Connecting nutritional deprivation and pubertal inhibition via GRK2-mediated repression of kisspeptin actions in GnRH neurons.
Energy balance
G protein-coupled receptors (GPCR)
GPR54
GRK2
GnRH
Kisspeptin
Puberty
Reproduction
Journal
Metabolism: clinical and experimental
ISSN: 1532-8600
Titre abrégé: Metabolism
Pays: United States
ID NLM: 0375267
Informations de publication
Date de publication:
04 2022
04 2022
Historique:
received:
17
10
2021
revised:
31
12
2021
accepted:
14
01
2022
pubmed:
26
1
2022
medline:
29
4
2022
entrez:
25
1
2022
Statut:
ppublish
Résumé
Perturbations in the timing of puberty, with potential adverse consequences in later health, are increasingly common. The underlying neurohormonal mechanisms are unfolded, but nutritional alterations are key contributors. Efforts to unveil the basis of normal puberty and its metabolic control have focused on mechanisms controlling expression of Kiss1, the gene encoding the puberty-activating neuropeptide, kisspeptin. However, other regulatory phenomena remain ill-defined. Here, we address the putative role of the G protein-coupled-receptor kinase-2, GRK2, in GnRH neurons, as modulator of pubertal timing via repression of the actions of kisspeptin, in normal maturation and conditions of nutritional deficiency. Hypothalamic RNA and protein expression analyses were conducted in maturing female rats. Pharmacological studies involved central administration of GRK2 inhibitor, βARK1-I, and assessment of gonadotropin responses to kisspeptin or phenotypic and hormonal markers of puberty, under normal nutrition or early subnutrition in female rats. In addition, a mouse line with selective ablation of GRK2 in GnRH neurons, aka G-GRKO, was generated, in which hormonal responses to kisspeptin and puberty onset were monitored, in normal conditions and after nutritional deprivation. Hypothalamic GRK2 expression increased along postnatal maturation in female rats, especially in the preoptic area, where most GnRH neurons reside, but decreased during the juvenile-to-pubertal transition. Blockade of GRK2 activity enhanced Ca Our data disclose a novel pathway whereby GRK2 negatively regulates kisspeptin actions in GnRH neurons, as major regulatory mechanism for tuning pubertal timing in nutritionally-compromised conditions.
Sections du résumé
BACKGROUND
Perturbations in the timing of puberty, with potential adverse consequences in later health, are increasingly common. The underlying neurohormonal mechanisms are unfolded, but nutritional alterations are key contributors. Efforts to unveil the basis of normal puberty and its metabolic control have focused on mechanisms controlling expression of Kiss1, the gene encoding the puberty-activating neuropeptide, kisspeptin. However, other regulatory phenomena remain ill-defined. Here, we address the putative role of the G protein-coupled-receptor kinase-2, GRK2, in GnRH neurons, as modulator of pubertal timing via repression of the actions of kisspeptin, in normal maturation and conditions of nutritional deficiency.
METHODS
Hypothalamic RNA and protein expression analyses were conducted in maturing female rats. Pharmacological studies involved central administration of GRK2 inhibitor, βARK1-I, and assessment of gonadotropin responses to kisspeptin or phenotypic and hormonal markers of puberty, under normal nutrition or early subnutrition in female rats. In addition, a mouse line with selective ablation of GRK2 in GnRH neurons, aka G-GRKO, was generated, in which hormonal responses to kisspeptin and puberty onset were monitored, in normal conditions and after nutritional deprivation.
RESULTS
Hypothalamic GRK2 expression increased along postnatal maturation in female rats, especially in the preoptic area, where most GnRH neurons reside, but decreased during the juvenile-to-pubertal transition. Blockade of GRK2 activity enhanced Ca
CONCLUSIONS
Our data disclose a novel pathway whereby GRK2 negatively regulates kisspeptin actions in GnRH neurons, as major regulatory mechanism for tuning pubertal timing in nutritionally-compromised conditions.
Identifiants
pubmed: 35074314
pii: S0026-0495(22)00019-1
doi: 10.1016/j.metabol.2022.155141
pmc: PMC10283027
mid: NIHMS1899492
pii:
doi:
Substances chimiques
Kisspeptins
0
Receptors, Kisspeptin-1
0
Gonadotropin-Releasing Hormone
33515-09-2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
155141Subventions
Organisme : NICHD NIH HHS
ID : R01 HD019938
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD082314
Pays : United States
Informations de copyright
Copyright © 2022. Published by Elsevier Inc.
