The small babies are not the only ones at risk—there is increased incidence of chronic disease, particularly type two diabetes, across the normal birth weight range, so birth weight is not the only issue at hand.
Mechanisms of inheritable epigenetics. Mammalian gene expression is tightly controlled by genetic as well as epigenetic mechanisms. Epigenetics modifies the phenotype without altering the genotype of a cell. Shown here are some well-defined epigenetic mechanisms that include histone modifications, DNA methylation, and the noncoding RNA-mediated modulation of gene expression. Some of these mechanisms are inheritable through successive cell divisions and contribute to the maintenance of cellular phenotype. Recent studies show that the association of components of transcriptional regulatory machinery with target genes on mitotic chromosomes is a novel epigenetic mechanism that poises genes involved in key cellular processes, such as growth, proliferation, and lineage commitment, for expression in progeny cells.
Key points: Glucose transfer increases in a liner manner with maternal glucose (this had been suggested previously but we confirm this unexpected finding) Glucose transfer does not seem to be transporter limited (we have demonstrated this with tracer studies) Glucose transfer may be flow limited (our simple model suggests this + a very old paper)
Please use the dd month yyyy format for the date for example 11 January 2008. The main title can be one or two lines long.
Prof. Mark Hanson's Fat, Fate & Obesity talk to IW Cafe Scientifique sept 2012
Consequences of childhood obesity. From Han et al (2010) Lancet 375:1737-45
Non-communicable disease (NCD)• Cardiovascular disease, diabetes, chronic lung disease, some cancers• World’s biggest killers – 36m deaths/year, 63% of all deaths globally. In developed countries but also -• 80% in low- and middle income countries, especially as they undergo socio-economic improvement following reductions in communicable disease• Risks of NCD exacerbated by Western lifestyle, urbanisation, migration, increased longevity, falling postnatal mortality, smaller family size• WHO projects an increase of 15% in NCDs over next decade globally Adapted from WHO Action Plan for the Global Strategy for the Prevention and• Preventable Control of Noncommunicable Diseases; Dr Ala Alwan, 2008• Prevention strategy not part of the Millennium Development Goals – but UN General Assembly held Summit in Sept ’11 to discuss this………
Likelihood and severity of risks to global development
Daniel Lambert (1770-1809) weighed 52 st = 335 kg when he died
The relationship between the quality of the start to life and longer-term consequences is not a matter of extremes 40Prevalence of Type 2 diabetes (%) 30 20 10 0 <5.5 6.5 7.5 8.5 9.5 >9.5 Birth weight (lbs) Godfrey, Eur J Obstet Gynecol Reprod Biol 1998;78:141-50
Our normal biology: of all mammals, we are the fattest at birth.
What processes influence fetal fat deposition? Fetal liver blood flow is affected by mother’s diet. It has long-term implications for liver metabolism, growth factor production and fat deposition
Pune Maternal Nutrition Study the ‘thin-fat’ Indian newborn SD score relative to UK newborns 0 Weight Head Abdomen Length Fat Arm circ -3 Adipose tissue relatively preservedIndia: 2.6 - 3.0 kgUK white: 3.3 - 3.5 kg Yajnik CS, Int J Obesity 2003; 27: 173-80
2h insulin (mU/l) Diabetes prevalence (%) 30 50 Prevention is easier if we know the cause. 40 20 South Asian Why does one person or 30 population group have a higher risk than 20 another, even in the 10 same environment? 10 Genetic predisposition? European 0 0 0.8 0.9 1 0.8 0.9 1 Waist / hip ratio Waist / hip ratioFrom Mckeigue et al. Lancet, 1991, 337: 382 McKeigue et al. Lancet, 1991, 337: 382
The case of the missing heritability• “When scientists opened up the human genome, they expected to find the genetic components of common traits and diseases. But they were nowhere to be seen……….” Nature news feature 6 Nov 2008
Mechanisms of inheritable epigeneticsZaidi S K et al. Mol. Cell. Biol. 2010;30:4758-4766
Which tissues are available for epigenetic analysis?
Epigenetic state at birth predicts body composition in childhood PAH study children SWS childrenChild’s aged 9 years aged 6 years fatmass 8.0 r=0.32, P=0.009 r=0.20, P=0.002 n=64 (kg) n=239 7.0 6.0 5.0 4.0 3.0 2-35% -59% -84% -100% Degree of epigenetic change in metabolic control geneGodfrey et al 2011 (Diabetes 60: 1528- 1534) Values are means + SEM
Low maternal carbohydrate intake in early pregnancy associated with higher umbilical cord RXRA gene promoter methylation 80 r=-0.26, 70 P=0.027, n=64 Epigenetic change in metabolic control gene 60 50 N.B. No association 40 with mother’s Lowest 2nd 3rd Highest BMI or Maternal carbohydrate intake offspring in early pregnancy (quartiles) birthweightGodfrey et al 2011 (Diabetes 60: 1528- 1534)
• The mother’s body influences her child’s development from the moment of conception• Her body composition, diet and lifestyle teach her baby about the world in which she lives. This affects epigenetic processes which influence her child’s risk of disease for the rest of life.
Human placental glucose transfer is not transporter limited 0.04 Glucose trasnfer to fetus (mmol/min) 0.02 0.00 0 5 10 15 20 Maternal plasma glucose (mmol/l) Dually-perfused term placentae. Day, Lewis et al (unpublished)
What is “abnormal”?Obesity (BMI ≥ 95th percentile) at age 4 years according to maternal first-trimester BMI 35 30 p < 0.001 Obesity (% of children) 25 ? ical o log 20 h is pat h 15 is t W hen 10 5 0 <18.5 18.5-24.9 25-29.9 30-39.9 >40 Maternal BMI From Whitaker, Pediatrics. 2004 Jul;114(1):e29-36.
