Growth and development are central characteristics of childhood. Deviations from normal growth can indicate serious health challenges. The adverse impact of early growth faltering and malnutrition on later health has long been known. In contrast, the impact of rapid early weight and body fat gain on programming of later disease risk have only recently received increased attention. Numerous observational studies related diet in early childhood and rapid early growth to the risk of later obesity and associated disorders. Causality was confirmed in a large, double-blind randomised trial testing the ‘Early Protein Hypothesis'. In this trial we found that attenuation of protein supply in infancy normalized early growth and markedly reduced obesity prevalence in early school age. These results indicate the need to describe and analyse growth patterns and their regulation through diet in more detail and to characterize the underlying metabolic and epigenetic mechanisms, given the potential major relevance for public health and policy. Better understanding of growth patterns and their regulation could have major benefits for the promotion of public health, consumer-orientated nutrition recommendations, and the development of improved food products for specific target populations.

Keywords:
Human growth trajectories, Infant nutrition, Obesity prevention, Metabolomics, Epigenetics
1.
Michaelsen KF: Child growth; in Koletzko B, Cooper P, Garza C, Makrides M, Uauy R, Wang W (eds): Pediatric Nutrition - A Practical Reference Guide. Basel, Karger, 2008.
2.
Ward LC, Poston L, Godfrey KM, Koletzko B: Assessing early growth and adiposity: report from an EarlyNutrition Academy workshop. Ann Nutr Metab 2013;63:120-130.
3.
de Onis M, Onyango A, Borghi E, Siyam A, Blossner M, Lutter C; WHO Multicentre Growth Reference Study Group: Worldwide implementation of the WHO child growth standards. Public Health Nutr 2012;15:1603-1610.
4.
de Onis M, Siyam A, Borghi E, Onyango AW, Piwoz E, Garza C: Comparison of the World Health Organization growth velocity standards with existing US reference data. Pediatrics 2011;128:e18-e26.
5.
Natale V, Rajagopalan A: Worldwide variation in human growth and the World Health Organization growth standards: a systematic review. BMJ Open 2014;4:e003735.
6.
Chang SM, Walker SP, Grantham-McGregor S, Powell CA: Early childhood stunting and later fine motor abilities. Dev Med Child Neurol 2010;52:831-836.
7.
Walker SP, Chang SM, Powell CA, Simonoff E, Grantham-McGregor SM: Early childhood stunting is associated with poor psychological functioning in late adolescence and effects are reduced by psychosocial stimulation. J Nutr 2007;137:2464-2469.
8.
Barker DJ: The fetal and infant origins of disease. Eur J Clin Invest 1995;25:457-463.
9.
Gluckman PD, Hanson MA, Cooper C, Thornburg KL: Effect of in utero and early-life conditions on adult health and disease. N Engl J Med 2008;359:61-73.
10.
Koletzko B, Symonds ME, Olsen SF: Programming research: where are we and where do we go from here? Am J Clin Nutr 2011;94:2036S-2043S.
11.
Symonds ME, Mendez MA, Meltzer HM, Koletzko B, Godfrey K, Forsyth S, van der Beek EM: Early life nutritional programming of obesity: mother-child cohort studies. Ann Nutr Metab 2013;62:137-145.
12.
Koletzko B, Bauer CP, Bung P, Cremer M, Flothkotter M, Hellmers C, Kersting M, Krawinkel M, Przyrembel H, Rasenack R, Schafer T, Vetter K, Wahn U, Weissenborn A, Wockel A: German national consensus recommendations on nutrition and lifestyle in pregnancy by the ‘Healthy Start - Young Family Network'. Ann Nutr Metab 2013;63:311-322.
13.
Patro B, Liber A, Zalewski B, Poston L, Szajewska H, Koletzko B: Maternal and paternal body mass index and offspring obesity: a systematic review. Ann Nutr Metab 2013;63:32-41.
14.
von Kries R, Koletzko B, Sauerwald T, von Mutius E, Barnert D, Grunert V, von Voss H: Breast feeding and obesity: cross sectional study. BMJ 1999;319:147-150.
15.
Arenz S, Ruckerl R, Koletzko B, von Kries R: Breast-feeding and childhood obesity - a systematic review. Int J Obes Relat Metab Disord 2004;28:1247-1256.
16.
Harder T, Plagemann A: Re: Duration of breastfeeding and risk of overweight: a meta-analysis - response. Am J Epidemiol 2006;163:872A-873A.
17.
