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Handbook of Famine, Starvation, and Nutrient Deprivation pp 1–23Cite as

Effects of Protein Deficiency on Perinatal and Postnatal Health Outcomes

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Abstract

There are a variety of environmental insults that can occur during pregnancy which cause low birth weight and lead to poor neonatal outcomes. One such insult is maternal malnutrition, which can be further narrowed down to a low protein diet during gestation. Studies demonstrate that perinatal protein deficiencies can impair proper organ growth and development, leading to long-term metabolic dysfunction. Understanding the molecular mechanisms that underlie how this deficiency results in adverse developmental outcomes is essential for establishing better therapeutic strategies that may alleviate or prevent diseases in later life. This chapter reviews how perinatal protein restriction in humans and animals leads to metabolic disease, and it identifies, to date, some of the underlying molecular mechanisms that have been elucidated. These include alterations in transcriptional and epigenetic mechanisms, as well as as endoplasmic reticulum (ER) stress and oxidative stress. Furthermore, nutritional and pharmaceutical interventions are highlighted to illustrate that the plasticity of the underdeveloped organs during perinatal life can be exploited to prevent the onset of long-term metabolic disease.

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Abbreviations

ADP:

Adenosine diphosphate

Akt1:

Protein kinase B

ALS:

Amyotrophic lateral sclerosis

Cyp1A2:

Cytochrome P450 1A2

Cyp2c11:

Cytochrome P450 2c11

Cyp3a1:

Cytochrome P450 3a1

Cyp7a1:

Cholesterol 7 alpha-hydroxylase

DOHaD:

Developmental origins of health and disease

ER stress:

Endoplasmic reticulum stress

G6Pase:

Glucose-6-phosphatase

GLUT4:

Glucose transporter type 4

GR:

Glucocorticoid receptor

GRP78:

Glucose-regulated protein 78

IGF-1:

Insulin-like growth factor 1

IRS-1:

Insulin receptor substrate 1

IUGR:

Intrauterine growth restriction

LDL:

Low-density lipoprotein

LP:

Low protein

LPL:

Lipoprotein lipase

LXR:

Liver X receptor

LXRE:

LXR response element

MEF2:

Myocyte enhancer factor-2

miRs:

MicroRNAs

MPR:

Maternal protein restriction

p-eIF2α:

Phosphorylated eukaryotic translation initiation factor 2

PND:

Postnatal day

PPARα:

Peroxisome proliferator-activated receptor alpha

PPAR-γ:

Peroxisome proliferator-activated receptor gamma

ROS:

Reactive oxygen species

SAM:

Severe acute malnutrition

SGA:

Small for gestational age

SIRT1:

Sirtuin 1

UPR:

Unfolded protein response

XBP1:

X-box binding protein 1

References

  • Badaloo AV, Forrester T, Reid M, Jahoor F (2006) Lipid kinetic differences between children with kwashiorkor and those with marasmus. Am J Clin Nutr 83:1283–1288

    CAS  PubMed  Google Scholar 

  • Barker DJ (1994) Outcome of low birthweight. Horm Res 42:223–230

    Article  CAS  PubMed  Google Scholar 

  • Barker D (2003) The midwife, the coincidence, and the hypothesis. BMJ 327:1428–1430

    Article  PubMed  PubMed Central  Google Scholar 

  • Barker DJ, Martyn CN, Osmond C, Hales CN, Fall CH (1993) Growth in utero and serum cholesterol concentrations in adult life. BMJ 307:1524–1527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barker DJ, Eriksson JG, Forsen T, Osmond C (2002) Fetal origins of adult disease: strength of effects and biological basis. Int J Epidemiol 31:1235–1239

    Article  CAS  PubMed  Google Scholar 

  • Bieswal F, Ahn MT, Reusens B, Holvoet P, Raes M, Rees WD, Remacle C (2006) The importance of catch-up growth after early malnutrition for the programming of obesity in male rat. Obesity Silver Spring 14:1330–1343

    Article  CAS  Google Scholar 

  • Blesson CS, Chinnathambi V, Kumar S, Yallampalli C (2017) Gestational protein restriction impairs glucose disposal in the gastrocnemius muscles of female rats. Endocrinology 158(4):756–767

    Article  PubMed  Google Scholar 

  • Bol VV, Delattre A-I, Reusens B, Raes M, Remacle C (2009) Forced catch-up growth after fetal protein restriction alters the adipose tissue gene expression program leading to obesity in adult mice. Am J Physiol Regul Integr Comp Physiol 297:R291–R299

    Article  CAS  PubMed  Google Scholar 

  • Boujendar S, Reusens B, Merezak S, Ahn MT, Arany E, Hill D, Remacle C (2002) Taurine supplementation to a low protein diet during foetal and early postnatal life restores a normal proliferation and apoptosis of rat pancreatic islets. Diabetologia 45:856–866

