title: Impaired hypothalamic mTOR activation in the adult rat offspring born to mothers fed a low-protein diet.
abstract: Several epidemiological and experimental studies have clearly established that maternal malnutrition induces a high risk of developing obesity and related metabolic diseases in the offspring. To determine if altered nutrient sensing might underlie this enhanced disease susceptibility, here we examined the effects of perinatal protein restriction on the activation of the nutrient sensor mTOR in response to acute variations in the nutritional status of the organism. Female Wistar rats were fed isocaloric diets containing either 17% protein (control) or 8% protein (PR) throughout pregnancy and lactation. At weaning offspring received standard chow and at 4 months of age the effects of fasting or fasting plus re-feeding on the phosphorylation levels of mTOR and its downstream target S6 ribosomal protein (rpS6) in the hypothalamus were assessed by immuno-fluorescence and western blot. Under ad libitum feeding conditions, PR rats exhibited decreased mTOR and rpS6 phosphorylation in the arcuate (ARC) and ventromedial (VMH) hypothalamic nuclei. Moreover, the phosphorylation of mTOR and rpS6 in these hypothalamic nuclei decreased with fasting in control but not in PR animals. Conversely, PR animals exhibited enhanced number of pmTOR imunostained cells in the paraventricular nucleus (PVN) and fasting decreased the activation of mTOR in the PVN of malnourished but not of control rats. These alterations occurred at a developmental stage at which perinatally-undernourished animals do not show yet obesity or glucose intolerance. Collectively, our observations suggest that altered hypothalamic nutrient sensing in response to an inadequate foetal and neonatal energetic environment is one of the basic mechanisms of the developmental programming of metabolic disorders and might play a causing role in the development of the metabolic syndrome induced by malnutrition during early life.
authors.affiliation: Unité Mixte de recherche 1280 Physiologie des Adaptations Nutritionnelles, Institut National de la Recherche Agronomique, Nantes, France ; Université de Nantes, Nantes Atlantique Université, Nantes, France.
authors.forename: Omar
authors.initials: O
authors.lastname: Guzmán-Quevedo
authors.forename: Raquel
authors.initials: R
authors.lastname: Da Silva Aragão
authors.forename: Georgina
authors.initials: G
authors.lastname: Pérez García
authors.forename: Rhowena J B
authors.initials: RJ
authors.lastname: Matos
authors.forename: André
authors.initials: A
authors.lastname: de Sa Braga Oliveira
authors.forename: Raul
authors.initials: R
authors.lastname: Manhães de Castro
authors.forename: Francisco
authors.initials: F
authors.lastname: Bolaños-Jiménez
mesh_terms: D000818:Animals; D001835:Body Weight; D018753:Diet, Protein-Restricted; D005260:Female; D007031:Hypothalamus / Q000503:physiopathology*; D007333:Insulin Resistance; D044342:Malnutrition / Q000503:physiopathology*; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D011247:Pregnancy; D011270:Pregnancy, Animal; D039401:Prenatal Nutritional Physiological Phenomena; D051381:Rats; D017208:Rats, Wistar; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014886:Weaning
chemical_list: C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases
references.citation: Cell Metab. 2009 Apr;9(4):362-74
references.pmid: 19356717
references.citation: Am J Physiol Regul Integr Comp Physiol. 2007 Dec;293(6):R2306-14
references.pmid: 17898113
references.citation: Med Hypotheses. 2012 Jan;78(1):88-94
references.pmid: 22047985
references.citation: Nat Cell Biol. 2007 Mar;9(3):316-23
references.pmid: 17277771
references.citation: FASEB J. 2012 May;26(5):1866-74
