Maternal obesity causes fetal hypothalamic insulin resistance and disrupts development of hypothalamic feeding pathways.
Animals
Arcuate Nucleus of Hypothalamus
/ metabolism
Body Weight
Brain
/ metabolism
Diet, High-Fat
Feeding Behavior
Female
Fetus
/ metabolism
Gene Expression
/ genetics
Gene Expression Regulation, Developmental
/ genetics
Hypothalamus
/ embryology
Insulin
/ metabolism
Insulin Resistance
/ physiology
Male
Maternal-Fetal Exchange
/ physiology
Mice
Mice, Inbred C57BL
Neural Stem Cells
/ metabolism
Neurons
/ metabolism
Obesity
/ metabolism
Obesity, Maternal
/ metabolism
Pregnancy
Prenatal Exposure Delayed Effects
/ metabolism
Weight Gain
Hypothalamus
Insulin
Maternal obesity
Neurogenesis
Notch
Journal
Molecular metabolism
ISSN: 2212-8778
Titre abrégé: Mol Metab
Pays: Germany
ID NLM: 101605730
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
04
08
2020
revised:
04
09
2020
accepted:
08
09
2020
pubmed:
13
9
2020
medline:
8
9
2021
entrez:
12
9
2020
Statut:
ppublish
Résumé
Perinatal exposure to maternal obesity results in predisposition of offspring to develop obesity later in life. Increased weight gain in offspring exposed to maternal obesity is usually associated with hyperphagia, implicating altered central regulation of food intake as a cause. We aimed to define how maternal obesity impacts early development of the hypothalamus to program lasting dysfunction in feeding regulatory pathways. Mice offspring of diet-induced obese mothers were compared to the offspring of lean control mothers. We analysed gene expression in the fetal hypothalamus, alongside neurosphere assays to investigate the effects of maternal obesity on neural progenitor cell proliferation in vitro. Western blotting was used to investigate the insulin signalling pathway in the fetal hypothalamus. Characterisation of cell type and neuropeptide profile in adulthood was linked with analyses of feeding behaviour. There was a reduction in the expression of proliferative genes in the fetal hypothalamus of offspring exposed to maternal obesity. This reduction in proliferation was maintained in vitro when hypothalamic neural progenitor cells were grown as neurospheres. Hypothalamic fetal gene expression and neurosphere growth correlated with maternal body weight and insulin levels. Foetuses of obese mothers showed hypothalamic insulin resistance, which may be causative of reduced proliferation. Furthermore, maternal obesity activated the Notch signalling pathway in neonatal offspring hypothalamus, resulting in decreased neurogenesis. Adult offspring of obese mothers displayed an altered ratio of anorexigenic and orexigenic signals in the arcuate nucleus, associated with an inability to maintain energy homeostasis when metabolically challenged. These findings show that maternal obesity alters the molecular signature in the developing hypothalamus, which is associated with disrupted growth and development of hypothalamic precursor cells and defective feeding regulation in adulthood. This is the first report of fetal hypothalamic insulin resistance in an obese pregnancy and suggests a mechanism by which maternal obesity causes permanent changes to hypothalamic structure and function.
Identifiants
pubmed: 32919096
pii: S2212-8778(20)30153-8
doi: 10.1016/j.molmet.2020.101079
pmc: PMC7549144
pii:
doi:
Substances chimiques
Insulin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
101079Subventions
Organisme : Medical Research Council
ID : MC_UU_12012/4
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 108926/B/15/Z
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/17/12/33167
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00014/5
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 106026/Z/14/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12012/5
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00014/4
Pays : United Kingdom
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier GmbH.. All rights reserved.
