5 ème Symposium de la Division d’endocrinologie, diabétologie et obésité pédiatriques 13 octobre 2016, CHUV Le « programming » au cours développement: entre environnement et génome Umberto Simeoni Service de pédiatrie, DMCP CHUV & FBM/UNIL Lausanne
The growing burden of noncommunicable diseases (cardiovascular disease, obesity, diabetes ,…) Lopez et al, Lancet 2006
Neonatal Mortality 70%: associated with low birth weight
Epigenetic Landscape and Biological Development: How the environment affects genes regulation and development C Waddington
Developmental programming : A process by which a stimulus applied during a criticial period of sensitivity during development exerts not only short term, but lifelong effects The effect of finite periods of undernutrition at different ages on the composition and the subsequent development of the rat Widdowson & Mc Cance, Proc. Roy Soc London 1966 CORONARY HEART DISEASE Standardised mortality ratios in 10141 men & 5585 women 120 Men 120 Women The effect of birth weight on the mortality ratio Standardised Mortality Ratio of coronary heart disease in human 100 100 Barker et al, Lancet 1989 80 80 60 60 40 40 20 20 £ 5.5 -6.5 -7.5 -8.5 -9.5 £ 5.5 -6.5 -7.5 -8.5 -9.5 >9.5 >9.5 Birthweight (pounds) Birthweight (pounds) �
The amplifying effect of the cycle of reproduction: Worldwide Type 2 Diabetes Mellitus Epidemic Increased prevalence of T2DM Diabetes in pregnancy Altered glucose tolerance in offspring Transgenerational transmission
Kidney: Developmental Programming of Hypertension and of Renal Function: Low maternal protein diet, IUGR & effect of postnatal overfeeding (OF) Systolic ABP 4 months Systolic ABP 1 month Controls IUGR OF IUGR + OF CCr 12 months (males) CCr 4 months Proteinuria 4 months 8 (ml/min/kg) 6 * 4 2 0 Controls IUGR OF IUGR + OF Control IUGR OF IUGR+OF Glomerular sclerosis Boubred et al., Am J Physiol Renal Physiol 2007, 2009
Hypertension and Renal Damage: Effects of high protein intakes IUGR, Maternal Diabetes (Inborn nephron deficit) ↓ Filtration surface area ↑ Single nephron ↑ Arterial glomerular filtration rate blood pressure (SNGFR) Glomerular hypertension RAS Proteinuria Glomerulosclerosis
Glucose tolerance * * glycaemia (g/l) 5 5 insulin (ng/ml) 4 4 * * 3 3 2 2 1 1 0 0 t0 t30 t120 t0 t30 t120 Glucose tolerance test *p<0.05 Control LP BET
Developmental « programming » & The Developmental Origins of Health and Disease (DOHaD) 2 nd hits Conception 1000 DAYS 2 nd birthday Adulthood Non Normal variations in nutrition, stress, environmental toxicants exposure , Communicable Nutrition , Diseases : Taste development Periconceptional & perinatal disorders and Hypertension Microbiome Diabesity interventions: Stress Cancer Preterm birth, Intra-uterine growth Toxicants restriction, Maternal diabetes/overweight, Broncho- C-section, ART pulmonary disease Infertility Neuro-psychic Epigenetic changes : DNA methylation, vulnerability, histones deacetylation/ methylation, Senescence… phosphorylation, ncRNA
Epigenetics: a long lasting, heritable molecular translation of early genome- environment interactions, in the absence of gene sequence alteration Royal gelly fed bees Non coding RNAs become bigger, live longer and are fertile.
