLD.

4.Role of miRNAs in CKD and why obesity and CKD are linked?

Answer : The chapter. 4 has been specifically added for that. To further clarify  the challenges, we have added, on line 177 and further

« The connection between miRNAs, obesity, and CKD is an emerging field of research. Studies have shown that miRNAs dysregulated in obesity can directly impact kidney function by promoting inflammation, fibrosis, and oxidative stress, all of which are hallmarks of CKD. Additionally, these miRNAs can serve as potential therapeutic targets for both obesity and CKD. Understanding the intricate network of miRNAs involved in CKD and obesity can pave the way for innovative diagnostic tools and therapeutic strategies. Targeting specific miRNAs may offer a way to mitigate kidney damage in obese individuals and slow the progression of CKD. »

And also on line 211 and further :

miRNAs play thus a crucial role in the pathogenesis of CKD, influencing various cellular processes implicated in the disease. When it comes to the link between obesity and CKD, miRNAs are emerging as key players in the complex interplay between these two conditions. Further research in this area holds promise for the development of novel therapies and diagnostic tools, offering hope for individuals at risk of or suffering from CKD, particularly those with obesity-related comorbidities.

5.How microRNA regulates the role of vascular smooth muscle cells in atherosclerosis?

Answer :

We have described in other reviews miRNA involved in pathological cardiac changes and how they could be modulated to improve cardiac function in Maitrias et al ATVB. We thus added in the present paper the following sentence line 374. These means are also summarized in the figure of the present paper.

Round 2

Reviewer 1 Report

Congratulations for the corrections made to the paper.