In the Brain, It Is Not All about Sugar

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Antunes et. al., describe in this review that Brain can utilize aletrnative fuels like fatty acids to sustain neuronal viability and activity. However, the authors should also discuss the physiological or pathological conditions in which brain is forced to rely on fatty acids.

Here are some minor comments:

Minor:

1.       Line 50: Can discuss the preference of neuronal soma for aerobic glycolysis and cite this paper Wei, Y., Miao, Q., Zhang, Q. et al. Aerobic glycolysis is the predominant means of glucose metabolism in neuronal somata, which protects against oxidative damage. Nat Neurosci 26, 2081–2089 (2023). https://doi.org/10.1038/s41593-023-01476-4.

 

2.       Line 52: Cite this and discuss glial cells are capable of metabolizing pyruvate. Consumption and Metabolism of Extracellular Pyruvate by Cultured Rat Brain Astrocytes. doi: 10.1007/s11064-022-03831-6.

 

3.       Line 69: MPC is responsible for uptake of pyruvate inside mitochondrial matrix and not glucose and lactate. See Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission. PMCID: PMC10983914. PMID: 38562794

 

4.       Line 103: Cite this article in introduction. Palmitoylation of the Parkinson's disease-associated protein synaptotagmin-11 links its turnover to α-synuclein homeostasis. PMID: 36787382 PMCID: PMC10150695 DOI: 10.1126/scisignal.add7220

 

5.       Line 204: Discuss the role of Ketone bodies during early brain development.

 

6.       Line 325: Should also discuss about the terminals lacking mitochondria (30-50% of the synaptic terminals lack mitochondria.)

 

7.       Line 340: Can cite this article, Axonal Transport of Mitochondria to Synapses Depends on Milton, a Novel Drosophila Protein. https://doi.org/10.1016/S0896-6273(02)01094-2

Major: Describe a pathological conditions in which metabolizing fattty acids is beneficial for the Brain.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript is interesting and the authors propose a novel review of metabolism (especially energy). However, I have the following comments.

I. Major comments:

1. The introduction is very general. I suggest including relevant aspects regarding brain metabolism and its relationship with brain composition. In addition, potential changes in the life cycle and potential changes in pathology. It is important that the authors explain very well why it is important to have written the review?

2. After the introduction, the authors should include a section on the criteria used to select the cited papers (methodology).

3. The authors focus the manuscript on the metabolism of fatty acids, especially in energetic aspects (energy production) but it is important that the authors include other points of fatty acid metabolism, specifically the synthesis of fatty acids.

3.1. What happens in the brain with the synthesis of fatty acids (saturates, monounsaturated and polyunsaturated)?

3.2. In the brain, polyunsaturated fatty acids (PUFAs) of the n-6 and n-3 series are essential in the brain. This should be included and discussed by the authors.

3.3. Regarding n-6 and n-3 PUFAs, the authors include aspects of biosynthesis and metabolism of these acids, focusing on the role of these fatty acids in neuronal activity (membranes, cellular signaling).

II. Minor comments:

1. Improve the writing of the objective of the article.

2. I think the title should include fatty acids.

Comments on the Quality of English Language

The manuscript is well written. But I suggest reviewing the wording of the manuscript.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Authors answered all the comments. Also, the manuscript was improved. Therefore, it can be accepted.