references.pmid: 22321728
references.citation: Exp Physiol. 2009 Jun;94(6):607-25
references.pmid: 19251980
references.citation: Nutrition. 2006 Nov-Dec;22(11-12):1152-61
references.pmid: 17029904
references.citation: Diabetologia. 1993 Jan;36(1):62-7
references.pmid: 8436255
references.citation: Endocrinology. 2009 Oct;150(10):4541-51
references.pmid: 19628573
references.citation: Diabetologia. 2004 Apr;47(4):669-75
references.pmid: 15298344
references.citation: Diabetologia. 1992 Jul;35(7):595-601
references.pmid: 1644236
references.citation: Br J Nutr. 2005 Dec;94(6):938-47
references.pmid: 16351771
references.citation: J Neurosci. 2008 Jul 9;28(28):7202-8
references.pmid: 18614690
references.citation: Kidney Int. 2001 Jan;59(1):238-45
references.pmid: 11135076
references.citation: J Endocrinol. 2006 May;189(2):355-63
references.pmid: 16648302
references.citation: Am J Physiol. 1997 Jul;273(1 Pt 1):E46-51
references.pmid: 9252478
references.citation: Trends Endocrinol Metab. 2004 May-Jun;15(4):183-7
references.pmid: 15109618
references.citation: J Endocrinol. 2007 Apr;193(1):31-7
references.pmid: 17400800
references.citation: Physiol Behav. 2009 Mar 2;96(3):481-92
references.pmid: 19100759
references.citation: Eur J Neurosci. 2008 Mar;27(6):1400-8
references.pmid: 18331342
references.citation: Hypertension. 2008 Feb;51(2):383-92
references.pmid: 18086952
references.citation: Int J Obes (Lond). 2011 Jan;35(1):72-83
references.pmid: 20548303
references.citation: PLoS One. 2009;4(3):e4950
references.pmid: 19308256
references.citation: Eur J Obstet Gynecol Reprod Biol. 2010 Apr;149(2):127-30
references.pmid: 20053495
references.citation: Reprod Sci. 2007 May;14(4):329-37
references.pmid: 17644805
references.citation: Mol Cell. 2007 Mar 23;25(6):903-15
references.pmid: 17386266
references.citation: J Nutr. 1997 May;127(5 Suppl):838S-841S
references.pmid: 9164249
references.citation: Clin Sci (Lond). 2005 Oct;109(4):413-20
references.pmid: 15992360
references.citation: J Physiol. 2006 Feb 15;571(Pt 1):221-30
references.pmid: 16339179
references.citation: Am J Physiol Endocrinol Metab. 2000 Jul;279(1):E83-7
references.pmid: 10893326
references.citation: Am J Physiol Regul Integr Comp Physiol. 2008 Feb;294(2):R494-500
references.pmid: 18094069
references.citation: Endocrinology. 2010 Feb;151(2):702-13
references.pmid: 20016030
references.citation: J Physiol. 2003 Oct 15;552(Pt 2):603-10
references.pmid: 14561840
references.citation: J Physiol. 2009 Oct 15;587(Pt 20):4963-76
references.pmid: 19723777
references.citation: World J Diabetes. 2011 Sep 15;2(9):149-57
references.pmid: 21954419
references.citation: Cell Metab. 2009 May;9(5):407-16
references.pmid: 19416711
references.citation: Science. 2006 May 12;312(5775):927-30
references.pmid: 16690869
references.citation: Am J Physiol Regul Integr Comp Physiol. 2005 Jan;288(1):R85-90
references.pmid: 15374820
references.citation: PLoS One. 2012;7(1):e30616
references.pmid: 22291999
references.citation: Cell Metab. 2008 Dec;8(6):459-67
references.pmid: 19041762
references.citation: Nutrition. 2008 Mar;24(3):270-8
references.pmid: 18312789
references.citation: Am J Physiol. 1996 Dec;271(6 Pt 1):E1128-34
references.pmid: 8997235
references.citation: Clin Sci (Lond). 2009 Jun 15;117(2):85-93
references.pmid: 19152506
references.citation: PLoS One. 2010 Oct 21;5(10):e13537
references.pmid: 20975839
references.citation: Nature. 2004 Sep 9;431(7005):200-5
references.pmid: 15306821
references.citation: Annu Rev Nutr. 2008;28:295-311
references.pmid: 18429698
references.citation: Obesity (Silver Spring). 2006 Aug;14(8):1330-43
references.pmid: 16988075
references.citation: Am J Physiol Endocrinol Metab. 2007 Jun;292(6):E1702-14
references.pmid: 17299084