optimisingthe balance between metabolic capacity and ......optimisingthe balance between metabolic...
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Optimising thebalancebetweenmetaboliccapacityandmetabolicload
forlifelonghealth
JonathanWellsProfessorofAnthropologyandPediatricNutrition
UCLInstituteofChildHealthLondon
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Life-longhealthMaternalhealth
- Pregnancyandchildbirth
Growthanddevelopment
Cardio-metabolicdisease- Heartdisease- Diabetes- Stroke
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Chronicdisease:typicalonsetinadulthood
+
Imagesource:UConnRuddCenterforFoodPolicy&Obesity
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Alife-courseperspective
Plasticity
NCDrisk
High
Low
Development Lifestyle
Plasticity
Criticalwindows
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Thriftyphenotypehypothesis
• Reducedinvestmentinorgans(pancreas,liver)=‘survivalphenotype’
• Lesstolerantof‘nutritionalexcess’inlaterlife(obesity,inactivity,richdiet)
Hales&Barker,Diabetologia 1992
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Stuntingandlaterbodycomposition
Wellsetal.,Eur JClin Nutr 2018
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Birthweightandlaterheartdisease
RichEdwardsetal.,BMJ1997
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Dose-responseassociations
• Mostofassociationlieswithin‘normal’birthweightrange
• Everyadditionalunitofbirthweightreduceschronicdiseaserisk
• Risktracksgrowthpatterns
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Theprocessofgrowth
Growth
Age
Hyperplasia
Hypertrophy
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Developmentandstructure
Growth
Age
Hyperplasia
HypertrophyMetaboliccapacity
Metabolicload
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Metaboliccapacity
• Characteristicsoforganstructureandfunction
• Conferhomeostaticcapacity
• Contingentonfetal/infantgrowth
Wells,AmJHumBiol 2011
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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
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Moresophisticatedmodels
Organ/tissuephysiology
Geneexpression
Metabolic/hormonalset-points
Gutbiota
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Challenginghomeostasis
Allostatic load
Stressresponse
HPAaxis
Cortisol
Metabolicload
Fuelhomeostasis
Metabolism
Insulin
McEwenandStellar,ArchInternMed1993
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Metabolicload
Wells,AmJHumBiol 2011
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Metabolicload
• Diet:fatorcarbohydrate?
• Activity:activegood,orsedentarybad?
• Obesity:BMI,centralfatormetabolism?
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Load/capacityanddiseaserisk
Wells,AmJHumBiol 2011
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Capacityanddiseaserisk
Wells,AmJHumBiol 2011
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Loadanddiseaserisk
Wells,AmJHumBiol 2011
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Load/capacityanddiseaserisk
Wells,AmJHumBiol 2011
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Supportingevidence:diabetes
Lietal.,BMJ2015
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Supportingevidence:hypertension
Lietal.,BMCMed2015
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Socialrankandmetaboliccapacity
Victora etal.,AnnHumBiol 1987
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Socialrankandmetabolicload
Obesityprevalence
NationalObesityObservatory
Levelofdeprivation
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Ethnicityandmetaboliccapacity
European Indian Pakistani Bangladeshi Caribbean African-15
-10
-5
0
5
10
15
Birth weight deficitProportion of low birth weight
%
Kellyetal,JPublicHealth2009
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Ethnicityandmetabolicload
Fat$Mass$Index$(kg/m2)$
Lean$Mass$Index$(kg/m2)$
Constant$BMI$values$Europeans$South$Asians$
A$B$C$
Wellsetal,FrontiersPublicHealth2016
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Maternalnutritionasacriticalperiod
Capacity
Load
Life-coursehealth
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Maternalnutritionasacriticalperiod
Life-coursehealth
Capacity
Load
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Inter-generationallinkages
Maternalobesity
Childobesity
Cnattingius etal.,2012Int JObes
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Inadequatecapacityforload
Maternalobesity
3*riskchildobesity
Cnattingius etal.,2012Int JObes
Lowbirthweight
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Infancyascriticalperiod
CAPACITY
LOAD
Elevateload
Constraincapacity
Fetallife Infancy Childhood Adolescence
Targetofgrowth
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Thedoubleburdenandchildbirth
Stun%ng'
Normal''growth'
+'
+' Obesity'
Gesta%onal''diabetes'
Normal'BMI'
Wells,Anat Record2017
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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
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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
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Fabiansen etal.,PLoS Med2017
Promotingcapacitynotload
RUTFsupplementation,n=~1600
LongitudinalmeasuresofLeanmassandFatmass
Benefitsinleannotfat
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