    Article  CAS  PubMed  Google Scholar 

  • Boujendar S, Arany E, Hill D, Remacle C, Reusens B (2003) Taurine supplementation of a low protein diet fed to rat dams normalizes the vascularization of the fetal endocrine pancreas. J Nutr 133:2820–2825

    CAS  PubMed  Google Scholar 

  • Burdge GC, Slater-Jefferies J, Torrens C, Phillips ES, Hanson MA, Lillycrop KA (2007) Dietary protein restriction of pregnant rats in the F0 generation induces altered methylation of hepatic gene promoters in the adult male offspring in the F1 and F2 generations. Br J Nutr 97:435–439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Burns SP, Desai M, Cohen RD, Hales CN, Iles RA, Germain JP, Going TC, Bailey RA (1997) Gluconeogenesis, glucose handling, and structural changes in livers of the adult offspring of rats partially deprived of protein during pregnancy and lactation. J Clin Invest 100:1768–1774

    Article  CAS  PubMed Central  Google Scholar 

  • Chamson-Reig A, Thyssen SM, Arany E, Hill DJ (2006) Altered pancreatic morphology in the offspring of pregnant rats given reduced dietary protein is time and gender specific. J Endocrinol 191:83–92

    Article  CAS  PubMed  Google Scholar 

  • Chamson-Reig A, Thyssen SM, Hill DJ, Arany E (2009) Exposure of the pregnant rat to low protein diet causes impaired glucose homeostasis in the young adult offspring by different mechanisms in males and females. Exp Biol Med Maywood 234:1425–1436

    Article  CAS  PubMed  Google Scholar 

  • Chen J-H, Martin-Gronert MS, Tarry-Adkins J, Ozanne SE (2009) Maternal protein restriction affects postnatal growth and the expression of key proteins involved in lifespan regulation in mice. PLoS One 4:e4950

    Article  PubMed Central  Google Scholar 

  • Craig WJ, Mangels AR (2009) Position of the American Dietetic Association: vegetarian diets. J Am Diet Assoc 109:1266–1282

    Article  CAS  PubMed  Google Scholar 

  • Crosby WM (1991) Studies in fetal malnutrition. Am J Dis Child 1960(145):871–876

    Google Scholar 

  • Desai M, Hales CN (1997) Role of fetal and infant growth in programming metabolism in later life. Biol Rev Camb Philos Soc 72:329–348

    Article  CAS  Google Scholar 

  • Eriksson JG (2006) Early growth, and coronary heart disease and type 2 diabetes: experiences from the Helsinki Birth Cohort Studies. Int J Obes 2005 30(Suppl 4):S18–S22

    Google Scholar 

  • Ferreira DJS, da Silva Pedroza AA, Braz GRF, da Silva-Filho RC, Lima TA, Fernandes MP, Doi SQ, Lagranha CJ (2016) Mitochondrial bioenergetics and oxidative status disruption in brainstem of weaned rats: immediate response to maternal protein restriction. Brain Res 1642:553–561

    Article  CAS  Google Scholar 

  • Forrester TE, Badaloo AV, Boyne MS, Osmond C, Thompson D, Green C, Taylor-Bryan C, Barnett A, Soares-Wynter S, Hanson MA et al (2012) Prenatal factors contribute to the emergence of kwashiorkor or marasmus in severe undernutrition: evidence for the predictive adaptation model. PLoS One 7:e35907

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Francis-Emmanuel PM, Thompson DS, Barnett AT, Osmond C, Byrne CD, Hanson MA, Gluckman PD, Forrester TE, Boyne MS (2014) Glucose metabolism in adult survivors of severe acute malnutrition. J Clin Endocrinol Metab 99:2233–2240

    Article  CAS  PubMed  Google Scholar 

  • García-Fernández M, Delgado G, Puche JE, González-Barón S, Castilla Cortázar I (2008) Low doses of insulin-like growth factor I improve insulin resistance, lipid metabolism, and oxidative damage in aging rats. Endocrinology 149:2433–2442

    Article  PubMed  Google Scholar 

  • Guan H, Arany E, van Beek JP, Chamson-Reig A, Thyssen S, Hill DJ, Yang K (2005) Adipose tissue gene expression profiling reveals distinct molecular pathways that define visceral adiposity in offspring of maternal protein-restricted rats. Am J Physiol Metab 288:E663–E673

    CAS  Google Scholar 

  • Hadden DR (1967) Glucose, free fatty acid, and insulin interrelations in kwashiorkor and marasmus. Lancet 290:589–593

    Article  Google Scholar 

  • Hales CN, Barker DJ (2001) The thrifty phenotype hypothesis. Br Med Bull 60:5–20

    Article  CAS  PubMed  Google Scholar 

  • Hales CN, Barker DJ, Clark PM, Cox LJ, Fall C, Osmond C, Winter PD (1991) Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 303:1019–1022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hales CN, Desai M, Ozanne SE, Crowther NJ (1996) Fishing in the stream of diabetes: from measuring insulin to the control of fetal organogenesis. Biochem Soc Trans 24:341–350

