Liens entre nutrition périnatale et développement post-natal : les leçons des modèles animaux...

Pascale Chavatte-Palmer, Docteur vétérinaire, PhD, Directrice de Recherches à l’Institut National de la Recherche Agronomique

Jeudi 18 février

Liens entre nutrition périnatale et développement post-natal : les leçons des modèles animaux.

Liege Creative, en partenariat avec :

Diet before and during pregnancy and offspring health: lessons from animal models

PASCALE CHAVATTE-PALMER

UMRBDR,INRA,ENVA,UniversitéParisSaclay,78350,JouyenJosas,France

[email protected]

mailto:[email protected]?subject=

Pascale CHAVATTE-PALMER 2

Barker'shypothesis

Barker'cohort:5000Englishpatients

Pascale CHAVATTE-PALMER4

Oddsratio:1,47 Oddsratio:1,36

Meta-analysisincluding>130.000patientsBirthweightasaproxyforfetalnutrition

Birthweight<2500g Birthweight>4000g

Harderetal,Am.J.Epidemiol.2007

CorrelationbetweenbirthweightandrisktodevelopType2diabetes


Lumeyetal,1992,PaedPerinatalEpidemiol;Lumeyetal,1997,AmJPublicHealth;Painteretal,2005,Toxicology;Painteretal,2005,HumanReproduction;Heijmansetal,2008

Calories(kcal)

July1944

Jan1945

April1945

July1945

Oct1945

Oct1944

2500

0

500

1000

1500

2000

Famine

Control

TheDutchFamine(1944-1945)cohortstudy



ADULTS

1sttrimester➔CVD,obesity2ndtrimester➔Hypertension3rdtrimester➔Glucosemetabolism

Calories(kcal)

July1944

Jan1945

April1945

July1945

Oct1945

Oct1944

2500

0

500

1000

1500

2000

Famine

Control




Noeffectonfertility

BUTreducedbirthweightingrandchildrenIncreasedperinatalmortality

(3rdtrimester)?

ADULTS


Calories(kcal)

July1944

Jan1945

April1945

July1945

Oct1945

Oct1944

2500

0

500

1000

1500

2000

Famine

Control




Noeffectonfertility

BUTreducedbirthweightingrandchildrenIncreasedperinatalmortality

(3rdtrimester)?

ADULTS


Calories(kcal)

July1944

Jan1945

April1945

July1945

Oct1945

Oct1944

2500

0

500

1000

1500

2000

Famine

Control


IGF2hypomethylationat60yearsofage

Pascale CHAVATTE-PALMER / PIANETANUTRIZION 25/06/20156


Veenendaaletal.BJOG2013

Impacton2ndgenerationn=360,meanage37years

Throughthemaleline..

Sons'children Daughters'children


Conception BirthFetaldevelopment Growth Adult



Nutritionormetabolicstatusoftheparents

Obesity,undernutrtion,diabetes…

Fetalgrowthadaptation

Epigenome,transcriptome,cells,tissues,organs



NeonatalPhenotype


Obesity,undernutrition,diabetes…





NeonatalPhenotype





IncreasedincidenceofNoncommunicablediseases

suchasType2diabetes

MetabolicsyndromeObesity

Predictiveadaptativeresponse

Gluckman,2005



Noncommunicablediseasessuchas

Type2diabetesMetabolicsyndrome

Obesity









Obesity



NeonatalPhenotype







Obesity


UnitedNationsGeneralAssemblyinSeptember2011

“...maternalandchildhealthisinextricablylinkedwithNCDsandtheirriskfactors...”

(clause26)


CH Waddington 1905-1975

The Strategy of the Genes

1957

Molecularbasis:Epigenetics

“… stably maintained mitotically (and potentially meiotically) heritable patterns of gene expression that occur without changes in the DNA sequence”


Epigeneticmechanisms


Genenotexpressed

Geneexpressed

MODELES ANIMAUX

Pascale CHAVATTE-PALMER / GFP - MODELES ANIMAUX 18/06/201516

Postnatalrestrictionbalanced

Postnatalrestrictioncafeteria

Inuterogrowthretardedbalanced

Inuterogrowthretardedcafeteria

Controlbalanced

Controlcafeteria


8%

8% balanced

cafeteria 807±21

20%

20%

20%

20%

814±25

8%

8% 20%

20% balanced

cafeteria

568±36

517±35

20%

20% balanced

cafeteria

765±22

715±21

OzanneandHales,Nature,2004

Gestation%proteins

Group Lactation%proteins

Post-weaning Lifespan(days)

Maternal nutrition, post-natal catch-upand obesity in males





Controlbalanced

Controlcafeteria


8%

8% balanced

cafeteria 807±21

20%

20%

20%

20%

814±25

8%

8% 20%

20% balanced

cafeteria

568±36

517±35

20%

20% balanced

cafeteria

765±22

715±21


Gestation%proteins





8%

8% balanced

cafeteria 807±21

20%

20%

20%

20%

814±25

8%

8% 20%

20% balanced

cafeteria

568±36

517±35

20%

20% balanced

cafeteria

765±22

715±21


-57%

Gestation%proteins








Controlbalanced

Controlcafeteria


8%

8% balanced

cafeteria 807±21

20%

20%

20%

20%

814±25

8%

8% 20%

20% balanced

cafeteria

568±36

517±35

20%

20% balanced

cafeteria

765±22

715±21


Gestation%proteins







Controlbalanced

Controlcafeteria

Fetalgrowth?Placenta?