Owen CG, Martin RM, Whincup PH, Smith GD, Cook DG: Effect of infant feeding on the risk of obesity across the life course: a quantitative review of published evidence. Pediatrics 2005;115:1367-1377.
18.
Weng SF, Redsell SA, Swift JA, Yang M, Glazebrook CP: Systematic review and meta-analyses of risk factors for childhood overweight identifiable during infancy. Arch Dis Child 2012;97:1019-1026.
19.
ESPGHAN Committee on Nutrition, Agostoni C, Braegger C, Decsi T, Kolacek S, Koletzko B, Michaelsen KF, Mihatsch W, Moreno LA, Puntis J, Shamir R, Szajewska H, Turck D, van Goudoever J: Breast-feeding: a commentary by the ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol Nutr 2009;49:112-125.
20.
Lutter CK, Morrow AL: Protection, promotion, and support and global trends in breastfeeding. Adv Nutr 2013;4:213-219.
21.
Health Canada; Canadian Paediatric Society; Dietitians of Canada; Breastfeeding Committee for Canada: Nutrition for healthy term infants: recommendations from birth to six months. Can J Diet Pract Res 2012;73:204.
22.
Koletzko B, Broekaert B, Demmelmair H, Franke J, Hannibal I, Oberle D, Schiess S, Baumann BT, Verwied-Jorky S: Protein intake in the first year of life: a risk factor for later obesity? The EU Childhood Obesity Project; in Koletzko B, Dodds P, Akerblom H, Ashwell M (eds): Advances in Experimental Medicine and Biology: Perinatal Programming of Adult Health - EC Supported Research. Berlin, Springer, 2005, pp 69-79.
23.
Koletzko B, von Kries R, Closa R, Escribano J, Scaglioni S, Giovannini M, Beyer J, Demmelmair H, Anton B, Gruszfeld D, Dobrzanska A, Sengier A, Langhendries JP, Rolland Cachera MF, Grote V: Can infant feeding choices modulate later obesity risk? Am J Clin Nutr 2009;89:1502S-1508S.
24.
Toschke AM, Grote V, Koletzko B, von Kries R: Identifying children at high risk for overweight at school entry by weight gain during the first 2 years. Arch Pediatr Adolesc Med 2004;158:449-452.
25.
Koletzko B, Beyer J, Brands B, Demmelmair H, Grote V, Haile G, Gruszfeld D, Rzehak P, Socha P, Weber M; European Childhood Obesity Trial Study Group: Early influences of nutrition on postnatal growth; in Gillman M, Gluckman P, Rosenfeld R (eds): Recent Advances in Growth Research: Nutritional, Molecular and Endocrine Perspectives. Basel, Karger, 2013, pp 11-27.
26.
Gale C, Logan KM, Santhakumaran S, Parkinson JR, Hyde MJ, Modi N: Effect of breastfeeding compared with formula feeding on infant body composition: a systematic review and meta-analysis. Am J Clin Nutr 2012;95:656-669.
27.
Escribano J, Luque V, Ferre N, Mendez-Riera G, Koletzko B, Grote V, Demmelmair H, Bluck L, Wright A, Closa-Monasterolo R: Effect of protein intake and weight gain velocity on body fat mass at 6 months of age: the EU Childhood Obesity Programme. Int J Obes (Lond) 2012;36:548-553.
28.
Brands B, Demmelmair H, Koletzko B, The EarlyNutrition Project: How growth due to infant nutrition influences obesity and later disease risk. Acta Paediatr 2014;103:578-585.
29.
Koletzko B, von Kries R, Monasterolo RC, Subias JE, Scaglioni S, Giovannini M, Beyer J, Demmelmair H, Anton B, Gruszfeld D, Dobrzanska A, Sengier A, Langhendries JP, Cachera MF, Grote V: Infant feeding and later obesity risk. Adv Exp Med Biol 2009;646:15-29.
30.
Koletzko B, von Kries R, Closa R, Escribano J, Scaglioni S, Giovannini M, Beyer J, Demmelmair H, Gruszfeld D, Dobrzanska A, Sengier A, Langhendries JP, Rolland Cachera MF, Grote V: Lower protein in infant formula is associated with lower weight up to age 2 y: a randomized clinical trial. Am J Clin Nutr 2009;89:1836-1845.
31.
