Role and Regulation of Glycogen Synthase Kinase-3 in Obesity-Associated Metabolic Perturbations
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsOverall, the authors present a well-articulated and original review of the current scientific knowledge on the role of GSK3 in a tissue-specific context towards affecting metabolic systemic functions including Obesity.
Nonetheless, this reviewer find a single major scientific incongruence which requires mandatory intervention towards allowing the manuscript to be of publication level.
In fact, he authors opted to use a traditional definition but currently to be considered scientifically incorrect by defining GSK3aand GSK3b “isoforms” throughout the text of their manuscript.
This definition has now been broadly proven to be incorrect given the current definitions of isoforms versus that (appropriate in this case) of paralogs.
Specifically, an isoform, by modern definition, is a transcriptional product of a single gene with a single common chromosomal loci and resulting from a single gene alternative splicing.
On the contrary, a paralog originates from the transcriptional regulation of two physically distinct genes with phylogenetic commonality (meaning possibly originated by duplication in millions of years as demonstrated by their presence in mammalian species) located on different chromosomal loci as is the case of GSK3 (as close as they can be at their sequence level).
The only exception to the above logical frame is provided by recently duplicated genes generated by gene amplification where the gene sequence is practically identical as well as their entire promoter sequence (this happens for example as result of disease evolution within the same individual in cancer cells to support increased specific cancer driver genes overall transcription rate).
As such, GSK3a and GSK3b cannot and should not be referred as isoforms but as paralogs. A review work to this effect making a clear distinction between isoforms and paralogs involved in metabolic and other diseases (including GSK3) can be found in available peer reviewed work available on NCBI’s PubMed as in PMCID: PMC7761347.
Upon remodulation the manuscript to replace the GSK3 genes definition (even by an introductory statement or period explaining the reasons for the correct terminology adoption as provided herein), this reviewer finds the manuscript to be worth of publication without any further delay.
Author Response
We appreciate the reviewers' time and suggestions for improving the paper. We have addressed all the reviewers' concerns; therefore, the revised manuscript is significantly improved. Specific responses to the reviewers' comments are as follows (blue font) . In the revised manuscript, changes are marked in blue font.
Overall, the authors present a well-articulated and original review of the current scientific knowledge on the role of GSK3 in a tissue-specific context towards affecting metabolic systemic functions including Obesity. We highly appreciate the reviewer's encouraging remark.
Nonetheless, this reviewer find a single major scientific incongruence which requires mandatory intervention towards allowing the manuscript to be of publication level. In fact, he authors opted to use a traditional definition but currently to be considered scientifically incorrect by defining GSK3aand GSK3b “isoforms” throughout the text of their manuscript. This definition has now been broadly proven to be incorrect given the current definitions of isoforms versus that (appropriate in this case) of paralogs. Specifically, an isoform, by modern definition, is a transcriptional product of a single gene with a single common chromosomal loci and resulting from a single gene alternative splicing.
On the contrary, a paralog originates from the transcriptional regulation of two physically distinct genes with phylogenetic commonality (meaning possibly originated by duplication in millions of years as demonstrated by their presence in mammalian species) located on different chromosomal loci as is the case of GSK3 (as close as they can be at their sequence level). The only exception to the above logical frame is provided by recently duplicated genes generated by gene amplification where the gene sequence is practically identical as well as their entire promoter sequence (this happens for example as result of disease evolution within the same individual in cancer cells to support increased specific cancer driver genes overall transcription rate). As such, GSK3a and GSK3b cannot and should not be referred as isoforms but as paralogs. A review work to this effect making a clear distinction between isoforms and paralogs involved in metabolic and other diseases (including GSK3) can be found in available peer reviewed work available on NCBI’s PubMed as in PMCID: PMC7761347. Upon remodulation the manuscript to replace the GSK3 genes definition (even by an introductory statement or period explaining the reasons for the correct terminology adoption as provided herein), this reviewer finds the manuscript to be worth of publication without any further delay.
Response: Thanks much for pointing this out and clarifying. We agree with the reviewer’s comment. In the revised manuscript, the two GSK-3s, i.e. GSK-3α and GSK-3β are referred to as paralogs instead of isoforms.
Reviewer 2 Report
Comments and Suggestions for AuthorsManuscript written by Lemon et al. presents the role and regulation of glycogen synthase kinase-3 in obesity-asscociatted metabolic perturbations. While reading and analyzing the manuscript, I decided to propose the following suggestions and ask quentions to the authors:
1. The purpose of the work appears twice in the abstract section. Please combine these two goals into one.
2. The statement "certain types of cancers" appears in the Introduction section. Please give examples of such cancers.
3. At the end of the Introduction section, the purpose of the work is missing. Please add the purpose of the review.
4. Please highlight in your text why GSK-3 is such an important molecule.
5. The introduction includes the WNT, Hedgehog, etc. signaling pathways. Please describe what these signaling pathways are involved in.
6. On page 3, "GSK-3B alters cardiac function" appears. Please provide examples of such functions
7. On page 5, "lowered inflammatory cytokines" appears. Please specify whether these are pro-inflammatory or anti-inflammatory cytokines.
8. Please check the abbreviations throughout the text
Author Response
We appreciate the reviewers' time and suggestions for improving the paper. We have addressed all the reviewers' concerns; therefore, the revised manuscript is significantly improved. Specific responses to the reviewers' comments are as follows (in blue) . In the revised manuscript, changes are marked in blue font.
Comment 1: The purpose of the work appears twice in the abstract section. Please combine these two goals into one.
Response 1: Thanks much for pointing this out. In the revised manuscript the two goals have been combined into one (Page 2, Lines 11-15 in the marked manuscript)
Comment 2: The statement "certain types of cancers" appears in the Introduction section. Please give examples of such cancers.
Response 2: Thanks much for pointing this out. As suggested, in the revised manuscript we have specified the types of cancers which are associated with obesity and GSK-3 overactivity (Page 3, Lines 4- 5 in the marked manuscript)
Comment 3: At the end of the Introduction section, the purpose of the work is missing. Please add the purpose of the review.
Response 3: Thanks much for the suggestion. As suggested, we have added the purpose of the review at the end of the introduction section (Page 4, Lines 27-30 in the marked manuscript)
Comment 4: Please highlight in your text why GSK-3 is such an important molecule.
Response 4: Thanks much for the suggestion (Page 3, lines 10-14 in the marked manuscript)
Comment 5: The introduction includes the WNT, Hedgehog, etc. signaling pathways. Please describe what these signaling pathways are involved in.
Response 5: Thanks much for pointing this out. As suggested, in the revised manuscript we have described the cellular functions regulated by these pathways (Page 4, lines 5-12 in the marked manuscript)
Comment 6: On page 3, "GSK-3B alters cardiac function" appears. Please provide examples of such functions.
Response 6: Thanks much for the suggestion: As suggested, we have provided examples of cardiac functions altered by GSK-3β (Page 5, lines 21-23 in the marked manuscript)
Comment 7: On page 5, "lowered inflammatory cytokines" appears. Please specify whether these are pro-inflammatory or anti-inflammatory cytokines.
Response 7: Thanks much for pointing this out. They are pro-inflammatory cytokines (Page 8, line 8 in the marked manuscript)
Comment 8: Please check the abbreviations throughout the text
Response 8: Thanks, and revised as suggested
