The Genetic Basis of Future Pharmacological Strategies for the Management of Comorbid Obesity and Depression: A Scoping Review

Round 1

Reviewer 1 Report

The review article "The genetic basis of future pharmacological strategies for the management of comorbid obesity and depression: a scoping re-view" is an intriguing study, and the author has compiled a one-of-a-kind research article using cutting-edge reviews on obesity and its association with depression via genes. In general, the paper is well written and structured. However, I believe the paper has some flaws in some data analyses and text, and I believe this unique dataset has not been used to its full potential. As the text is frequently ambiguous and lengthy, I have provided numerous comments below. The manuscript needs significant revision to fit the "Int. J. Transl. Med." format, according to the comments below.

Comments

Why author, Epigenetic studies were not included in this review?

The author must explain what factors influence the conditions in the smaller populations of young adults (n = 2), adolescents (n = 1), and pregnant women (n = 1).

The Q-Genie score one study has poor sore, which is why it was included in the study.

 

The author must thoroughly explain any relationships, particularly cellular, biological, and metabolically, with identified genes, such as a protein-protein neural network. If so, what we have identified hub genes?

 

 

Author Response

I thank the reviewer for their thoughtful critique of my manuscript. I have made corrections to the same to the best of my ability, as described below:

1. The text is frequently ambiguous and lengthy

Response: I agree with the reviewer. I have edited the manuscript to reduce superfluous verbiage and have reduced the length of the sections on synthetic and pharmacological therapies to reflect the scope of the Journal.

2. Why author, Epigenetic studies were not included in this review?

Response: Epigenetic studies were not included as they have been extensively covered in a recent review (Gharipour et al., Int. J. Mol. Sci. 2020) which identified three target genes (BDNF, SORBS2 and TAPBP) as being related to the epigenetics of obesity and depression. However, to integrate the findings of this review with those of Gharipour et al., certain changes were made to the manuscript as follows:

Methods (lines 98-102): "Epigenetic studies were not included in this review, as have been extensively reviewed in a recent publication, which covered all published studies up to 2020 and identified variations in the methylation of three specific genes as being linked to both obesity and depression [35]. However, the results of the current review are subsequently examined in the light of these epigenetic findings."

Methods (lines 136-142): "In addition to these conventional methods, an attempt to delineate protein-protein interactions, and thereby identify potential molecular hubs that link obesity and depression, was made through queries from the Search Tool for the Retrieval of Interacting Genes / Proteins (STRING) database. Two separate queries were conducted. The first included only those genes for which there were unequivocal positive findings (n = 14). The second included both the positive and equivocal findings from Table 2, as well as the three genes identified as targets of epigenetic modification by the earlier review (n = 19)."

Results (lines 270-278): "In the second model, all the sixteen genes identified as having some supporting evidence in Table 2, as well as the three genes identified in the earlier review of the epigenetics of obesity and depression (BDNF, SORBS2 and TAPBP) [35] were entered into the database. The resulting map (marked 2b in the figure) demonstrates protein-protein interactions of likely significance between thirteen of the nineteen genes included. Once again, there appeared to be a “network” involving genes related to monoaminergic transmission, neural plasticity and the stress response, which was in turn linked to another “network” related to food intake, energy utilization, and lipid metabolism through the genes LEP, MC4R and FTO. The possible significance of these findings is discussed below."

Discussion (lines 451-460): "It should also be noted that for six of the genes included in this analysis – AKR1C2, KCNE1, MCHR2, SORBS2, TAL1 and TAPBP – no significant protein-protein interaction was identified. This may reflect limitations in the methodology employed (for example, AKR1C2 was identified in a study of pregnant women, and may not be related to obesity in other populations), or in our existing knowledge of protein-protein networks. It remains possible that examination of the physiological effects of these genes in the context of depression and obesity could yield valuable insights into the pathophysiology and treatment of these conditions. One likely mechanism of importance in this context is immune-inflammatory dysregulation, which is known to occur in both depression and obesity, and in which some of these genes have already been implicated [35]."

3. The author must explain what factors influence the conditions in the smaller populations of young adults (n = 2), adolescents (n = 1), and pregnant women (n = 1).

Response: I agree that this is a limitation of relying on such studies. This has been mentioned in the revised paper as follows:

Discussion (lines 451-454): "It should also be noted that for six of the genes included in this analysis – AKR1C2, KCNE1, MCHR2, SORBS2, TAL1 and TAPBP – no significant protein-protein interaction was identified. This may reflect limitations in the methodology employed (for example, AKR1C2 was identified in a study of pregnant women, and may not be related to obesity in other populations)."

Limitations (lines 504-507): "Fourth, some of the included studies were conducted in special populations, such as pregnant women, adolescents and the elderly, in whom the biological processes related to obesity and depression may be unique to some extent. Therefore, these findings may not be directly applicable to obesity or depression in the general population."

4. The Q-Genie score one study has poor sore, which is why it was included in the study.

Response: I thank the reviewer for raising this issue. This has been discussed in the revised Methods section (lines 122-129) as follows:

"It should be noted that the rating of a study as “poor” using Q-Genie does not disqualify it from inclusion in a review; however, any positive findings from such a study should be interpreted with caution due to the risk of false-positive results arising from various biases. As the single study rated “poor” in this review did not yield any positive results, it was included for the sake of completeness. This is in accordance with the PRISMA-ScR guidelines (item 16), which recommend a critical appraisal of such papers, but not their exclusion [34]."