Weber M, Grote V, Closa-Monasterolo R, Escribano J, Langhendries JP, Dain E, Giovannini M, Verduci E, Gruszfeld D, Socha P, Koletzko B; European Childhood Obesity Trial Study Group: Lower protein content in infant formula reduces BMI and obesity risk at school age: follow-up of a randomized trial. Am J Clin Nutr 2014;99:1041-1051.
32.
Koletzko B, von Kries R, Closa R, Escribano J, Scaglioni S, Giovannini M, Beyer J, Demmelmair H, Gruszfeld D, Dobrzanska A, Sengier A, Langhendries JP, Rolland Cachera MF, Grote V; European Childhood Obesity Trial Study Group: Lower protein in infant formula is associated with lower weight up to age 2 y: a randomized clinical trial. Am J Clin Nutr 2009;89:1836-1845.
33.
Thorisdottir B, Gunnarsdottir I, Thorisdottir AV, Palsson GI, Halldorsson TI, Thorsdottir I: Nutrient intake in infancy and body mass index at six years in two population-based cohorts recruited before and after revision of infant dietary recommendations. Ann Nutr Metab 2013;63:145-151.
34.
Socha P, Grote V, Gruszfeld D, Janas R, Demmelmair H, Closa-Monasterolo R, Subias JE, Scaglioni S, Verduci E, Dain E, Langhendries JP, Perrin E, Koletzko B; European Childhood Obesity Trial Study Group: Milk protein intake, the metabolic-endocrine response, and growth in infancy: data from a randomized clinical trial. Am J Clin Nutr 2011;94:1776S-1784S.
35.
Hogg J, Han VK, Clemmons DR, Hill DJ: Interactions of nutrients, insulin-like growth factors (IGFs) and IGF-binding proteins in the regulation of DNA synthesis by isolated fetal rat islets of Langerhans. J Endocrinol 1993;138:401-412.
36.
Ketelslegers JM, Maiter D, Maes M, Underwood LE, Thissen JP: Nutritional regulation of insulin-like growth factor-I. Metabolism 1995;44:50-57.
37.
Newsholme P, Gaudel C, McClenaghan NH: Nutrient regulation of insulin secretion and beta-cell functional integrity. Adv Exp Med Biol 2010;654:91-114.
38.
Muntoni S: Insulin resistance: pathophysiology and rationale for treatment. Ann Nutr Metab 2011;58:25-36.
39.
Yang J, Chi Y, Burkhardt BR, Guan Y, Wolf BA: Leucine metabolism in regulation of insulin secretion from pancreatic beta cells. Nutr Rev 2010;68:270-279.
40.
Polak P, Hall MN: mTOR and the control of whole body metabolism. Curr Opin Cell Biol 2009;21:209-218.
41.
Polak P, Cybulski N, Feige JN, Auwerx J, Ruegg MA, Hall MN: Adipose-specific knockout of raptor results in lean mice with enhanced mitochondrial respiration. Cell Metab 2008;8:399-410.
42.
Raiten DJ, Raghavan R, Kraemer K: Biomarkers in growth. Ann Nutr Metab 2013;63:293-297.
43.
Hellmuth C, Demmelmair H, Schmitt I, Peissner W, Bluher M, Koletzko B: Association between plasma nonesterified fatty acids species and adipose tissue fatty acid composition. PLoS One 2013;8:e74927.
44.
Hellmuth C, Koletzko B, Peissner W: Aqueous normal phase chromatography improves quantification and qualification of homocysteine, cysteine and methionine by liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2011;879:83-89.
45.
Hellmuth C, Uhl O, Segura-Moreno M, Demmelmair H, Koletzko B: Determination of acylglycerols from biological samples with chromatography-based methods. J Sep Sci 2011;34:3470-3483.
46.
Hellmuth C, Weber M, Koletzko B, Peissner W: Nonesterified fatty acid determination for functional lipidomics: comprehensive ultrahigh performance liquid chromatography-tandem mass spectrometry quantitation, qualification, and parameter prediction. Anal Chem 2012;84:1483-1490.
47.
Reinehr T, Wolters B, Knop C, Lass N, Hellmuth C, Harder U, Peissner W, Wahl S, Grallert H, Adamski J, Illig T, Prehn C, Yu Z, Wang-Sattler R, Koletzko B: Changes in the serum metabolite profile in obese children with weight loss. Eur J Nutr 2014, Epub ahead of print.
48.
Harder U, Koletzko B, Peissner W: Quantification of 22 plasma amino acids combining derivatization and ion-pair LC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci 2011;879:495-504.
49.
