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Peer-Review Record

New Metabolic Influencer on Oxytocin Release: The Ghrelin

Molecules 2019, 24(4), 735; https://doi.org/10.3390/molecules24040735
Reviewer 1: Anonymous
Reviewer 2: Anonymous
Molecules 2019, 24(4), 735; https://doi.org/10.3390/molecules24040735
Received: 28 January 2019 / Revised: 11 February 2019 / Accepted: 13 February 2019 / Published: 18 February 2019
(This article belongs to the Special Issue Bioactive Compounds for Metabolic Syndrome and Type 2 Diabetes-II)

Round  1

Reviewer 1 Report

In recent years it has been shown that ghrelin and oxytoxin interact and there have been suggestions about a crosstalk between both signalling systems

Szabo et al in their paper entitled New metabolic influencer on oxytocin release: The ghrelin make an effort to shed more light on the mechanism of interaction; the authors examine the effects of ghrelin on the release of oxytoxin after central or systemic administrayion in rats. The paper is well organized and well written. The data presenting in the results although very limited are interesting since the experiments have been prerformed in whole animals and not just in cells.

Comments

Title: Since the interraction of ghrelin and oxytoxin is known the title is rather exaggerating

Methodology Have the authors tried intermediate doses of ghrelin between 1and 10pmol or less than 1 nmol for icv and iv administration respectively. or other doses of the ghrelin antagonist?

Discussion The discussion could be enriched with more recent references showing the interaction of the two hormones

Language needs minor editing


Author Response

Please find enclosed the revised version of our MS (molecules-445282). We have substantially revised our MS and responded the reviewer’s comments. 

Response to Reviewer 1 Comments

Point 1: Title: Since the interaction of ghrelin and oxytocin is known the title is rather exaggerating

Response 1: According to the reviewer’s comment, the title of the MS has been modified as follows:

Ghrelin-induced oxytocin secretion: A potential mechanism for metabolic disorders

Point 2: Methodology: Have the authors tried intermediate doses of ghrelin between 1 and 10 pmol or less than 1 nmol for icv and iv administration respectively or other doses of the ghrelin antagonist?

Response 2: Thank you for this comment. In our current experiment, only these doses were examined.

Point 3: Discussion: The discussion could be enriched with more recent references showing the interaction of the two hormones

Response 3: According to the reviewer’s comment, new references have been inserted into the Discussion.

Point 4: Language needs minor editing

Response 4: The English language has been revised and the typographical mistakes have been corrected through the MS.

Author Response File: Author Response.pdf

Reviewer 2 Report

The authors demonstrated that i.c.v. or i.v. administration of ghrelin cause significant elevation of plasma oxytocin levels in male Wistar rats. These effects were significantly attenuated by pretreatment with ghrelin antagonist. The obtained results are clear and represented adequately. However, there are several points that should be clarified as below.

(1) Introduction: Page 2, line 5-6: It is difficult to understand this sentence. Please rewrite it.

(2) The volume is 10 microL for i.c.v. This volume is relatively large. If i.c.v. is performed twice (for example, ghrelin antagonist and ghrelin), total 20 microL is expected to be administered. Is it true?

(3) In conscious rat, did you observe behavioral changes for 30 min after i.c.v. or i.v. administration of ghrelin? What happened? This point should be described in the Result section.

(4) Ghrelin is a potent orexigenic peptide, on the other hand oxytocin is anorexigenic peptide. How do you explain orexigenic peptide (ghrelin) stimulates secretion of anorexigenic peptide (oxytocin)? This point should be described in the Discussion section.

Author Response

Please find enclosed the revised version of our MS (molecules-445282). We have substantially revised our MS and responded the reviewer’s comments. 

Response to Reviewer 2 Comments

Point 1 Introduction: Page 2, line 5-6: It is difficult to understand this sentence. Please rewrite it.

Response 1: According to the reviewer’s comment, this sentence has been rewritten as follows:

“In our previous work we proved that ghrelin administration enhances oxytocin secretion in neurohypophyseal cell cultures. Based on our in vitro results, the aim of our current study is to examine the effects of centrally and systemically administrated ghrelin on oxytocin release in rats.”

Point 2 The volume is 10 microL for i.c.v. This volume is relatively large. If i.c.v. is performed twice (for example, ghrelin antagonist and ghrelin), total 20 microL is expected to be administrated. Is it true?

Response 2: Thank you for this question. Based on our earlier studies i.c.v. administrations were performed in a volume of 10 µl. The pause between the administrations of ghrelin antagonist and ghrelin was 15 min. (Gyöngyi K. Kis et al.: The osmotically and histamine-induced enhancement of the plasma vasopressin level is diminished by intracerebroventricularly administered orexin in rats, Pflugers Arch - Eur J Physiol (2012) 463:531–536; Molnár A et al..: Inhibitory effects of different galanin compounds and fragments on osmotically and histamine-induced enhanced vasopressin secretion in rats, Eur J Pharmacol. 2005 Jun 1;516(2):174-9; Landry et al.: Short-Term Effects of Centrally Administered Galanin on the Hyperosmotically Stimulated Expression of Vasopressin in the Rat Hypothalamus, Neuroendocrinology. 1995 Apr;61(4):393-404)

Point 3 In conscious rat, did you observe behavioral changes for 30 min after i.c.v. or i.v. administration of ghrelin? What happened? This point should be described in the Result section.

Response 3: According to the reviewer’s comment, the following part has been inserted into Results section:

Available data suggest that ghrelin possesses a dual role in stress and related behavioral disorders (Bali A. and Jaggi AS: An Integrative Review on Role and Mechanisms of Ghrelin in Stress, Anxiety and Depression, Curr Drug Targets. 2016;17(5):495-507) as well as it can change feeding behavior (Olszewski et al.: Intraventricular ghrelin activates oxytocin neurons: implications in feeding behavior, Neuroreport. 2007 Mar 26;18(5):499-503). During this 30-min-experiment, we did not observe neither behavioral changes, nor a significant change in the consumption of the rats.

(Page 8, lines 22-26)

Point 4 Ghrelin is a potent orexigenic peptide, on the other hand oxytocin is anorexigenic peptide. How do you explain orexigenic peptide (ghrelin) stimulates secretion of anorexigenic peptide (oxytocin)? This point should be described in the Discussion section.

Response 4: Thank you for this comment. This supplement is inserted into the Discussion. (Page 9, lines 15-24)

Previous data suggest that i.c.v. administration of ghrelin increases c-Fos immunoreactivity, which shows that ghrelin modulates neuronal activity in the hypothalamic paraventricular nucleus (Olszewski et al.: Hypothalamic paraventricular injections of ghrelin: effect on feeding and c-Fos immunoreactivity. Peptides, 2003. 24(6): p. 919-23). Consequently, there is a functional link between ghrelin and oxytocin producing cells/ oxytocin neuropeptide. Olszewski et al. demonstrated that oxytocin serves as a negative feedback regulator in feeding-related mechanisms driven by ghrelin. Interplay of ghrelin and oxytocin may limit ghrelin-induced excessive level of food-intake, whereas interactions with orexigenic peptides (e.g. orexin, neuropeptide Y) promote ghrelin-induced food-intake (Olszewski et al.: Intraventricular ghrelin activates oxytocin neurons: implications in feeding behavior, Neuroreport. 2007 Mar 26;18(5):499-50). Based on our earlier observations related to neurohypohyseal oxytocin secretion, the stimulatory effect between oxytocin and ghrelin seems to be similar by i.c.v. and i.v. administrations of ghrelin.  

Author Response File: Author Response.pdf

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