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Referee Comments: Referee 1

Posted by PLOS_ONE_Group on 07 Apr 2008 at 22:42 GMT

Referee 1's Comments:

Review of the original submission:

Appetite Enhancement and Weight Gain by Peripheral Administration of TrkB Agonists in Non-human Primates

This paper describes a novel, potentially exciting therapeutic intervention to stimulate food intake and weight gain, to possibly treat wasting disorders. The authors show several lines of evidence that confirm central TrkB /BDNF signaling decreases body weight. But, the authors also provide good evidence that peripheral TrkB signaling has the potential to stimulate food intake and fat deposition in primates.

The literature review is appropriate, even modest, and the discussion is similarly even tempered.

This study is most interesting, but I have very serious reservations about the way it is described. Especially given the stated potential conflicts' of interest. The lack of experimental detail is startling. In contrast to most papers I review, the primate work in this manuscript is of much better quality, and interpretability than the rodent work. That is a bit bothersome.

Before I can offer strong support to this paper I would like to see the methods section greatly expanded, and put in the body of the paper. It does not seem to me that how things were done is an extra detail, it is critical to interpreting the results.


The authors launch into a discussion of the effects of NT-4 without ever defining it. I think this is unfair to the readers. I may know what it is, but they must define it at least once. In particular I think the authors need t o define what its agonism profile is at relevant receptors.

What are the "DIO" mice,there are many similar models, some are leptin resistant, some are not. What is their basal weight? Basal food intake? This data needs to be presented at least once, along with the % changes.

What is the "selective TrkB agonist antibody" ? How specific is it? Does a different antibody also cause decreases in body weight? LPS certainly does. Without better definition of the drugs used I am not compelled by this series of studies. In the supplemental methods they state "experimental details will be described elsewhere" with all due respect, that is not acceptable to this reviewer. I need to see what was done. I suggest removing these studies, or fully describing them.

Where in the hypothalamus? Were post-injection anatomical studies performed? Even excellent neuroanatomy labs do not claim to hit the hypothalamus all the time, and post-hoc test where their injectors resided. I think at a minimum we ought to see similar from this group too. Hits vs misses vs vehicle injected is the standard way to present intranuclear injection in the brain.

The data in figure 2 is derived from n=2 or n=4? What are the statistics used to generate error bars? What is the data transform to provide the line/ Average? Any data smoothing? How large are the time bins? How often were measurements taken? Did all animals receive saline and drug, in what order? Or is this an n=12, 3 parallel arm study. The lack of experimental detail is very frustrating, and makes the paper difficult to interpret.

The figure quality is very poor, and the writing on the figures is unreadable. Although I assume that this is a problem at the journal, not with the original files.

Review of the first revised manuscript:

7-PONE-RA-02091R1 Appetite Enhancement and Weight Gain by Peripheral Administration of TrkB Agonists in Non-human Primates

This is a rebuttal/resubmission of a previously reviewed paper. The authors have incorporated new data, and make reference to a published characterization of the TrkB antibody that they use.

The authors have satisfactorily addressed my question about endotoxin

The in vivo studies provide conclusive and interesting data.

Indeed all my concerns but one (see below) have been addressed. I feel that some additional methodological detail will flesh out this paper nicely. I hope it is not commercial concerns that is preventing disclosure of complete experimental details.

The description of the generation of the antibodies remains inadequate. "conventional hybridoma techniques" does not tell me anything. Certainly not enough to allow another lab to try to repeat aspects of the work. They do provide more details in the supplemental section, and should reference this in the main methods description.
While the data remain interesting, and likely worthy of publishing, until we know more about what was done, it is impossible to determine what to recommend for this paper.
In particular, what portion of the "extracellular domain of recombinant trkB protein" was used to generate the antibodies?

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N.B. These are the comments made by the referee when reviewing an earlier version of this paper. Prior to publication the manuscript has been revised in light of these comments and to address other editorial requirements.