This document summarizes research on the developmental origins of obesity and cancer risk. It finds that both low and high birth weights are associated with increased risk of diseases like diabetes and cardiovascular disease later in life. Rapid postnatal growth and catch-up growth are also linked to obesity and disease risk. Experimental studies with animal models demonstrate that maternal diet, nutrition during pregnancy and lactation, and post-weaning diets can program offspring's risk of obesity and cancer through metabolic and epigenetic mechanisms.

1. Susan OzanneSusan Ozanne
Developmental Origins of ObesityDevelopmental Origins of Obesity
andand
Cancer RiskCancer Risk

2. U-Shaped RelationshipU-Shaped Relationship
BIRTH WEIGHTBIRTH WEIGHT
LOWLOW HIGHHIGH
RiskRisk RiskRisk
• Type 2 DiabetesType 2 Diabetes
• Cardiovascular DiseaseCardiovascular Disease
• Insulin ResistanceInsulin Resistance
• Type 2 DiabetesType 2 Diabetes
• Cardiovascular DiseaseCardiovascular Disease
• Insulin ResistanceInsulin Resistance
• ObesityObesity

3. Associations with Birth WeightAssociations with Birth Weight
Type 2 DiabetesType 2 Diabetes
Cardiovascular DiseaseCardiovascular Disease
Insulin ResistanceInsulin Resistance
HypertensionHypertension
ObesityObesity
Mental HealthMental Health
Immune HealthImmune Health
CancerCancer

4. Detrimental Effects ofDetrimental Effects of
Catch up GrowthCatch up Growth
 Hypertension (Hypertension (LeonLeon et alet al., 1996., 1996))
 Cardiovascular disease (Cardiovascular disease (ErikssonEriksson et alet al., 1999., 1999))
 Type 2 diabetes (Type 2 diabetes (ForsenForsen et alet al., 2000., 2000))
 Obesity (Obesity (OngOng et alet al., 2000., 2000))

5. Rapid Postnatal GrowthRapid Postnatal Growth
Is Associated WithIs Associated With
Later ObesityLater Obesity
Systematic Reviews:Systematic Reviews:
 Ong et al., 2008Ong et al., 2008
 Monteiro & Victoria 2005Monteiro & Victoria 2005
 Baird et al., 2005Baird et al., 2005

6. Evidence for Environmental FactorsEvidence for Environmental Factors
HumansHumans
• Periods of faminePeriods of famine
• Twin studiesTwin studies
• Discordant sib-pair studies - gestational diabetesDiscordant sib-pair studies - gestational diabetes
• Discordant sib-pair studies - bariatric surgeryDiscordant sib-pair studies - bariatric surgery
• Randomized neonatal nutrition studiesRandomized neonatal nutrition studies
Animal ModelsAnimal Models
• Non human primatesNon human primates
• SheepSheep
• PigsPigs
• RatsRats
• MiceMice

7. Developmental Programming of ObesityDevelopmental Programming of Obesity
ControlControl
Low ProteinLow Protein
ControlControl
Caloric RestrictionCaloric Restriction
ControlControl
Litter Size ManipulationLitter Size Manipulation
ControlControl
Maternal ObesityMaternal Obesity
20%20%20%20%
8%8%
PregnancyPregnancy LactationLactation
Ad lib.Ad lib.Ad libAd lib
ChowChowChowChow
Ob.dietOb.diet Ob.dietOb.diet
Ad lib.Ad lib. Ad lib.Ad lib.
Ad lib.Ad lib. Ad lib.Ad lib.
50%50%
Post WeaningPost Weaning
LifecourseLifecourse
LifecourseLifecourse
LifecourseLifecourse
LifecourseLifecourse
LifecourseLifecourse
LifecourseLifecourse
LifecourseLifecourse
LifecourseLifecourse
Normal Body WeightNormal Body Weight
ObesityObesity
20%20%
Ad lib.Ad lib.
Normal Body WeightNormal Body Weight
ObesityObesity
Normal Body WeightNormal Body Weight
ObesityObesity
Normal Body WeightNormal Body Weight
ObesityObesity

8. Experimental DesignExperimental Design
FetalFetal LactationLactation Post-weaningPost-weaning
BirthBirth WeaningWeaning
ControlControl 20%20% 20%20%
ChowChow
Highly PalatableHighly Palatable
8%8% 20%20%RecuperatedRecuperated
ChowChow
Highly PalatableHighly Palatable
PostnatalPostnatal
Low ProteinLow Protein
8%8%20%20%
ChowChow
Highly PalatableHighly Palatable