Niesser M, Harder U, Koletzko B, Peissner W: Quantification of urinary folate catabolites using liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2013;929:116-124.
50.
Deaton AM, Bird A: CpG islands and the regulation of transcription. Genes Dev 2011;25:1010-1022.
51.
Choi S-W, Friso S: Epigenetics: a new bridge between nutrition and health. Adv Nutr 2010;1:8-16.
52.
Gambari R, Fabbri E, Borgatti M, Lampronti I, Finotti A, Brognara E, Bianchi N, Manicardi A, Marchelli R, Corradini R: Targeting microRNAs involved in human diseases: a novel approach for modification of gene expression and drug development. Biochem Pharmacol 2011;82:1416-1429.
53.
Sato F, Tsuchiya S, Meltzer SJ, Shimizu K: MicroRNAs and epigenetics. FEBS J 2011;278:1598-1609.
54.
Relton CL, Davey Smith G: Epigenetic epidemiology of common complex disease: prospects for prediction, prevention, and treatment. PLoS Med 2010;7:e1000356.
55.
Sebert S, Sharkey D, Budge H, Symonds ME: The early programming of metabolic health: is epigenetic setting the missing link? Am J Clin Nutr 2011;94:1953S-1958S.
56.
Bateson P, Barker D, Clutton-Brock T, Deb D, D'Udine B, Foley RA, Gluckman P, Godfrey K, Kirkwood T, Lahr MM, McNamara J, Metcalfe NB, Monaghan P, Spencer HG, Sultan SE: Developmental plasticity and human health. Nature 2004;430:419-421.
57.
Waterland RA, Kellermayer R, Rached M-T, Tatevian N, Gomes MV, Zhang J, Zhang L, Chakravarty A, Zhu W, Laritsky E, Zhang W, Wang X, Shen L: Epigenomic profiling indicates a role for DNA methylation in early postnatal liver development. Hum Mol Genet 2009;18:3026-3038.
58.
Reik W, Dean W, Walter J: Epigenetic reprogramming in mammalian development. Science 2001;293:1089-1093.
59.
Dolinoy DC, Huang D, Jirtle RL: Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Acad Sci 2007;104:13056-13061.
60.
Carone BR, Fauquier L, Habib N, Shea JM, Hart CE, Li R, Bock C, Li C, Gu H, Zamore PD, Meissner A, Weng Z, Hofmann HA, Friedman N, Rando OJ: Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 2010;143:1084-1096.
61.
Crider KS, Yang TP, Berry RJ, Bailey LB: Folate and DNA methylation: a review of molecular mechanisms and the evidence for folate's role. Adv Nutr 2012;3:21-38.
62.
Parle-McDermott A, Ozaki M: The impact of nutrition on differential methylated regions of the genome. Adv Nutr 2011;2:463-471.
63.
Godfrey KM, Sheppard A, Gluckman PD, Lillycrop KA, Burdge GC, McLean C, Rodford J, Slater-Jefferies JL, Garratt E, Crozier SR, Emerald BS, Gale CR, Inskip HM, Cooper C, Hanson MA: Epigenetic gene promoter methylation at birth is associated with child's later adiposity. Diabetes 2011;60:1528-1534.
64.
Seki Y, Williams L, Vuguin PM, Charron MJ: Minireview: epigenetic programming of diabetes and obesity: animal models. Endocrinology 2012;153:1031-1038.
65.
Engeham SF, Haase A, Langley-Evans SC: Supplementation of a maternal low-protein diet in rat pregnancy with folic acid ameliorates programming effects upon feeding behaviour in the absence of disturbances to the methionine-homocysteine cycle. Br J Nutr 2010;103:996-1007.
66.
Alexander BT: Epigenetic changes in gene expression: focus on ‘the liver X-receptor gene promoter is hypermethylated in a mouse model of prenatal protein restriction'. Am J Physiol Regul Integr Comp Physiol 2010;298:R272-R274.
67.
Burdge GC, Lillycrop KA, Phillips ES, Slater-Jefferies JL, Jackson AA, Hanson MA: Folic acid supplementation during the juvenile-pubertal period in rats modifies the phenotype and epigenotype induced by prenatal nutrition. J Nutr 2009;139:1054-1060.
68.
Gong L, Pan Y-X, Chen H: Gestational low protein diet in the rat mediates Igf2 gene expression in male offspring via altered hepatic DNA methylation. Epigenetics 2010;5:619-626.
69.
