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closeReferee comments: Referee 2
Posted by PLOS_ONE_Group on 18 Mar 2008 at 10:47 GMT
Referee 2's review:
The authors revised their manuscript and provide new sets of data. Overall, relatively solid circumstantial evidence is provided to suggest that ghrelin's action is mediated by CB1 receptors.
However, the data is not conclusive and remains to be indirect. Specifically, the reluctance of the authors to provide thorough electrophysiological proof that ghrelin is not capable generating increased or decreased action potentials in any neuronal system of CB1 KO mice is unfortunate. There are numerous publications by various laboratories analyzing ghrelin's action on neuronal firing in various hypothalamic and extrahypothalamic sites without GFP guidance. The paper by Luquet et al. (Luquet S, Phillips CT, Palmiter RD. NPY/AgRP neurons are not essential for feeding responses to glucoprivation.Peptides. 2007 Feb;28(2):214-25. Epub 2006 Dec 27.) clearly shows the pivotal role of NPY/AgRP neurons in mediating ghrelin's effect on feeding. The PVN, which may be affected by ghrelin, cannot be a surrogate for such a critical conclusion to be made. NPY/AgRP neurons have been recorder from without a GFP construct in rats: van den Top M, Lyons DJ, Lee K, Coderre E, Renaud LP, Spanswick D. Pharmacological and molecular characterization of ATP-sensitive K(+) conductances
in CART and NPY/AgRP expressing neurons of the hypothalamic arcuate nucleus. Neuroscience. 2007 Feb 9;144(3):815-24. Epub 2006 Nov 28.; van den Top M, Lee K, Whyment AD, Blanks AM, Spanswick D. Orexigen-sensitive NPY/AgRP pacemaker neurons in the hypothalamic arcuate nucleus. Nat Neurosci. 2004 May;7(5):493-4. Epub 2004 Apr 18. Is it difficult to carry out these experiments? Yes. But are there necessary to reach a reliable conclusion? In the view of the reviewers is yes.
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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.