5. The author must thoroughly explain any relationships, particularly cellular, biological, and metabolically, with identified genes, such as a protein-protein neural network. If so, what we have identified hub genes?

Response: I sincerely thank the reviewer for identifying this limitation of the original manuscript. An attempt has been made to elucidate these protein-protein relationships as follows:

Methods (lines 136-142): "In addition to these conventional methods, an attempt to delineate protein-protein interactions, and thereby identify potential molecular hubs that link obesity and depression, was made through queries from the Search Tool for the Retrieval of Interacting Genes / Proteins (STRING) database. Two separate queries were conducted. The first included only those genes for which there were unequivocal positive findings (n = 14). The second included both the positive and equivocal findings from Table 2, as well as the three genes identified as targets of epigenetic modification by the earlier review (n = 19)."

Results (new section 4.3, lines 252-278):

"

To extend the results of this review beyond the scope of single-gene associations, an attempt was made to examine interactions between the proteins encoded by these genes. To this end, the genes identified in this review were entered into the STRING database, and a map of possible protein-protein interactions was constructed, which is illustrated in Figure 2. This process was carried out in two steps. In the first, only the fourteen genes with unequivocal evidence of an association with depression and obesity, as noted in Table 2, were entered. In this model (marked 2a in the figure), associations could be identified between ten of the fourteen protein products. Genes related to brain monoaminergic transmission (COMT, SLC6A3, and MAOA) were strongly linked to the glucocorticoid receptor NR3C1, which was itself linked to LEP (Ob). LEP was, in turn, linked with FTO and MC4R. FTO was linked to genes related to lipid metabolism (APOA5 and PCSK9), while MC4R showed a significant connection to NPY2R. Thus, there appear to be two distinct “networks” – one more directly associated with stress and depression, and one with energy utilization and lipid metabolism – which appear to be linked via the stress-related genes NR3C1 and LEP.

In the second model, all the sixteen genes identified as having some supporting evidence in Table 2, as well as the three genes identified in the earlier review of the epigenetics of obesity and depression (BDNF, SORBS2 and TAPBP) [35] were entered into the database. The resulting map (marked 2b in the figure) demonstrates protein-protein interactions of likely significance between thirteen of the nineteen genes included. Once again, there appeared to be a “network” involving genes related to monoaminergic transmission, neural plasticity and the stress response, which was in turn linked to another “network” related to food intake, energy utilization, and lipid metabolism through the genes LEP, MC4R and FTO. The possible significance of these findings is discussed below."

A new figure (Figure 2) illustrating possible protein-protein interactions has also been added to the revised manuscript.

This is also discussed in the Results (new section 5.3, lines 434-450): 

"When examining possible networks of interactions between the protein products of genes implicated in obesity and depression (Figure 2), similar findings were obtained both when considering the genes identified in this review, and when incorporating those identified as being subject to epigenetic modification in obesity and depression. In both cases, there appeared to be two closely linked “networks”, one involving genes related to monoaminergic transmission and neural plasticity, and one related to energy intake and utilization. In both cases, the “bridge” between these two tightly interconnected networks appeared to involve the genes NR3C1, Ob (LEP), FTO and MC4R. These findings suggest that therapies for co-occurring depression and obesity may be more effective if they are directed at one or more of these molecular targets. They also suggest that evaluation of the efficacy of anti-obesity treatments, particularly in the presence of depression, may be improved by the study of these genes or their products as potential biomarkers: this could include measures of the methylation of these genes, or the expression of their respective protein products, in relation to changes in body weight or in depressive symptoms. These findings might also explain the relative inefficacy of antidepressants in the management of obesity, as their effects may be confined to the first network without meaningfully influencing the second."

Reviewer 2 Report

In this paper, the authors wrote a scoping review of studies that evaluated the contribution of specific genetic variants to the comorbidity between obesity and depression. Overall, the manuscript is well written. The introduction provides sufficient information to get the reader familiarised with the subject and a clear aim. The methodology on how the papers were selected and included is very well described, with all relevant details. The topics described what you the read should expect to find and everything is presented in a very straightforward manner. The topics are properly discussed in a direct way and even limitations are presented to make the reader aware of how to use association studies. Therefore, I recommend the publication of the manuscript the way it is presented with some minor corrections, such as the one found in the page 2, line 78, with the word “safter”.

Author Response

In this paper, the authors wrote a scoping review of studies that evaluated the contribution of specific genetic variants to the comorbidity between obesity and depression. Overall, the manuscript is well written. The introduction provides sufficient information to get the reader familiarised with the subject and a clear aim. The methodology on how the papers were selected and included is very well described, with all relevant details. The topics described what you the read should expect to find and everything is presented in a very straightforward manner. The topics are properly discussed in a direct way and even limitations are presented to make the reader aware of how to use association studies. Therefore, I recommend the publication of the manuscript the way it is presented with some minor corrections, such as the one found in the page 2, line 78, with the word “safter”.

Response: I thank the reviewer for their kind and insightful comments on my manuscript. I apologize for the above typographical errors and have corrected the same in the revised manuscript. 

Round 2

Reviewer 1 Report