Références
Brain Res. 2005 Jan 21;1031(2):276-83
pubmed: 15649453
Metabolism. 2014 May;63(5):682-92
pubmed: 24636055
J Nutr. 2010 Mar;140(3):653-7
pubmed: 20107150
Neuroscience. 2018 Feb 10;371:1-15
pubmed: 29203230
Neuron. 2001 Jan;29(1):45-55
pubmed: 11182080
Int J Dev Neurosci. 2015 Feb;40:35-42
pubmed: 25450527
J Neurosci. 2004 Mar 17;24(11):2797-805
pubmed: 15028773
Genes Dev. 2002 Feb 1;16(3):324-38
pubmed: 11825874
Cell. 2000 May 26;101(5):499-510
pubmed: 10850492
Drug Discov Today Dis Models. 2007;4(1):17-24
pubmed: 18193096
Nat Med. 2011 Jul 31;17(8):961-7
pubmed: 21804540
Am J Physiol Endocrinol Metab. 2018 Aug 1;315(2):E180-E195
pubmed: 29486138
Neural Dev. 2013 Dec 23;8:25
pubmed: 24360028
Trends Endocrinol Metab. 2015 May;26(5):248-55
pubmed: 25805408
J Nutr Biochem. 2014 Feb;25(2):227-31
pubmed: 24445048
Int J Dev Neurosci. 2009 Nov;27(7):627-33
pubmed: 19695321
Brain Res. 1983 Dec;313(2):315-8
pubmed: 6365247
Endocrinology. 2012 Aug;153(8):3657-67
pubmed: 22621961
Mol Metab. 2014 Sep 16;3(9):813-22
pubmed: 25506547
Front Neurosci. 2011 Jun 14;5:78
pubmed: 21716644
Cell. 2019 Feb 7;176(4):729-742.e18
pubmed: 30661757
Diabetologia. 2006 Dec;49(12):2993-9
pubmed: 17063325
PLoS One. 2009 Jul 16;4(7):e6259
pubmed: 19606226
Mol Endocrinol. 2006 Jul;20(7):1623-32
pubmed: 16469766
Cell. 1980 Dec;22(3):649-55
pubmed: 7460009
Adv Exp Med Biol. 2020;1227:131-144
pubmed: 32072503
Diabetologia. 2019 Oct;62(10):1779-1788
pubmed: 31451868
Science. 2004 Apr 2;304(5667):108-10
pubmed: 15064420
Diabetes Care. 2009 Jun;32(6):1076-80
pubmed: 19460915
Brain Res Dev Brain Res. 2001 Mar 29;127(1):41-9
pubmed: 11287063
Endocrinology. 2014 Jul;155(7):2566-77
pubmed: 24773340
Front Neuroendocrinol. 2015 Oct;39:3-16
pubmed: 26296796
Psychoneuroendocrinology. 2018 Mar;89:46-52
pubmed: 29324300
J Clin Endocrinol Metab. 2009 Nov;94(11):4275-83
pubmed: 19820018
Nature. 1990 Oct 25;347(6295):762-5
pubmed: 2172829
Cell. 2014 Jan 30;156(3):495-509
pubmed: 24462248
Metabolism. 1998 Jul;47(7):855-62
pubmed: 9667235
Neuron. 2008 Apr 10;58(1):52-64
pubmed: 18400163
Mol Cell Endocrinol. 2018 Sep 5;472:57-67
pubmed: 29183809
Cell Rep. 2019 Mar 19;26(12):3429-3443.e3
pubmed: 30893613
Front Neurosci. 2019 Sep 13;13:962
pubmed: 31572115
J Clin Invest. 2012 Jan;122(1):142-52
pubmed: 22201680
PLoS One. 2009 Jun 11;4(6):e5870
pubmed: 19516909
Diabetes. 2017 Jul;66(7):1797-1806
pubmed: 28174292
PLoS One. 2018 Feb 21;13(2):e0193196
pubmed: 29466413
Mol Cell Endocrinol. 2016 Feb 15;422:192-202
pubmed: 26687064
PLoS Biol. 2020 Mar 12;18(3):e3000296
pubmed: 32163401
Am J Physiol Regul Integr Comp Physiol. 2009 Oct;297(4):R1049-57
pubmed: 19657097
Development. 2013 Sep;140(17):3511-21
pubmed: 23884446
Sci Rep. 2017 Mar 14;7:44650
pubmed: 28291256
Endocrinology. 2012 Dec;153(12):5961-71
pubmed: 23070543
J Clin Invest. 2015 Feb;125(2):846-58
pubmed: 25607843
Mol Metab. 2014 Jan 20;3(3):325-33
pubmed: 24749062
J Nutr. 2004 Mar;134(3):648-54
pubmed: 14988462
Brain Res. 1984 Jun 8;302(2):323-34
pubmed: 6329460
Cold Spring Harb Symp Quant Biol. 2008;73:403-10
pubmed: 19022746
Diabetes. 2013 Dec;62(12):4052-62
pubmed: 23990360