The Role of Thermogenic Fat Tissue in Energy Consumption
Round 1
Reviewer 1 Report
A very interesting review, quite fully covers the problem of adipocyte differentiation, UCP-1 related and independent adipocyte thermogenesis. The review is written clearly, logically, the data is presented consistently. The data presented in the review are modern.
I will note a few minor remarks that are advisory in nature and can be accepted by the authors at their discretion.
Because the purpose of the manuscript is: This review discusses the roles that thermogenic fat play in energy consumption and offers insight into the challenges associated with its application in the treatment of obesity and type 2 diabetes; therapeutic targets for DM-2 therapy is the important and very interesting part of manuscript; it would be better to indicate in the title that it will be discussed, including thermogenesis of adipose tissue as targets for DM therapy.
Figure 1. It is unclear what factors influence the conversion of white adipocytes to beige. This problem is covered in detail below, and the mechanism of formation of beige adipocytes can be drawn on the figure as the most interesting facts.
As a discussion, I invite the authors to discuss the problem of regulation of thermogenesis in diabetes: lipolysis in white adipocytes due to cold stimulation and β3 adrenergic receptor stimulates insulin secretion and contributes to the facilitation of lipid uptake into activated brown adipocytes. How does this process change in diabetes?
Another reason for discussion is UCP-independent pathways of thermogenesis in diabetic patients. Thus, it is known that the expression of SERCA-2 and RyR2 is increased in patients with diabetes, at least in the stage of its latent course (DOI: 10.1007/s10517-021-05346-6). Authors can discuss this fact as a possible compensatory mechanism.
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Reviewer 2 Report
Overall, this is an interesting a needed work to advance the field in understanding the contemporary advancements in the understanding of lipid metabolism. This work outlines some of the contemporary and non-contemporary methods of beiging of lipid cells. I believe this work does an okay job at outlining the work done. I feel more work can be done to elucidate the relationship between beiging via stem cell progenitors vs changes via white adipocytes. I ask that that the authors address in a more concise manner the actual relevance of this work in clinical practice and actual implications for the presented work
Line 75, the postulation is that only one can exist. There is no evidence of this singularity in a pathway. Would advise rewriting these sentences.
Line 87, why is this hypothesis a cause for concern?
Line 107, what transcription factor is suppressed?
Line 115, would recommend changing to non-shivering thermogenesis, since it is sparsely used in the remaining paragraph, it is confusing when the acronym is used after only being referenced once before.
Line 277-282, what does this mean as far as lipid reduction or the potential ablation of lipid accumulation?
Line 368, can you further describe how it relates to the mechanism.
Line 390, confused on why this paragraph is here. Seems out of place with the subsequent paragraph.
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Reviewer 3 Report
Line 13-14 and generally in the MS: thermogenic fat cells exist as an expression, but thermogenic fat is a very strange one as fatty acids are not classified as thermogenic and non-thermogenic fatty acids.
Line 15: „whether it is applicable to the treatment of obesity and type 2 diabetes.” It is very optimistic wording and would sound better as a suggestion.
Line 50: „Type 2 diabetes is characterized as insulin deficiency caused by pancreatic β cell function and/or insulin resistance” instead of this: Type 2 diabetes is characterized by insulin resistance and /or deficiency caused by pancreatic β cell function.
Figure 1: term of adipocytes progenitor should change to progenitor adipocytes form.
Figure 1 legend is very superficial, and should contain more detailed information. There is no information about SMA in the text.
Line 85: de novo should be in italic
Line 122-123: β3-adrenergic receptor
Line 143-144: „This glucose is used for glycolysis via glucose-6-phosphate, which subsequently moves into mitochondria (Figure2)” The authors should provide much more detailed information about this metabolic process (mitochondrial glucose-6-phosphate) which should also be also illustrated in the figure.
Figure 2. legend and the figure are very superficial and should contain detailed information.
There is an unusual representation of the fatty acids, due to the fact that it is located in the brown adipose tissue, it looks like more "small lipid droplets". It would be beneficial to change to saturated long-chain and unsaturated fatty acids as the authors explained the mechanism of supporting the heat production by the UCP-1.
Figure 3.: Sarcolipin is not indicated in the figure. As it is a beige adipocyte the lipid droplets are missing.
Line 187: „Sarcolipin (SLN) is potentially involved in Ca2+ cycling and binds to SERCA to facilitate ATP production.” Is there any ATP production there?
Line 241: Irisin is an adipokine or myokine.
Line 245: IL-6
Author Response
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Reviewer 4 Report
In their review Horino et al described the last advances in the study of brown and beige adipose tissues. The review is exhaustive and well documented. The manuscript is clear, well-written and well-illustrated. It will be of great help for researchers wanting an overview on thermogenic fat.
A few details:
-The authors described two futile cycles: Ca2+ cycling and creatine cycling that can be responsible for UCP1-independent non shivering thermogenesis. The authors could indicate if these futile cycles are specific for adipocytes or if they are also observed in others cell types.
-In figure 3 the meaning of “ETC” (electron transport chain) should be written in full in the legend figure.
Lane 187:
The authors write: “Sarcolipin (SLN) is potentially involved in Ca2+ cycling and binds to SERCA to facilitate ATP production.”
Since SERCA is an ATP-ase did the authors mean “to facilitate ATP hydrolysis” ?
lane 225 :
The authors write: « Rosiglitazone stables PRDM16 expression… » .
Did the authors mean “stabilizes” ?
lane 320:
The authors write: “a recent review indicated that increased an IL-6 level delays gastric emptying …”
Did the authors mean “in IL-6 levels” ?
Author Response
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