Hoile SP, Lillycrop KA, Thomas NA, Hanson MA, Burdge GC: Dietary protein restriction during F0 pregnancy in rats induces transgenerational changes in the hepatic transcriptome in female offspring. PLoS ONE 2011;6:e21668.
70.
Jousse C, Parry L, Lambert-Langlais S, Maurin A-C, Averous J, Bruhat A, Carraro V, Tost J, Letteron P, Chen P, Jockers R, Launay J-M, Mallet J, Fafournoux P: Perinatal undernutrition affects the methylation and expression of the leptin gene in adults: implication for the understanding of metabolic syndrome. FASEB J 2011;25:3271-3278.
71.
Lillycrop KA, Phillips ES, Jackson AA, Hanson MA, Burdge GC: Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr 2005;135:1382-1386.
72.
Lillycrop KA, Phillips ES, Torrens C, Hanson MA, Jackson AA, Burdge GC: Feeding pregnant rats a protein-restricted diet persistently alters the methylation of specific cytosines in the hepatic PPAR alpha promoter of the offspring. Br J Nutr 2008;100:278-282.
73.
Lillycrop KA, Slater-Jefferies JL, Hanson MA, Godfrey KM, Jackson AA, Burdge GC: Induction of altered epigenetic regulation of the hepatic glucocorticoid receptor in the offspring of rats fed a protein-restricted diet during pregnancy suggests that reduced DNA methyltransferase-1 expression is involved in impaired DNA methylation and changes in histone modifications. Br J Nutr 2007;97:1064-1073.
74.
Slater-Jefferies JL, Lillycrop KA, Townsend PA, Torrens C, Hoile SP, Hanson MA, Burdge GC: Feeding a protein-restricted diet during pregnancy induces altered epigenetic regulation of peroxisomal proliferator-activated receptor-alpha in the heart of the offspring. J Dev Orig Health Dis 2011;2:250-255.
75.
van Straten EME, Bloks VW, Huijkman NCA, Baller JFW, van Meer H, Lütjohann D, Kuipers F, Plösch T: The liver X-receptor gene promoter is hypermethylated in a mouse model of prenatal protein restriction. Am J Physiol Regul Integr Comp Physiol 2010;298:R275-R282.
76.
Lillycrop KA, Burdge GC: Epigenetic changes in early life and future risk of obesity. Int J Obes 2011;35:72-83.
77.
Groom A, Potter C, Swan DC, Fatemifar G, Evans DM, Ring SM, Turcot V, Pearce MS, Embleton ND, Smith DG, Mathers JC, Relton CL: Postnatal growth and DNA methylation are associated with differential gene expression of the TACSTD2 gene and childhood fat mass. Diabetes 2011;61:391-400.
78.
Fryer AA, Emes RD, Ismail KMK, Haworth KE, Mein C, Carroll WD, Farrell WE: Quantitative, high-resolution epigenetic profiling of CpG loci identifies associations with cord blood plasma homocysteine and birth weight in humans. Epigenetics 2011;6:86-94.
79.
Steegers-Theunissen RP, Obermann-Borst SA, Kremer D, Lindemans J, Siebel C, Steegers EA, Slagboom PE, Heijmans BT: Periconceptional maternal folic acid use of 400 µg per day is related to increased methylation of the IGF2 gene in the very young child. PLoS One 2009;4:e7845.
80.
Almén MS, Jacobsson JA, Moschonis G, Benedict C, Chrousos GP, Fredriksson R, Schiöth HB: Genome wide analysis reveals association of a FTO gene variant with epigenetic changes. Genomics 2012;99:132-137.
81.
Chernausek SD: Update: consequences of abnormal fetal growth. J Clin Endocrinol Metab 2012;97:689-695.
82.
Koletzko B, Kolacek S, Phillips A, Troncone R, Vandenplas Y, Baumann U, van Goudoever J, de Swarte C, Benninga M, Mearin L: Research and the promotion of child health: a position paper of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2014;59:274-278.
83.
Koletzko B, Benninga MA, Godfrey KM, Hornnes PJ, Kolacek S, Koletzko S, Lentze MJ, Mader S, McAuliffe FM, Oepkes D, Oddy WH, Phillips A, Rzehak P, Socha P, Szajewska H, Symonds ME, Taminiau J, Thapar N, Troncone R, Vandenplas Y, Veereman G: Public-private collaboration in clinical research during pregnancy, lactation, and childhood: joint position statement of the Early Nutrition Academy and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr 2014;58:525-530.
© 2014 S. Karger AG, Basel
2014
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.