Exercise, Prostaglandin E2, and Cardiometabolic Health: From Molecular Signaling to Systemic Adaptation
, Mike M. Ravn Pedersen 3,4, Shaheen Y. Bhat 3,4 and Timothy D. Bryson 3,4,*Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsIn the current review the authors synthesized current evidence on PGEâ‚‚ biosynthesis and signaling in the context of exercise, with a focus on its role in broader cardiometabolic health and disease.
Some suggestions:
- Point 1, Cardiometabolic disorders:
-please update the statistical information presented at lines 35-38
-lines 50-51, you wrote “exercise is known to positively regulate insulin, glucose balance…”
Exercise is associated with improved insulin sensitivity and glucose regulation, but the magnitude and consistency of these effects may vary depending on population, exercise modality, and disease state.
-please make a clearer stratification of exercise modalities, as aerobic, resistance, and combined training may induce distinct metabolic and inflammatory adaptations.
- you wrote about the “concept of exercise mimetics”. This concept is promising but remains speculative at this stage. Please clarify the current translational limitations of this approach.
-please discuss the proposed role of prostaglandin E2 more cautiously, because its effects are context-dependent and may vary between pro- and anti-inflammatory states.
- At lines 103-110 you discussed about lipoproteins and the subtitle is “1.2. Exercise-Induced Lipid Mediators”. Lipoproteins are not mediators.
The mention of prostaglandin E2 is abrupt and not well connected to the discussion of lipid profile changes. A clearer explanation is needed to link exercise-related changes in lipoproteins with bioactive lipid signaling.
- Point 3.1. Difference in PGE2 Production via a Variety of Exercise Modalities:
-the discussion should benefit from clearer separation between exercise-induced physiological responses and NSAID-mediated pharmacological effects. Both can affect PGE2, but in different directions and mechanisms.
The subtitle is “…exercise modalities” and you wrote about “NSAIDs ibuprofen and acetaminophen administration”.
- Point 4. PGE2 Response to Exercise in Adipose Tissue:
-the discussion is based on indirect evidence from adipocyte biology, fasting, and pharmacological models, rather than direct measurements of PGE2 responses in adipose tissue following exercise. Please underline this limitation throughout the text.
-the connection between exercise-induced lipolysis and PGE2 production in adipose tissue remains indirect and should be stated more cautiously.
-lines 336-342 - The GLP-1 receptor agonist data should be interpreted with caution, as drug effects on COX-2 signaling may not reflect the same processes that occur during exercise.
5.Point 5. Preclinical Large Animal Evaluations of PGE2 and Implications for Sensitization of Autonomic Response Mechanisms
- In this section you presented combined experimental and clinical findings with mechanistic hypotheses. It is not always clear which conclusions are well established and which are still speculative.
- The roles of PGE2 compared to other COX-derived mediators should be clearly separated, and the proposed mechanisms should be described more cautiously, given the limited in vivo evidence
Author Response
The authors thank the reviewer for their positive critiques and suggestions to make our review more comprehensive and a more valuable contribution to the field. We believe we have adequately addressed all the points raised by the reviewer, which can be found in bold below:
- Point 1, Cardiometabolic disorders:
-please update the statistical information presented at lines 35-38
The statistics on CVD death have been updated to the latest 2026 report, and the corresponding reference has been replaced.
-lines 50-51, you wrote “exercise is known to positively regulate insulin, glucose balance…”
Exercise is associated with improved insulin sensitivity and glucose regulation, but the magnitude and consistency of these effects may vary depending on population, exercise modality, and disease state.
Thank you for pointing this out. This caveat has been added in.
-please make a clearer stratification of exercise modalities, as aerobic, resistance, and combined training may induce distinct metabolic and inflammatory adaptations.
This is discussed beginning with the paragraph “From a clinical standpoint, understanding the patients’ ….”. We have now referenced this section based on the previous point raised by the reviewer. Hopefully this raises the readers’ attention to the fact there are multiple exercise modalities.
- you wrote about the “concept of exercise mimetics”. This concept is promising but remains speculative at this stage. Please clarify the current translational limitations of this approach.
This paragraph has been added, explaining the limitations of the exercise mimetic field.
-please discuss the proposed role of prostaglandin E2 more cautiously, because its effects are context-dependent and may vary between pro- and anti-inflammatory states.
- At lines 103-110 you discussed about lipoproteins and the subtitle is “1.2. Exercise-Induced Lipid Mediators”. Lipoproteins are not mediators.
The mention of prostaglandin E2 is abrupt and not well connected to the discussion of lipid profile changes. A clearer explanation is needed to link exercise-related changes in lipoproteins with bioactive lipid signaling.
Fair point. We thank you for catching this. The subtitle has been changed to be more general regarding all lipids. We have introduced PGE2 in a more coherent manner now by briefly introducing the concept of lipid mediators.
- Point 3.1. Difference in PGE2 Production via a Variety of Exercise Modalities:
-the discussion should benefit from clearer separation between exercise-induced physiological responses and NSAID-mediated pharmacological effects. Both can affect PGE2, but in different directions and mechanisms.