Intrauterine growth restricted (IUGR) neonatal rats: transcriptome analysis IUGR vs control rats 1800 transcripts altered over 2 X 760 up-regulated 1040 down-regulated IUGR kidneys
Epigenetic effectors: IUGR rats Analysis of specific groups of genes : epigenetic regulators Buffat et al, PLoS Genet 2011
Apoptosis and p53 gene methylation In IUGR rat kidney Pham et al, Am J Physiol 2003;285:R962
Intergenerational programming of impaired nephrogenesis Harrisson & Langley-Evans, Br J Nutr 2009
Peroxysome proliferator activated receptor – a in offspring of rats fed a protein restricted (PR) diet during gestation, prevented by folate supplementation (F) Adapted from Lillycrop et al, 2005 & Burdge et al 2008 , Gluckman NEJM 2008
Kidney: Effect of Postnatal High Protein Diet in IUGR Rat Pups « Pup-in-the cup model » (HP diet) 13,0 g/dL IUGR Standard diet (NP diet) 8,7 g/dL G 22 D 5 D 21 * D 160 J 0 * * HP diet * -> Postnatal HP diet induces glomerular hyperfiltration, hypertension and long term glomerular sclerosis Boubred et al, Pediatr Res 2016
High protein intakes in infants • Metabolic effects: – Increased circulating insulin & IGF-1 concentrations, decreased IGF-BP concentrations – Increased branched chain amino acids concentrations Ziegler et al 2006; Socha et al 2011 • Renal and cardio-vacular effects: – Increased renal osmotic load – Glomerular sclerosis Boubred et al 2007, 2009 Accelerated growth Long term insulin-resistance, overweight Long term altered renal function and structure, hypertension
Long term effects of high protein intakes on BMI: CHOP trial RCT in the first year of age: • Higher protein formula (2.05 followed by 3.2g/dL, up ) • Lower protein formula (1.25 followed by 1.6g/dL) • Breast-feeding (>3 months) Results at 6 years of age: Higher protein formula -> BMI increased by .51 kg/cm2 -> Risk for obesity x 2.43 Weber et al, Am J Clin Nutr 2014
Fat intakes during infancy Dietary fat should contribute to 40-60% energy during the first 6 months of life and should decrease gradually to 35% from 6 to 24 months. FAO, Rome 2010 Diet of 8- to 24-month old children in various industrialized countries contains about 16% energy from proteins and 26-35% from fats; in sharp contrast with the composition of breast milk (low- protein (7%) and high-fat (55%) contents). Butte et al, J Am Diet Assoc 2010 Uauy & Dangour, Ann Nutr Metab 2009
Association of nutrition in early life with body fat and serum leptin at adult age Rolland-Cachera MF et al, Int J Obesity 2012 A 1% increased energy intake from fat at 2 years is associated, at the age of 20 years, with: lower subscapular skinfold thickness (-2.3% SF, -4.41 to – 0.18, p = 0.03), lower fat mass (-0.31 kg, - 0.60 to – 0.01, p= 0.04) lower serum leptin concentration (0.21 ug/l, -0.39 to 0.03, p= 0.02) Low fat intakes in the first 2 years of life are associated with higher body fat, particularly at the trunk site and higher leptin concentrations at adult age. Most children consumed the equivalent of more than four times their protein needs, whereas dietary fat intakes were below current recommendations
Effects of varying proteins concentrations in infant forumlas on infants weight between 3 and 12 months of age Patro-Golab et al, J Nutr 2016
Developmental programming Quelle ampleur d’effet?
Leptin/adiponectin ratio in young, healthy adults 2.5 2 1.5 Mean L/A ratio 1 0.5 >77 Adult weight -77 0 (kg) ≤67.5 ≤12.4 12.4-13.3 >13.3 Weight at age 2y (kg) p < 0.001
Prevalence of hypertension 80 60 % 40 -3.0 -3.5 Birth 20 -4.0 -weight >4.0 (kg) 0 M -74.8 -81.5 -88.0 -96.5 >96.5 M F -62.6 -68.7 -75.2 -83.9 >83.9 F Fifths of current weight (kg) Barker DJ, Osmond C, Forsen TJ, Kajantie E, Eriksson JG. N Engl.J Med. 2005;353:1802-9
Conséquences à long terme de la prématurité
Indicators of Glucose Regulation in VLBW Young Adults (Hovi et al, NEJM 2007)
Prevalence of cardio-metabolic complications in adults born preterm Sipola-Leppanen et al, Am J Epidemiol 2015
Altered adiposity in adult phenotype of preterm infants Total body MRI, MRS, urinary metabolomics Preterm vs Term Subjects Mean difference/ratio p Total adipose tissue 2.21 L (0.3 – 4.1) 0.03 Abdominal adipose tissue 0.51 L (0.1 – 0.9) 0.007 Systolic blood pressure 6.5 mm Hg (2.2 – 10.8) 0.004 Diastolic blood pressure 5.9 mm HG (1.8 -10.1) 0.006 Intrahepatocellular lipid 3.01 (ratio) (1.78 – 5.28) < 0.001 Tibialis intramyocellular lipid 1.31 (ratio) (1.02 – 1.09) 0.04 Greater internal adipose tissue and sinificant urinary metabolome differences in preterm vs term men. Modi N et al Pediatr Res 2011
140 Arterial Blood Pressure in 120 Arterial pressure (mmHg) 122 * 112 Young Adults Born Preterm 100 80 89 * 85 Postnatal growth 60 69 * 65 53 * 46 40 20 0 SBP DBP MBP PP Preterm Controls Growth Systolic blood pressure Systolic blood pressure r p 1,5 correlations 1 Change in Z-score for weight (4- 0.426 0.048 0,5 12 months) 0 Z score Weight gain : 6-21 years 0.419 0.03 -0,5 (absolute) -1 -1,5 Weight gain : 6-21 years 0.582 0.001 Preterm, height Control, height -2 (relative) Preterm, weight Control, weight -2,5 Change in Z-score for weight (6- 0.381 0.05 -3 21 years) Birth 4M 12M 48M 6Y 21Y Change in BMI (6-21 years) 0.489 0.011 Tauzin et al, JDOHaD 2014
Low birth weight and later hypertension Cord blood circulating endothelial progenitor cells (ECFC) Low BW Controls NBW LBW altered in vitro angiogenic capacity of low-BW infants cord blood Endothelial Progenitor Cells Ligi et al, Blood 2011
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