9. Early Growth DataEarly Growth Data
ControlControl 1.57 ± 0.06 1.77 ± 0.03 3.82 ± 0.04 6.53 ± 0.05 7.75 ± 0.141.57 ± 0.06 1.77 ± 0.03 3.82 ± 0.04 6.53 ± 0.05 7.75 ± 0.14
PLPPLP 1.57 ± 0.06 1.76 ± 0.03 3.10 ± 0.09*** 4.47 ± 0.07*** 5.96 ± 0.20***1.57 ± 0.06 1.76 ± 0.03 3.10 ± 0.09*** 4.47 ± 0.07*** 5.96 ± 0.20***
RecuperatedRecuperated 1.13 ± 0.03** 1.70 ± 0.04 4.23 ± 0.06*** 8.13 ± 0.10*** 9.33 ± 0.15***1.13 ± 0.03** 1.70 ± 0.04 4.23 ± 0.06*** 8.13 ± 0.10*** 9.33 ± 0.15***
GROUP Day 0 Day 3 Day 7 Day 14 Day 21GROUP Day 0 Day 3 Day 7 Day 14 Day 21
(g) (g) (g) (g) (g)(g) (g) (g) (g) (g)
*** p < 0.001 compared to controls*** p < 0.001 compared to controls
** p < 0.01 compared to controls** p < 0.01 compared to controls

10. Mice Early Postnatal Weight GainMice Early Postnatal Weight Gain
Bodyweight(g)Bodyweight(g)
Lab ChowLab Chow
1414121210108866442200
00
1010
2020
3030
4040
Age (weeks)Age (weeks)
Postnatal low-proteinPostnatal low-protein
ControlControl
RecuperatedRecuperated
Bodyweight(g)Bodyweight(g)
1414121210108866442200
00
1010
2020
3030
4040
Highly palatableHighly palatable
Age (weeks)Age (weeks)

11. Mice Weight Gain IncrementMice Weight Gain Increment
on Highly Palatable Dieton Highly Palatable Diet
00
55
1010
1515
2020
00 55 1010 1515
POSTNATAL LOW PROTEINPOSTNATAL LOW PROTEIN
RECUPERATEDRECUPERATED
CONTROLCONTROL
AGE (Weeks)AGE (Weeks)
WeightGain(%chow)WeightGain(%chow)

12. Mammary Tumour RiskMammary Tumour Risk

13. ProtocolProtocol
Offspring dietOffspring diet
LPLP
ControlControl
ChowChow
Highly PalatableHighly Palatable
20%20% 20%20% Chow (20%)Chow (20%)
ChowChow
Highly PalatableHighly Palatable
8%8% 8%8% Chow (20%)Chow (20%)
BirthBirth WeaningWeaning
Maternal dietMaternal diet
NMU injections
3, 4, 5 wks of age
GestationGestation LactationLactation
7 weeks7 weeks

14. Mammary TumourMammary Tumour
IncidenceIncidence
HR (95% CI) P value
Effect of LP 2.13 (1.015, 4.45) 0.046
HPD on Control 1.74 (1.02, 2.96) 0.04
Additive effect of HPD on LP 1.36 (1.09, 1.70) 0.006
00
22
44
66
88
1010
1212
1414
1616
1818
2020
ControlControl Control + obesityControl + obesity LPLP LP + obesityLP + obesity
Nutritional groupsNutritional groups
NMU-inducedmammarytumourNMU-inducedmammarytumour
incidenceincidence

15. Programming by MaternalProgramming by Maternal
Diet-Induced ObesityDiet-Induced Obesity

16. Experimental DesignExperimental Design
ControlControl
ObeseObese
GestationGestation LactationLactation WeaningWeaningPre-matingPre-mating
6 WEEKS6 WEEKS
6 WEEKS6 WEEKS
3 WEEKS3 WEEKS
3 WEEKS3 WEEKS 3 WEEKS3 WEEKS
3 WEEKS3 WEEKS
Gestation Lactation
100100
200200
300300
***
***
***p< 0.001 versus control
ControlControl
ObeseObese
Energyintake(kJ/day)Energyintake(kJ/day)
00

17. Maternal Body CompositionMaternal Body Composition
ControlControl ObeseObese P-valueP-value
Total bodyweight (g) 28.7 ± 1.1 36.5 ± 3.0 0.008
Lean mass (g) 21.7 ± 1.0 20.2 ± 0.9 NS
Fat mass (g) 4.8 ± 0.4 14.1 ± 2.7 <0.001
% Fat 17.9 ± 0.72 39.8 ± 5.25 <0.001