The subtitle is “…exercise modalities” and you wrote about “NSAIDs ibuprofen and acetaminophen administration”.
Thank you. The subtitle was not appropriate for this discussion, it has been changed to better reflect the discussion. We have also bulked up the discussion to make it more clear regarding the effects of NSAIDs.
- Point 4. PGE2 Response to Exercise in Adipose Tissue:
-the discussion is based on indirect evidence from adipocyte biology, fasting, and pharmacological models, rather than direct measurements of PGE2 responses in adipose tissue following exercise. Please underline this limitation throughout the text.
-the connection between exercise-induced lipolysis and PGE2 production in adipose tissue remains indirect and should be stated more cautiously.
-lines 336-342 - The GLP-1 receptor agonist data should be interpreted with caution, as drug effects on COX-2 signaling may not reflect the same processes that occur during exercise.
We appreciate the critique on this section of the manuscript. Throughout the entire section we have added points to tone down the definitive nature of our discussion and hopefully have now pointed out that the information, where appropriate, is hypothesis-driving and/or lacking direct evidence.
5.Point 5. Preclinical Large Animal Evaluations of PGE2 and Implications for Sensitization of Autonomic Response Mechanisms
- In this section you presented combined experimental and clinical findings with mechanistic hypotheses. It is not always clear which conclusions are well established and which are still speculative.
We thank the reviewer for their response. We agree clarity is warranted and we have taken the time to accentuate which conclusions and areas that are more established vs those that are more speculative. We also believe it is important to note that with regard to large animal model systems and human research, PGE2 research has been limited. Hence, this section was intended to highlight the need for more studies related to skeletal muscle and preclinical/clinical environments.
- The roles of PGE2 compared to other COX-derived mediators should be clearly separated, and the proposed mechanisms should be described more cautiously, given the limited in vivo evidence
We thank the reviewer for the comment. While we agree more clear separation would provide greater insight, the current literature has limited separation in preclinical models and human models related to prostaglandins vs COX derived mediators. However, we have taken the time to clarify aspects of these mediators throughout this section to improve clarity and over all understanding for readers and we believe, as the reviewers suggest, that it improves the manuscript.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsThis review covers an interesting and relevant topic and includes many recent references.The manuscript is well organized and easy to follow. However, in its current form it is too descriptive and doesnot provide enough critical analysis:
The Introduction (lines 27–114) is too long and contains general information thatis already well known. It should be shortened so that more attention can be given to the main topic.
The manuscript mainly summarizes published studies without discussing their strengths, limitations, or conflicting findings. This is especially evident in the sections on EP receptors(lines 206–293) and adipose tissue (lines 294–353), where many conclusions are based on animal studies or indirect evidence but are presented as broadly applicable. The authors should clearly distinguish established findings from hypotheses.
The section on large-animal studies and autonomic regulation(lines 354–406) is only loosely related to the main focus of the review and could be shortened.
The conclusions (lines 408–426) are stronger than the available evidence supports.Most of the evidence discussed is preclinical, while direct human evidence remains limited. Therefore, statements suggesting that PGE2 is a therapeutic target or a key mediator of exercise adaptation should be presented more cautiously.
Overall, the review has potential, but it requires a more critical evaluation of the literature, less speculation, and a clearer focus on the main topic.
Comments on the Quality of English LanguageEnglish needs minor polishing
Author Response
Reviewer 2
This review covers an interesting and relevant topic and includes many recent references. The manuscript is well organized and easy to follow. However, in its current form it is too descriptive and does not provide enough critical analysis:
The Introduction (lines 27–114) is too long and contains general information that is already well known. It should be shortened so that more attention can be given to the main topic.
Based on the comments brought forth by reviewer #1, we have made some substantial edits to this section. We hope it now gives more attention to the main point of the manuscript.
The manuscript mainly summarizes published studies without discussing their strengths, limitations, or conflicting findings. This is especially evident in the sections on EP receptors (lines 206–293) and adipose tissue (lines 294–353), where many conclusions are based on animal studies or indirect evidence but are presented as broadly applicable. The authors should clearly distinguish established findings from hypotheses.
These sections have been heavily edited to distinguish direct evidence from hypothesis-generating speculation.
The section on large-animal studies and autonomic regulation (lines 354–406) is only loosely related to the main focus of the review and could be shortened.
Based on reviewer #1’s comments, this entire section has been re-written extensively to be more focused. This section was intended to highlight the need for more studies related to exercise, skeletal muscle and preclinical/clinical environments.
The conclusions (lines 408–426) are stronger than the available evidence supports. Most of the evidence discussed is preclinical, while direct human evidence remains limited. Therefore, statements suggesting that PGE2 is a therapeutic target or a key mediator of exercise adaptation should be presented more cautiously.
Throughout the manuscript, we have included statements that we believe clearly delineate between speculation and direct evidence.
Overall, the review has potential, but it requires a more critical evaluation of the literature, less speculation, and a clearer focus on the main topic.
Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsI appreciate the authors for addressing my questions and suggestions. The revised manuscript looks good to me.
Best regards,
