Peptide Hormones in Appetite Regulation: A Complex Network

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Regarding manuscript pharmaceuticals-4350884 entitled Peptide Hormones in Appetite Regulation: A Complex Network, which provides a biochemically oriented scoping review of appetite regulation. The Authors have prepared a comprehensive manuscript, well supported by literature sources, that attempts to map the regulatory pathways involved in appetite control in humans, both at the central and peripheral levels. The review further discusses the consequences of dysfunctions within this regulatory system and outlines pharmacological strategies for appetite modulation.

1. First, I would like to highlight that the Authors present a responsible and balanced perspective, emphasizing that appetite management in obesity is a complex issue that often requires dedicated therapeutic interventions and long-term lifestyle modifications, rather than focusing solely on body weight reduction. Nonetheless, as I identify this manuscript as a scoping review rather than a narrative review, I would suggest rephrasing the statement in the Abstract:

"This review argues that durable obesity management will require multi-target and precision-based strategies that address pathway redundancy and inter-individual variability, rather than reliance on single-hormone approaches."

The role of the Authors in a scoping review is not to argue for a particular position, but rather to synthesize and present the available evidence. Therefore, the Authors may instead conclude that the evidence gathered and analyzed in the review suggests that multi-target and precision-based approaches may offer the greatest therapeutic potential.

1. As mentioned above, I identify this manuscript as a scoping review. Therefore, the Authors should present their literature screening protocol and include a PRISMA-ScR flow diagram and methodology in accordance with accepted reporting standards for scoping reviews. Also, Authors should briefly describe research strategy – databases, used terms, criteria, or inclusion or exclusion.
2. The Authors have done an excellent job synthesizing and presenting the complexity of the regulatory network governing appetite. The manuscript gradually guides the reader from central regulation, through peripheral signaling mechanisms, to the gut-brain axis and the role of the microbiota. This section is broad and constitutes the dominant part of the manuscript. However, I do not consider this a weakness, as such complex mechanisms require detailed and careful presentation.
3. Table 1 provides a useful summary of central and peripheral regulatory pathways. However, some editorial improvements are needed. The text, particularly within the columns “Central Pathway” and “Mechanism…”, appears visually crowded and occasionally overlaps between rows, making it difficult to determine which information belongs to a particular pathway. Please revise the table formatting to improve clarity and readability.
4. On page 6, beginning with the paragraph starting “Grzelka et al. …” and continuing through the paragraph beginning “c-Fos-like …”, the Authors discuss studies focused on appetite modulation interventions. Immediately afterwards, the manuscript returns to the mechanistic description of appetite regulation. I suggest moving these paragraphs to Section 5, “Therapeutic Implications”, where they would fit more naturally and improve the logical flow of the manuscript.
5. Figure 3, presenting the regulation of blood glucose by gut microbiota, is not effective in its current form. I am unable to identify how the figure actually illustrates regulatory mechanisms or causal relationships. In my opinion, the figure should either be completely redesigned or removed from the manuscript.
6. While I highly appreciate the sections describing the mechanisms of appetite regulation, I have substantial concerns regarding the section devoted to appetite regulation disorders. This section is broad and, in my opinion, does not align well with the main focus of the manuscript. Appetite dysregulation disorders are consequences of malfunctions within the regulatory network rather than components of the network itself. Providing extensive discussion of various disorders, pathological conditions, and clinical consequences dilutes the central message of the review. I believe this section should be substantially reduced or removed, with only brief mention of major consequences included in the Introduction. Nevertheless, I encourage the Authors to consider using the removed material as the foundation for a future review specifically dedicated to appetite dysregulation and related disorders.
7. The section entitled “Therapeutic Implications” should be strengthened. At present, it appears somewhat fragmented and lacks a clear organizational structure. It may be beneficial to categorize interventions according to their physiological outcomes (e.g., satiety induction, appetite suppression, modulation of reward pathways, enhancement of energy expenditure) rather than discussing individual agents separately. Currently, the manuscript is built upon two major pillars: (i) the mechanisms of appetite regulation and (ii) the possibilities for therapeutic modulation of those mechanisms. However, these two components are not equally developed. I encourage the Authors to expand and strengthen the discussion of therapeutic strategies to match the quality and depth of the mechanistic sections.
8. The reference list requires editorial revision. Please ensure full compliance with the journal guidelines. At present, some references include DOI numbers while others do not; author names and journal titles are formatted inconsistently; and capitalization styles vary throughout the bibliography. A careful review and standardization of the reference section are necessary.

Author Response

Attached

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

In this review “Peptide Hormones in Appetite Regulation: A Complex Net-work” the authors provided a comprehensive narrative review of the integrated central and peripheral networks governing appetite control and energy homeostasis. This review is highly relevant given the current clinical paradigm shift toward peptide-based metabolic therapies. Also, the authors successfully connected fundamental biochemistry with complex neuroendocrine circuitries and current translational challenges in the current review manuscript. The manuscript requires a minor revision to address a few minor typographical and formatting issues. I recommend that the authors address the following comments in the revised manuscript before it’s considered further.

1. There are few minor typographical issues in the Figure 1 and Table 1. "CKK" is used interchangeably with "CCK" (Cholecystokinin) in Figure 1 and Table 1 as well. This should be standardized to CCK globally throughout the manuscript.
2. In Figure 3, overlapping concepts and visual clutter including "Emotional eating", "Stress", "Fatigue" juxtaposed inelegantly next to LPS production and short-chain fatty acids (SCFC). I suggest the authors streamline to focus exclusively on how microbial metabolites trigger gut peptides.
3. The authors are not discussed in detail and looks like inconclusive about of eating disorders including Anorexia Nervosa and Binge Eating Disorder. I suggest the authors evidently clarify whether GLP-1 agonists show active clinical efficacy in Binge Eating Disorder or if the data remains strictly localized to early preclinical findings.
4. In general, please check all typographical and formatting issues throughout the manuscript globally.

Author Response

Attached

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Authors,

 

thank you for considering my comments and your wokr to improve the manuscript. I believe that now it is ready to be published in the Pharmceuticals.