Molecular Basis of Irisin Regulating the Effects of Exercise on Insulin Resistance

Round 1

Reviewer 1 Report

- The authors did not critically review all available and relevant literature. There are inconsistencies about the relevance of irisin in humans. The regulation of FNDC5 expression by exercise and contraction could not be reproduced by some human studies using several exercise protocols and in vitro approaches (Reference: PMID: 24781257). 

-Is there a receptor for irisin? Please discuss that.

Line 44: ‘’…irisin is provoked by exercise, secreted from muscle, …’’ - Irisin is secondarily secreted by adipose tissue in small amounts. Please discuss that in the manuscript.

Line 116: ‘’in fatty tissue’’ – Please write adipose tissue

Lines 131-133: ‘’Mitochondrial dysfunction is a term used to describe changes in mitochondrial content, activity, and oxidative phosphorylation that occur under a variety of physiological situations [36], has been linked to IR in myocytes, adipocytes, and hepatocytes.’’ – Please split this sentence into two sentences.

Lines 133-134: ‘’Irisin improves IR by increasing oxidative phosphorylation capability and mitochondrial content.’’ - The reference is missing.

Lines 143-144: ‘’Moreover, irisin increases the expression of betatrophin which can promote pancreatic beta-cell proliferation and improve glucose tolerance and insulin action [9].’’ – Please discuss a possible PGC1α–irisin–betatrophin axis that has been proposed for regulating glucose homeostasis.

Lines 148-150: ‘’Furthermore, the treatment of r-irisin on C2C12 myocytes markedly increased the gene expression of mitochondrial transcription factor A (TFAM).’’ – Please specify the concentration of r-irisin.

Lines 164-165: ‘’Therefore, the evidence suggests that irisin improves IR via up-regulating hepatic mitochondrial content and action.’’ – There is not adequate evidence to suggest that irisin improves IR. Please provide more and stronger evidence to support this.

Lines 171-172: ‘’ Irisin can reduce IR by enhancing the intracellular trafficking and action of GLUT4.’’ – The authors did not provide enough evidence to support a possible role of irisin in reducing IR.

Line 197: ‘’Irisin can improve insulin action by down-regulating inflammatory cytokines.’’ - In which concentration irisin can improve insulin action? Please also discuss the type of studies, including in vitro, in vivo, and ex vivo, for supporting the role of irisin in improving insulin action.

Line 221: ‘’4. Signaling pathways of irisin regulating exercise and insulin resistance’’ – Irisin does not regulate exercise.  The authors may write 4. Signaling pathways mediating the link between exercise, irisin, and insulin sensitivity

Lines 298-300: ‘’Therefore, Irisin plays a crucial role in modifying the beneficial effects of exercise on IR by promoting the content and trafficking of GLUT4 within myocytes.’’ Line 317: ‘’Irisin can reduce IR by enhancing the function of mitochondria.’’ - The authors did not provide sufficient and strong evidence to conclude that irisin plays a crucial role in reducing insulin resistance.

Line 342-344: ‘’It is proposed that exercise increases serum concentrations of irisin and it enters organs or tissues where it acts as an inhibitor of inflammation cytokines.’’ -The reference is missing.

Line 360: Please justify using ‘’6. Patents’’ in the manuscript. 

Author Response

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Author Response File: Author Response.docx

Reviewer 2 Report

Lin et al. have written the review paper entitled  "Molecular basis of irisin regulating the effects of exercise on insulin resistance" satisfactorily. However, the reviewer would like to suggest authors to check the grammar carefully.

1. Please check Page 8 and line no. 360. Why the heading has been given as Patents?

Author Response

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Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Line 363: ‘’…as well as I kappa kinase β (IKKβ) in fatty tissue of obese 363 mice.’’ - Please write adipose tissue.

Author Response

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Author Response File: Author Response.docx

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.