Obesity: Genetic Insights, Therapeutic Strategies, Pharmacoeconomic Impact, and Psychosocial Dimensions

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is generally a well-written review paper on the causes and available treatments for obesity.  The beginning part of the review is clear, informative and easy to read.  This breaks down at Section 6 (artificial intelligence).  Although section 6 has the potential to be very interesting, it was hard to read/follow and understand, leaving several questions and confusion.  Major and minor comments are below:

• A recent paper has come out showing that prevalence of obesity in the United States increases to 68% when using a new definition that takes into account anthropomorphic measures (see Fourman, L. T. et al. Implications of a New Obesity Definition Among the All of Us Cohort. JAMA Netw Open 8, e2537619 (2025)). This would be useful to include in your introduction.
• Under pathophysiology and mechanisms of obesity, I would also mention the role of satiety signals and reward pathways in the brain.
• Very important to mention the role of high fat diets in leading to hypothalamic inflammation which then disrupts satiety signaling (e.g., leptin-melanocortin pathway). This could be included under Section 2.3 “ghrelin and appetite dysregulation” or have its own section.
• Also worth mentioning hypothalamic inflammation as a possible link between obesity and psychological health.
• There are several places that are missing references (lines 200, 206, 219, 245, 280, 432)
• You provide conflicting information for the amount of weight loss in response to semaglutide vs liraglutide: ref 55 indicates a 14.9% average weekly loss while ref 57 indicates a 35% reduction for semaglutide vs 16% for liraglutide. Please check ref 57, as I do not think these numbers are accurate.
• Some abbreviations have not been defined (e.g., AOM, LMIC), while others are defined more than once (e.g., MBS, QALY, ICER).
• Line 385, remove “Special populations” before “Adolescents…”
• Section 4.4.3, Emerging therapy, gene therapy: it is unclear why you talk about the monogenic forms of obesity, but of these genes, only mention leptin as a potential gene therapy. Either include more examples or introduce this paragraph in a different way.
• Line 436, remove “…it basically…”
• Lin 461: make sure to clarify that these early results are in preclinical models.
• Section 4.5: Nanotechnology and obesity management: it is not clear how nanotechnology is being used to treat obesity. Can you go into a bit more detail on ref 93 – how does this work? Are there other examples from Table 1 that you can describe in more detail?  Also, make sure you refer the reader to Table 1.
• Section 6: Artificial Intelligence: this section was very confusing and hard to follow. This applies both to the bigger picture/message as well as individual sentences that were hard to follow (e.g., lines 667, 775 (what is a UCB1 multi-armed bandit?), 782, 794 (what do you mean by minimum unit price?), 797, 825, 829 (what is TRIPOD-AI and CONSORT-AI?). Please update this entire section.
• Conclusion: Maternal health should have its own section prior to the conclusion

Comments on the Quality of English Language

Section 6 was hard to follow and may benefit from improved use of English.

Author Response

done with highlights through the manuscript 

Reviewer 2 Report

Comments and Suggestions for Authors

Gladious Naguib El-hadidy et al. have submitted a comprehensive review on Genetic Insights, Therapeutic Strategies, Pharmacoeconomic Impact, and Psychosocial Dimensions Of Obesity. While this is a well-written manuscript, there are certain areas the authors need to address to clarify their approaches and conclusions, as outlined below. Furthermore, some formal and language checking is necessary, as mentioned below.

 

The format of multiple references is not uniform. Sometimes (##, ##) or (##), (##) ??

Line 56: The World Health Organization (WHO) defines overweight as a BMI ≥25 kg/m² and obesity as a BMI ≥30 kg/m², … The authors should mention that in pediatric cohorts age-and gender related BMI SDS scores are the basis for obesity definition.

L 216: … in obese patients. In one study …

L286: … and significant improvements …

L 291 and 293, 301, 315, 357, 385, 391, 445, 525, 752 and many more: a blank is missing.

L303: … tolerability issues. These findings …

L317: … of 72 weeks. Significantly larger …

L354: … and obese adults (65). Also, a meta-analysis …

L378: … non-surgical weight loss.??? lose weight through non-…

L395: … (70). Preoperative assessment and comprehensive evaluation (nutrition,…

L426: The authors should add a section and discuss potential side effects and late effects of bariatric procedures (dumping syndrome,vitamin deficiencies,…).

L???: The authors should mention novel findings on the effectiveness of setmelanotide in acquired hypothalamic obesity. The results of a RCT trial will be published soon. First results were reported under: https://ir.rhythmtx.com/news-releases/news-release-details/rhythmpharmaceuticals-announces-pivotal-phase-3-transcend-trial

L437: … and gives a metabolic benefit_ …

L486, section 4.5.: Nanotechnology – Sequence of too many sections. Please combine.

L501: grammar?!

L517: The authors should include and discuss a recently published study on patient claims data analysing the health care costs for treatment of acquired hypothalamic obesity. (Witte J, Touchot N, Surmann B, Braegelmann K, Flume M, Beckhaus J, Friedrich C, Müller HL. Economics of hypothalamic obesity in patients with craniopharyngioma and other rare sellar/suprasellar tumors. Eur J Health Econ. 2025 May 9. doi: 10.1007/s10198-025-01786-3. Epub ahead of print. PMID: 40343652).

L567: Furthermore, imperfect … for example … (grammar?!)

L574: … without killing all tumors – “deleting” or “erasing” all tumors are better terms.

L573-579: This sentence is way too long: The suboptimal therapy selection is another limitation, which encompasses the failure of the traditional cancer treatment without killing all tumors such as radiation therapy leads to damage the surrounding tissues, also using a single drug for a single target disease could lead to undesirable repercussions, a prime example bicalutamide which is a selective androgen receptor (AR) antagonist, implicated in gynecomastia for men as monotherapy, and may trigger occurrence of late stage of prostatic cancer. (119).

L584: … 3) therapeutic personalization …

L595: … prostate. (118). Ceylan underscored …

L599:  A breast cancer (ER+/HER2−) study highlighted…

L611: In the breast cancer model discussed the role of leptin in enhancing the tumor growth of MCF-7 cells through activation of STAT3 and the MAP kinase (MAPK) pathway. Grammatical mistake – something is missing in this sentence.

L652: why bold font: level, HSD17B8 metabolic

L668: explain abbreviation GBM when it first appears.

L903-911: Furthermore, the impact of obesity extends into maternal health, where… This section would better fit in the main part of the text and not in the conclusion (where it is mentioned for the first time).

Comments for author File: Comments.pdf

Comments on the Quality of English Language

Gladious Naguib El-hadidy et al. have submitted a comprehensive review on Genetic Insights, Therapeutic Strategies, Pharmacoeconomic Impact, and Psychosocial Dimensions Of Obesity. While this is a well-written manuscript, there are certain areas the authors need to address to clarify their approaches and conclusions, as outlined below. Furthermore, some formal and language checking is necessary.

Author Response

done and highlighted through the manuscript