18. Effects on the OffspringEffects on the Offspring

19. Physical and Metabolic ConsequencesPhysical and Metabolic Consequences
Samuelsson et al., 2008Samuelsson et al., 2008
• FatterFatter
• HypertensiveHypertensive
• Glucose IntolerantGlucose Intolerant
• Insulin ResistantInsulin Resistant

20. 8 Week Physical Characteristics8 Week Physical Characteristics
ControlControl ObeseObese P-valueP-value
Body weight (g) 24.0 ± 0.4 23.5 ± 0.7 NS
DEXA % Lean mass 83.3 ± 0.7 82.2 ± 1.0 NS
DEXA % Fat mass 16.8 ± 0.5 17.9 ± 1.0 NS

21. Plasma ParametersPlasma Parameters
glucoseglucose
ControlControl ObeseObese
00
22
44
66
Glucose(mmol/l)Glucose(mmol/l)
insulininsulin
ControlControl ObeseObese
00
5050
100100
150150
Insuin(pmol/l)Insuin(pmol/l)
P < 0.05P < 0.05

22. From BaudryFrom Baudry et alet al.,., EMBO Reports (2002) 3: 323-328EMBO Reports (2002) 3: 323-328

23. Insulin Signalling PathwaysInsulin Signalling Pathways
PP**
PI(3,4,5)PPI(3,4,5)P33
PP
PP
PP
PP
PP
PP
PI(4,5)PPI(4,5)P22
Protein kinasesProtein kinases
(e.g. PKB/Akt, PKC(e.g. PKB/Akt, PKCζζ, GSK3), GSK3)
Small G-Small G-
proteinsproteins
(e.g. rac, rab,(e.g. rac, rab,
ras)ras)
Recycling pathways
(e.g. glucose transporter translocationglucose transporter translocation
transferrin receptor recruitment to PM)
Metabolic regulation
(e.g. glycogen synthase activation
and lipolysis inhibition) Cytoskeletal organization
(e.g.membrane ruffling)
Mitogenic eventsMitogenic events
rasras
GDPGDP
rasras
GTPGTP
GRBGRB
22
SHCSHC
SOSSOS
SHTPTSHTPT
22NckNck
IRS-1/2IRS-1/2
GRBGRB
22
P
P
P
P P
P
PI 3KPI 3K
InsulinInsulin
ReceptorReceptor
InsulinInsulin
............
P
P
P

24. Adipose Tissue Insulin SignallingAdipose Tissue Insulin Signalling
Fernandez-Twinn, Martin-Gronert & Ozanne, unpublishedFernandez-Twinn, Martin-Gronert & Ozanne, unpublished
**
00
2020
4040
6060
8080
100100
120120
140140
IRIRββ
%ofMeanControl%ofMeanControl
** P < 0.01** P < 0.01
* P < 0.05* P < 0.05
ControlControl
ObeseObese
****
** **
IRS1IRS1 p110p110ββ p85p85αα
****
**
Akt1Akt1 Akt2Akt2 GLUT4GLUT4

25. Future DirectionsFuture Directions

26. InterventionIntervention
StrategiesStrategies

27. (a) To the mother(a) To the mother

28. What are the key programming factors?What are the key programming factors?

29. (b) To the child(b) To the child

30.  Targeted interventions?Targeted interventions?
 Markers of disease riskMarkers of disease risk
 Time windows?Time windows?

31. ConclusionsConclusions
 Maternal environment influences long-termMaternal environment influences long-term
health of offspringhealth of offspring
 Multiple mechanisms involvedMultiple mechanisms involved
 Further understanding of mechanisms could giveFurther understanding of mechanisms could give
potential for targeted interventionpotential for targeted intervention

32. Current Group MembersCurrent Group Members
Maria AlfaradhiMaria Alfaradhi
Sarah BarnesSarah Barnes
Lindsey BerendsLindsey Berends
Heather BlackmoreHeather Blackmore
Daniella Duque-GuimaraesDaniella Duque-Guimaraes
Denise Fernandez-TwinnDenise Fernandez-Twinn
Malgosia MartinMalgosia Martin
Naomi PenfoldNaomi Penfold
Jane Tarry-AdkinsJane Tarry-Adkins
CollaboratorsCollaborators
Dino GiussaniDino Giussani (University of Cambridge)(University of Cambridge)
Lucilla PostonLucilla Poston (Kings College London)(Kings College London)
AcknowledgementsAcknowledgements
Funding BodiesFunding Bodies
British Heart FoundationBritish Heart Foundation
Diabetes UKDiabetes UK
EU (FP7 Early Nutrition)EU (FP7 Early Nutrition)
Wellcome TrustWellcome Trust