Références
Pediatrics. 2012 Nov;130(5):e1058-68
pubmed: 23085608
Sci Rep. 2017 Apr 12;7:46381
pubmed: 28401948
Nat Rev Endocrinol. 2016 Aug;12(8):452-66
pubmed: 27199290
Endocrinology. 2009 Jul;150(7):3214-20
pubmed: 19299459
Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10972-6
pubmed: 12944565
N Engl J Med. 2003 Oct 23;349(17):1614-27
pubmed: 14573733
Semin Cell Dev Biol. 2016 Feb;50:95-104
pubmed: 26773211
Endocrinology. 1999 Jun;140(6):2562-9
pubmed: 10342843
Endocrinology. 2012 Jul;153(7):2985-96
pubmed: 22581458
J Neurosci. 2012 Aug 15;32(33):11486-94
pubmed: 22895731
J Pain. 2014 Mar;15(3):250-61
pubmed: 24216329
PLoS One. 2009 Dec 24;4(12):e8450
pubmed: 20041184
J Neurosci. 2009 Sep 23;29(38):11859-66
pubmed: 19776272
Endocrinology. 2006 Dec;147(12):5817-25
pubmed: 16959837
Brain Res. 2010 Dec 10;1364:103-15
pubmed: 20951683
Sci Rep. 2015 Jun 18;5:11208
pubmed: 26084728
Endocrinology. 2012 Oct;153(10):4883-93
pubmed: 22893725
Int J Mol Sci. 2019 Mar 25;20(6):
pubmed: 30934608
Eur J Pediatr. 2018 Nov;177(11):1593-1601
pubmed: 30056577
Endocrinology. 2019 Jun 1;160(6):1480-1491
pubmed: 31083714
J Neurosci. 2012 Feb 15;32(7):2388-97
pubmed: 22396413
Endocrinology. 2015 Feb;156(2):576-88
pubmed: 25490143
J Neurosci. 2005 Dec 7;25(49):11349-56
pubmed: 16339030
Endocrinology. 1998 Apr;139(4):1781-8
pubmed: 9528962
Br J Pharmacol. 2010 Jun;160(4):821-32
pubmed: 20590581
Eur J Neurosci. 2010 Dec;32(12):2003-10
pubmed: 21143655
Nat Neurosci. 2016 Jun;19(6):835-44
pubmed: 27135215
Endocrinology. 2005 Apr;146(4):1689-97
pubmed: 15637288
Nat Genet. 2009 Mar;41(3):354-358
pubmed: 19079066
Endocrinology. 2010 Aug;151(8):3479-89
pubmed: 20501670
Sci Rep. 2016 Jan 12;6:19206
pubmed: 26755241
J Endocrinol. 2019 Aug;242(2):R51-R65
pubmed: 31189134
Proc Natl Acad Sci U S A. 2018 Nov 6;115(45):E10758-E10767
pubmed: 30348767
Metabolism. 2021 Feb;115:154460
pubmed: 33285180
Int J Environ Res Public Health. 2017 Oct 24;14(10):
pubmed: 29064384
Front Neuroendocrinol. 2017 Jul;46:1-14
pubmed: 28551304
Sci Signal. 2015 Jul 21;8(386):ra73
pubmed: 26198359
Nat Genet. 2017 Jun;49(6):834-841
pubmed: 28436984
Recent Prog Horm Res. 1980;36:53-88
pubmed: 6774388
Nat Commun. 2018 Oct 10;9(1):4194
pubmed: 30305620
Trends Pharmacol Sci. 2012 Mar;33(3):154-64
pubmed: 22277298
Endocrinology. 2005 Sep;146(9):3917-25
pubmed: 15932928
Hum Reprod Update. 2017 Nov 1;23(6):737-763
pubmed: 28961976
Front Pharmacol. 2019 Feb 19;10:112
pubmed: 30837878
Endocrinology. 2011 Sep;152(9):3396-408
pubmed: 21712362
Front Pharmacol. 2019 Feb 19;10:125
pubmed: 30837883
Mol Cell Endocrinol. 2018 Mar 5;463:131-141
pubmed: 29102564
Endocrinology. 2012 Jan;153(1):316-28
pubmed: 22067321
Physiol Rev. 2012 Jul;92(3):1235-316
pubmed: 22811428
Endocrinology. 2013 Dec;154(12):4939-45
pubmed: 24092638
Pediatrics. 2009 May;123(5):e932-9
pubmed: 19403485
Endocrinology. 2005 Jan;146(1):156-63
pubmed: 15375028
Pediatr Obes. 2014 Aug;9(4):292-9
pubmed: 23713062
Pediatrics. 2007 Mar;119(3):e624-30
pubmed: 17332182
Endocr Rev. 2018 Jun 1;39(3):333-368
pubmed: 29351662
Mol Endocrinol. 2009 Dec;23(12):2060-74
pubmed: 19846537
Mol Cell Endocrinol. 2006 Sep 26;257-258:75-83
pubmed: 16930819