1stcriticalperiod"Actor"


8%

8% balanced

cafeteria 807±21

20%

20%

20%

20%

814±25

8%

8% 20%

20% balanced

cafeteria

568±36

517±35





Controlbalanced

Controlcafeteria 20%

20% balanced

cafeteria

765±22

715±21


Gestation%proteins



Neonatalnutrition?Meanstoact?

2ndcriticalperiod"Revelator"


Dams OffspringControl Control High Fat High Fat

Control High Fat Control High Fat

Howie et al, J Physiol 2009

females males

Role of maternal obesity in rats

Growthcurveofoffspring





females males

%fatmass







females males

%fatmass

- Offspring from obese females are predisposed to obesity - When exposed to an obesogenic environment, they develop a more severe phenotype




Diet and obesity before conceptionRats: Obesogenic diet 3 weeks before conception then control diet during gestation and

lactation Offspring fed normal or high fat diet (HFD)

Shankar et al, 2008

Control/control Control/HFDMother/offspring

HFD/Control HFD/HFDMother/offspring

Maternal obesity before

conception can enhance offspring

response to a high fat diet


Rabbit model Diet supplemented in fat and cholesterol

10 w 12 w 18 w 22 wGestation

Puberty Reproduction Birth Weaning

26 wLactation

High fat/cholesterol diet (HH) = 6% soy oil +0.2% cholesterol

Control diet

Picone et al. 2011 Theriogenology

HH

C Components of the metabolic syndrome

in adults





26 wLactation


Control diet

Intrauterine growth retardation from D9


HH


in adults





26 wLactation

Tarrade et al. 2013 PloS One

Placental response in late gestation

C HH





26 wLactation


Sexual dimorphism

⬈ Cholesterol esters

⬈ Triglycerides ⬈ Cholesterol esters

ì Fatty acid storage îLXRα

HH:î fatty acid and amino acid transporters

C HH

Severe dyslipidemia Mild dyslipidemiaFeto-placental response in late gestation





26 wLactation


⬈ lipid droplets, Modifications of expression of fatty acid, glucose and amino acid transporters





26 wLactation


8-16 cells Overexpression of adipophilin

Involved in lipid droplet formation At the onset of zygotic genome





26 wLactation

Delay in puberty î Number of follicles ì Follicular atresia

C HH

Cordier et al. 2013 PloS One





26 wLactation

Delay in puberty î Number of follicles ì Follicular atresia

ì Follicular atresia

➘ Testicular weight ➘ Testosteronemia

C HH

Cordier et al. 2013 PloS One; Léveillé et al. 2014 J DOHAD; Dupont et al. 2014 J DOHAD.


Differentexposuresindifferentanimalmodels withsimilarcardiometabolicconsequences

Exposures

Energyrestriction

Proteinrestriction

Uterinearteryligation

Glucocorticoidexposure

Highfatdiet

Obesity

Diabetes

Small

Normal

Large

Outcomes

Hypertension

Insulinresistance

Glucoseintolerance

Increasedadiposity

Reducedmusclemass

Obesity

Type2Diabetes

Sizeatbirth


Aagaard-Tilleryetal,JMolEndocrinol2010

Maternaldietinducedobesitymodifiestheexpressionofenzymesinvolvedintheepigeneticmachinaryintheoffspringliver

Geneexpression

Protein

Enzymeactivity

D20BirthFertilizationD-3.5

18%

18%9%

Proteins(%ofcasein)

18%

Oo-LPD

Fertilization D20Birth

18%

18%

9%

9%

Proteins(%ofcasein)

18%

9%

Watkinsetal.,2008bWatkinsetal.,2008a

NPD

LPD

Embr-LPD

D3.5

Challenging different phases of the periconceptional period for their vulnerability to environmental changes:

Experimental Design in the mouse

D3.5-D3.5

39.

NPD

EmbryoLPD OocyteLPD

LPD during preimplantation development but not during oocyte maturation affects post-natal growth.

40.Watkinsetal.,2008bWatkinsetal.,2008a

EmbryoLPD OocyteLPD

LPD during preimplantation development or during oocyte maturation leads to changes into postnatal behaviour.

41.