Interaction between parity and mother’s body composition mean % body fat from skinfold thickness in 276 men & women aged 28-31 years 35.0 Parity p=0.004 Mother’s BMI in early pregnancy p<0.001 Primiparous % body Multiparous fat 30.0 25.0 -21.5 -24.2 >24.15 Mother’s body mass index in Adjusted for age, sex & early pregnancy (kg/m2 ) current smokingReynolds & Godfrey et al (2010)
Obesity and NCDs are increasing in every country• Interventions to promote exercise and healthy diet often do not work for the people most at risk• Many people lose weight, only to gain it again, as if their body’s weight control systems are set to a higher level.• These systems are set in development, so the interventions in adult life may be too late.
Current focus of action on obesity and NCDs• Target adult lifestyle, especially physical exercise, diet (reduce sugar, salt, fat), alcohol abuse• Target multinational food industry• Make individuals responsible for what they eat and how much they exercise• It’s all about choice• Make us all feel guilty for “gluttony” and “sloth” - even children• If that doesn’t work, there’s surgery or drugs
Influences on diet Education Not smoking Watching little television Prudent Dieting DietTaking strenuous exercise Older age Not living with children
Southampton Women’s Survey. Following Southampton families. Young women with a lowerlevel of educational attainment are more likely to eat an unbalanced diet % % 3 .5 % consuming 2 .9 % 1 .5 5% % degrety 8 3. .4 e an unhealthy 4 9 rsi 7% 3 1 diet 4. Unive 5 oma Diplonal 60% ti er Na % examel 50 s lev % High 40 nced levelmediate s exam 0% Adva 3 0% examel s 2 Inter v er le % 10 s Low xam 32 Educational level 0% Robinson et al EJCN 2004; 58:1174-80
Infant guidelines pattern score according to prudent diet score of the mother High 1.0 0.5 guidelines score 6 month infant Medium 0 -0.5 Low -1.0 to -1 to -0.5 to 0 to 0.5 to 1 >1 Low Medium High Mothers prudent diet score Robinson et al. Br J Nutr. 2007
IQ at 4 years of age in relation to infant guidelines score Values are mean (95% CI) 114 112 Adjusted IQ at 4 yr 110 108 106 104 102 Lowest 2 3 Highest Standardized Infant Guidelines Score at 6 mIQ adjusted for sex, birth order, gestational age, birth weight,maternal age, IQ, social class, education and HOME score Gale et al. J Child Psychol Psychiatry. 2009
Lifestyles of SWS women who did and did notbecome pregnant within 3 months of interview 80 Not pregnant Pregnant 70 60 50 40 30Pgnacert 20 10 0 Not smoking > 5 portions fruit & Any strenuous activity in vegetables per day past 3 months Inskip et al. BMJ 2009
Womens compliance with nutrition and lifestylerecommendations before pregnancy: general populationcohort study.Inskip et al. BMJ. 2009 Feb 12;338:b481Conclusion: Only a small proportion of womenplanning a pregnancy in UK follow therecommendations for nutrition and lifestyle(folic acid supplement intake, alcoholconsumption, smoking, diet, and physicalactivity)and the unplanned pregnancies……?
Poor educational attainment Poor diet Take less exercise ObesePoorer educationalattainment Ill-prepared for pregnancy. Minimal changes in diet and health behavioursGreater fat mass,less lean mass andlower IQ at age 4 Poor infant diet 37
Poor educational attainment Poor diet Take less exercise ObesePoorer educationalattainment Ill-prepared for pregnancy. Minimal changes in diet and health behavioursGreater fat mass,less lean mass andlower IQ at age 4 Poor infant diet 38
Kain J et al (inc Simon Murphy, Cardiff Institute of Society and Health) Obesity Prevention in Primary School Settings: evidence from intervention studies In Preventing Childhood Obesity. BMJ Books 2010.“Interventions struggle to achieve changes in BMI despitefinding effectiveness on behavioural and other outcomes………The school setting is subject to a number of barriers inimplementing sustainable obesity prevention programs,requiring infrastructure and resources that may well not exist inpoor schools……………….Many interventions have beencriticised for focusing on the most accessible setting andgroups and for conceptualising setting as a channel ofdelivery rather than a dynamic context that both shapesand is shaped by those within it”. 39
Hospital-based classroom & School of Medicine Hands-on activities+ pre and post school-based lessons
Me, my healthand my children’s healthWhat do the students 41
How healthy are my arteries?Carotid arteryin the neck The carotid artery 42
At what age do you think your diet starts to affect your future health? 60 *** 50percentage of respondants 40 30 20 10 0 Before you were born 0-10 11_20 Adulthood/never Post Lifelab Lifelab peers 48 Grace et al, Health Education, Vol. 112 Iss: 6 (Date online 12/9/2012)
“A particularly successful workshop, ‘LifeLabSouthampton, is based at the local hospital andis making an important contribution to students’understanding of the need to adopt healthylifestyles.”OFSTED 2009“the impact of Life Lab on students’ learning andenthusiasm for science [was judged] to be‘Outstanding’Senior Secondary Inspector, Southampton City Council 50
New Insights - Summary• There is a very strong case for interventions in early life for NCD prevention• We have biomarkers of later NCD risk which can be measured in early life• NCD risk is graded across the entire normal range of development• Pre-conception period may be critical in terms of parents’ health literacy and behaviour• Promoting a healthy start to life means that we could show a beneficial effect of interventions within a short (<5 years) timeframe.