Obesity and Leptin Resistance in the Regulation of the Type I Interferon Early Response and the Increased Risk for Severe COVID-19

Round 1

Reviewer 1 Report

This review is focused on the relationship between obesity, leptin resistance with the regulation of the type I interferon early response and the increased risk for severe COVID-19.  The text of this manuscript  is divided into 11 paragraphs. The manuscript is written on the basis of 270 references. In my opinion this manuscript is very interesting  but  suffers from some flaws.

1. Line 851: “Insulin Modulates Inflammatory Cytokine Release The chronically slightly elevated proinflammatory cytokines (including leptin) and insulin cause SOCS1/3 induction, which inhibits the signaling of cytokines (such as interferons), leptin and insulin [267]”. Is it correct?
2. Please include (in a table or graph) the evidences that show the link between leptin concentration/resistance and severity of COVID-19 in the animal or human studies.
3. Adipose tissue is a source of many adipokines that are related with inflammation and insulin-resistance. Please indicate the reasons why you focus on leptin?
4. Please verify that the abbreviations are used after the first time they appear in the text (e.g. ICU).
5. Figure 1 is incomplete (page 7)
6. Some references should be described shorter e.g. ref. 175
7. Please briefly summarize each paragraph. The text will be more reader friendly
8. The aim (page 2) and the main conclusion (page 18) do not correspond to the title of this manuscript (e.g. the leptin resistance, the type I interferon early response) . 

Author Response

We thank the reviewer for his/her very thoughtful and constructive feedback on our manuscript. Please find a point-by-point response to the reviewer's comments attached.

Author Response File: Author Response.docx

Reviewer 2 Report

The aim of this manuscript is to review the relationship between severe COVID-19 PNA and obesity/metabolic syndrome. The author reviewed the risk factors of severe COVID-19, the mechanism of SARS-CoV-2 infection and the following immune response. They emphasis the possible pathophysiology of SARS-CoV-2 in disruptive of Interferons and the role of obesity/metabolic syndrome in inflammation and immune response.

1. In Fig. 1, what is the unfilled blank box mean? Please explain and filled with relative information. 
2. A Schematic representation of signaling pathway of leptin and Insulin resistance in inflammation pathway should be presented in Figure which will be helpful for the general readers.
3. The role of Obesity/Metabolic syndrome in regulation of oxidative stress in ARDS has been well studied, please reviewed. 
4. Insulin resistance in ROS signaling should be reviewed as well.
5. Current COVID-19 treatment including Baricitinib (JAK inhibitor) and Tocilizumab (IL-6 inhibitor) and Remdesivir should be mentioned and review.

Author Response

We thank the reviewer for his/her very thoughtful and constructive feedback on our manuscript. Please find a point-by-point response to the reviewer's comments attached.

Author Response File: Author Response.docx

Reviewer 3 Report

This review attempts to find an answer to the question why SARS-CoV-2 infection in people with obesity can lead to serious illness and death: A very last advice is to recommend the authors to use the term “people with obesity” or “population with obesity” as advised by the latest Guidelines to manage obesity instead of the term “obese” or overweight that may not currently sound politically correct. It is important to make those modifications in the article.

By altering the metabolic set point, hyperleptinemia and insulin resistance disrupt T-cell function: In line 594 explain how the disruption of T-Cell function occurs.

The strong link between the COVID-19 pandemic and the pre-existing obesity pandemic has led to a contraction to “CoVesity”: The term CoVesity could be described by the authors in more detail, because, the dual pandemic will have a detrimental outcome in the short, medium, and long term.

In the conclusions, the authors describe that preventive measures should include not only vaccination and the typical well-known measures intended to avoid infection, but also diet, and lifestyle interventions. It is important to mention which lifestyle elements are important to modulate the metainflammation, since it was explained that reversing leptin resistance was physical exercise.

Author Response

We thank the reviewer for her/his very thoughtful and constructive feedback on our manuscript. Please find a point-by-point response to the comments in the attached document.

Author Response File: Author Response.docx