Optimisingthe balance between metabolic capacity and ......Optimisingthe balance between metabolic...

Optimising thebalancebetweenmetaboliccapacityandmetabolicload

forlifelonghealth

JonathanWellsProfessorofAnthropologyandPediatricNutrition

UCLInstituteofChildHealthLondon

Life-longhealthMaternalhealth

- Pregnancyandchildbirth

Growthanddevelopment

Cardio-metabolicdisease- Heartdisease- Diabetes- Stroke

Chronicdisease:typicalonsetinadulthood

+

Imagesource:UConnRuddCenterforFoodPolicy&Obesity

Alife-courseperspective

Plasticity

NCDrisk

High

Low

Development Lifestyle

Plasticity

Criticalwindows

Thriftyphenotypehypothesis

• Reducedinvestmentinorgans(pancreas,liver)=‘survivalphenotype’

• Lesstolerantof‘nutritionalexcess’inlaterlife(obesity,inactivity,richdiet)

Hales&Barker,Diabetologia 1992

Stuntingandlaterbodycomposition

Wellsetal.,Eur JClin Nutr 2018

Birthweightandlaterheartdisease

RichEdwardsetal.,BMJ1997

Dose-responseassociations

• Mostofassociationlieswithin‘normal’birthweightrange

• Everyadditionalunitofbirthweightreduceschronicdiseaserisk

• Risktracksgrowthpatterns

Theprocessofgrowth

Growth

Age

Hyperplasia

Hypertrophy

Developmentandstructure

Growth

Age

Hyperplasia

HypertrophyMetaboliccapacity

Metabolicload

Metaboliccapacity

• Characteristicsoforganstructureandfunction

• Conferhomeostaticcapacity

• Contingentonfetal/infantgrowth

Wells,AmJHumBiol 2011

Birthweightandmetaboliccapacity

87654320

100

200

300

543211

2

3

4Leanmass

FEV0.5

Manalich et al: Glomerular size and weight at birth772

Fig. 1. Relationship between the weight at birth and the number ofFig. 3. Negative correlation between the weight at birth and the glo-glomeruli. There is a significant (r � 0.870, P ⇥ 0.0001) relationshipmerular volume (r � 0.840, P ⇥ 0.0001). Symbols are: (d, s) females;between the number of glomeruli in the subcapsular cortex and the(j, h) males; (d, j) black race; (s, h) white race; ( , ) gestationweight at birth. It appears that the number of glomeruli increase progres-⇥38 weeks.sively until the weight at birth reaches 3 kg and remains steady thereaf-

ter. Symbols are: (d, s) females; (j, h) males; (d, j) black race; (s,h) white race; ( , ) gestation ⇥38 weeks.

Fig. 4. Negative correlation between the number of glomeruli andglomerular volume (r � 0.816, P ⇥ 0.0001). Symbols are: (d, s) females;Fig. 2. Positive correlation between the percentage area of the renal(j, h) males; (d, j) black race; (s, h) white race; ( , ) gestationcortex occupied by glomeruli and the weight at birth (r � 0.935, P ⇥⇥38 weeks.0.0001). Symbols are: (d, s) females; (j, h) males; (d, j) black race;

(s, h) white race; ( , ) gestation ⇥38 weeks.

shown that populations with a very high incidence ofin humans ranges between 300,000 and 1.1 million, with essential hypertension have a relatively small kidney size,a mean of approximately 600,000 [15–17]. The number suggesting a diminished number of nephrons [20, 21].of nephrons is a critical variable in the progression to The African American population, known to have a highchronic renal failure, because reductions in nephron incidence and increased severity of arterial hypertensionnumber result in glomerular hypertension in the re- (abstract; Falkerner et al, J Am Soc Nephrol 7:1549,maining nephron population, which, in turn, triggers a 1996), appears to be endowed with smaller numbers ofvicious cycle of progressive loss of functioning units [15]. larger glomeruli (abstract; ibid) [22], changes consideredReduced number of nephrons at birth may be associated to be evolutionary because in tropical conditions, sodiumwith a diminished resistance to any mechanism of renal conservation would be an adaptive priority [19, 23, 24].damage in adult life. Our findings are in agreement with the observations

Brenner and coworkers have recruited impressive evi- of others, in that smoking and arterial hypertension indence in favor of the theoretical construct that low neph- the parents are risk factors for intrauterine growth retar-ron number is a risk factor for essential hypertension dation and LBW [25–27]. Studies have shown that

marked retardation in intrauterine growth exerts pro-[10, 18, 19]. For instance, demographic studies have

Nephronnumber

Birthweight

Ethiopiancohort

Coronaryarterydiameter

Jiangetal.,Pediatr 2006;Dezateux etal.,Thorax 2004;Manalich etal.,KidneyInt 2000Birthweight

Moresophisticatedmodels

Organ/tissuephysiology

Geneexpression

Metabolic/hormonalset-points

Gutbiota

Challenginghomeostasis

Allostatic load

Stressresponse

HPAaxis

Cortisol

Metabolicload

Fuelhomeostasis

Metabolism

Insulin

McEwenandStellar,ArchInternMed1993

Metabolicload


Metabolicload

• Diet:fatorcarbohydrate?

• Activity:activegood,orsedentarybad?

• Obesity:BMI,centralfatormetabolism?

Load/capacityanddiseaserisk


Capacityanddiseaserisk


Loadanddiseaserisk


Load/capacityanddiseaserisk


Supportingevidence:diabetes

Lietal.,BMJ2015

Supportingevidence:hypertension

Lietal.,BMCMed2015

Socialrankandmetaboliccapacity

Victora etal.,AnnHumBiol 1987

Socialrankandmetabolicload

Obesityprevalence

NationalObesityObservatory

Levelofdeprivation

Ethnicityandmetaboliccapacity

European Indian Pakistani Bangladeshi Caribbean African-15

-10

-5

0

5

10

15

Birth weight deficitProportion of low birth weight

%

Kellyetal,JPublicHealth2009

Ethnicityandmetabolicload

Fat$Mass$Index$(kg/m2)$

Lean$Mass$Index$(kg/m2)$

Constant$BMI$values$Europeans$South$Asians$

A$B$C$

Wellsetal,FrontiersPublicHealth2016

Maternalnutritionasacriticalperiod

Capacity

Load

Life-coursehealth

Maternalnutritionasacriticalperiod

Life-coursehealth

Capacity

Load

Inter-generationallinkages

Maternalobesity

Childobesity

Cnattingius etal.,2012Int JObes

Inadequatecapacityforload

Maternalobesity

3*riskchildobesity

Cnattingius etal.,2012Int JObes

Lowbirthweight

Infancyascriticalperiod

CAPACITY

LOAD

Elevateload

Constraincapacity

Fetallife Infancy Childhood Adolescence

Targetofgrowth

Thedoubleburdenandchildbirth

Stun%ng'

Normal''growth'

+'

+' Obesity'

Gesta%onal''diabetes'

Normal'BMI'

Wells,Anat Record2017

Supportingevidence:cesareanrisk

4.03.53.02.52.01.51.00.50.0

Obese

Overweight

Normal BMI Normal heightShort

Odds Ratio for Cesarean delivery

Wellsetal,FrontiersPublicHealth2018

India2015-2016survey

Fabiansen etal.,PLoS Med2017

Promotingcapacitynotload

RUTFsupplementation,n=~1600

LongitudinalmeasuresofLeanmassandFatmass

Benefitsinleannotfat

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