EmbryoLPD OocyteLPD

Inverse effects on behavior in response to open field test

Less stressed More stressed


Reducedexcessmaternalseruminflammation

Heerwagen et al, PloS One 2013

Dietary-inducedobeseC57BL/6JTransgeneFAT-1

Reducedplacentalinflammation

Interventionthroughmembraneremodeling

N-3fattyacids

Maternalseruminflammatorycytokines

Placentainflammatorycytokines

Conversionofn-6PUFAton-3

PUFAviaubiquitousn-3saturase

expression

Fetalweight


Reducingexcessmaternalinflammationmaybeapromisingtargetforpreventingadversefetalmetabolicoutcomesinpregnanciescomplicatedbymaternalobesity.

Heerwagen et al, PloS One 2013

Dietary-inducedobeseC57BL/6J

CD HFD

TransgeneFAT-1

InterventionthroughmembraneremodelingN-3fattyacids


Physicalexerciseandimprovementofmaternalbiologicalparameters

Nathanielszetal,NutrReviews2013




Bodyweight Fat Adipodityindex


Controversialoutcomesaftermaternalweightloss throughbariatricsurgerybeforeconception

Before maternal surgery N=54

After maternal surgery N=57

Kraletal,Pediatrics2006

Beforesurgery

Aftersurgery

Meanbirthweight(kg) 3.3+/-0.1 2.9+/-0.1 0.003Macrosomia(%) 14.8% 1.8% 0.03OffspringBMIpercentile(%) 79.4+/-3.4 68.4+/-4.0 0.04Offspringglycemia(mmol/l) 5.08+/-0.06 4.86+/-0.05 0.008

p

Smithetal,JCEM2009

UnderweightNormalOverweightObese UnderweightNormalOverweightObese




Willmeretal,PloSOne2013

Controversialoutcomesaftermaternalweightloss throughbariatricsurgerybeforeconception


Animalexperimentationneeded!!!

Toevaluate/prevent- Risksofvitaminicdeficiency- Risksoffetaldenutrition- Evaluatepost-surgicalperiods

49

Takehomemessages


Birth Genome activation

ImplantationOrganogenesis

Gonadal differntiation

Stages of development

Placental function

Suckling

Maternalnutritionandenvironment

Sexspecificconditioningleadingtopathologies

Puberty

TakeHomemessage1:Criticalperiodsandsexualdimorphism


DeVinci/1510

TakeHomemessage2:Animalmodelsareessentialbutcanbedifferent

Bewareofmouseas«the»Animal


DeVinci/1510

TakeHomemessage2:Animalmodelsareessentialbutcanbedifferent

Bewareofmouseas«the»AnimalWatchout!

Miceisnotthebestmodel…

Embryonic,gestationalandpost-natalmetabolismdifferlargelyfromhumans…

Proofsfromseveralmodelsarenecessary!


Theenvironmentaffectsthemother(F0)1

TakeHomemessage3:Severalgenerationscanbeaffected



Theplacentaregulatesfetalintakeandthefetus(F1)adaptsitsmetabolismthroughepigeneticmodifications,withsexspecificdifferences

2




3Gonadaldevelopmentand

fetalgametescanbeaffected,thusinducingeffectsonfertilityandon

secondgenerationoffspring(F2)


2








2

4Epigeneticmodificationpersistinginthegermlinecaninducetrasngenerationaleffects(F>2








2

4Epigeneticmodificationpersistinginthegermlinecaninducetrasngenerationaleffects(F>2

…andthefather

TakeHomemessage3:alsothroughmales




Meanbirthweight(kg) 3.3+/-0.1 2.9+/-0.1 0.003Macrosomia(%) 14.8% 1.8% 0.03OffspringBMIpercentile(%) 79.4+/-3.4 68.4+/-4.0 0.04Offspringglycemia(mmol/l) 5.08+/-0.06 4.86+/-0.05 0.008

p

Smithetal,JCEM2009

Improvementofchildrenoutcomesaftermaternalweightloss throughbariatricsurgerybeforeconception


Plasticity

↑risksofdevelopingpathologies

Earlyintervention

Littleimpactinadulthood

TakeHomemessage4:Earlyinterventionwillhelp

Forexhaustivereview:HansonandGluckman2014,PhysRev,94:1027-1076

1000daystoact,anWHOinitiative

Nutritional,ecological,psychological,socio-economical

environment

2years(http://www.thousanddays.org/)

1000daystoact,anWHOinitiative

Nutritional,ecological,psychological,socio-economical

environment

2years

->nottoforgetthefatherandtransgenerationaleffects«100yearsofdevelopment»

(http://www.thousanddays.org/)


PEPPSteam:Placenta,EnvironmentandProgrammingofPhenotypeS

Thankyou

[email protected]

mailto:[email protected]

Liens entre nutrition périnatale et développement post-natal : les leçons des modèles animaux...

Health & Medicine

Transcript of Liens entre nutrition périnatale et développement post-natal : les leçons des modèles animaux...