    Article  CAS  PubMed  Google Scholar 

  • Honório de Melo Martimiano P, de Sa Braga Oliveira A, Ferchaud-Roucher V, Croyal M, Aguesse A, Grit I, Ouguerram K, Lopes de Souza S, Kaeffer B, Bolaños-Jiménez F (2017) Maternal protein restriction during gestation and lactation in the rat results in increased brain levels of kynurenine and kynurenic acid in their adult offspring. J Neurochem 140:68–81

    Article  PubMed  Google Scholar 

  • Koutsaki M, Sifakis S, Zaravinos A, Koutroulakis D, Koukoura O, Spandidos DA (2011) Decreased placental expression of hPGH, IGF-I and IGFBP-1 in pregnancies complicated by fetal growth restriction. Growth Horm IGF Res 21:31–36

    Article  CAS  PubMed  Google Scholar 

  • Lillycrop KA, Phillips ES, Jackson AA, Hanson MA, Burdge GC (2005) Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr 135:1382–1386

    CAS  PubMed  Google Scholar 

  • Mariani A, Chalies S, Jeziorski E, Ludwig C, Lalande M, Rodière M (2009) Consequences of exclusive breast-feeding in vegan mother newborn – case report. Arch Pediatr 16:1461–1463

    Article  CAS  PubMed  Google Scholar 

  • Michan S, Sinclair D (2007) Sirtuins in mammals: insights into their biological function. Biochem J 404:1–13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nolan K, Walter F, Tuffy LP, Poeschel S, Gallagher R, Haunsberge S, Bray I, Stallings RL, Concannon CG, and Prehn JH (2016) Endoplasmic reticulum stress-mediated upregulation of miR-29a enhances sensitivity to neuronal apoptosis. Eur J Neurosci 43(5):640–652

    Google Scholar 

  • Ogata ES, Bussey ME, Finley S (1986) Altered gas exchange, limited glucose and branched chain amino acids, and hypoinsulinism retard fetal growth in the rat. Metabolism 35:970–977

    Article  CAS  PubMed  Google Scholar 

  • de Oliveira JC, Gomes RM, Miranda RA, Barella LF, Malta A, Martins IP, Franco CC da S, Pavanello A, Torrezan R, Natali MRM et al (2016) Protein restriction during the last third of pregnancy malprograms the neuroendocrine axes to induce metabolic syndrome in adult male rat offspring. Endocrinology 157:1799–1812

    Google Scholar 

  • Ong KK, Ahmed ML, Emmett PM, Preece MA, Dunger DB (2000) Association between postnatal catch-up growth and obesity in childhood: prospective cohort study. BMJ 320:967–971

    Article  CAS  PubMed Central  Google Scholar 

  • Ozanne SE, Hales CN (2004) Lifespan: catch-up growth and obesity in male mice. Nature 427:411–412

    Article  CAS  PubMed  Google Scholar 

  • Ozanne SE, Wang CL, Coleman N, Smith GD (1996a) Altered muscle insulin sensitivity in the male offspring of protein-malnourished rats. Am J Phys 271:E1128–E1134

    CAS  Google Scholar 

  • Ozanne SE, Smith GD, Tikerpae J, Hales CN (1996b) Altered regulation of hepatic glucose output in the male offspring of protein-malnourished rat dams. Am J Phys 270:E559–E564

    CAS  Google Scholar 

  • Petrik J, Reusens B, Arany E, Remacle C, Coelho C, Hoet JJ, Hill DJ (1999) A low protein diet alters the balance of islet cell replication and apoptosis in the fetal and neonatal rat and is associated with a reduced pancreatic expression of insulin-like growth factor-II. Endocrinology 140:4861–4873

    Article  CAS  PubMed  Google Scholar 

  • Petry CJ, Ozanne SE, Hales CN (2001) Programming of intermediary metabolism. Mol Cell Endocrinol 185:81–91

    Article  CAS  PubMed  Google Scholar 

  • Phipps K, Barker DJ, Hales CN, Fall CH, Osmond C, Clark PM (1993) Fetal growth and impaired glucose tolerance in men and women. Diabetologia 36:225–228

    Article  CAS  Google Scholar 

  • Piccoli GB, Clari R, Vigotti FN, Leone F, Attini R, Cabiddu G, Mauro G, Castelluccia N, Colombi N, Capizzi I et al (2015) Vegan-vegetarian diets in pregnancy: danger or panacea? A systematic narrative review. BJOG 122:623–633

    Article  CAS  PubMed  Google Scholar 

  • Proud CG (2005) eIF2 and the control of cell physiology. Semin Cell Dev Biol 16:3–12

    Article  CAS  PubMed  Google Scholar 

  • Ravelli GP, Stein ZA, Susser MW (1976) Obesity in young men after famine exposure in utero and early infancy. N Engl J Med 295:349–353

    Article  CAS  PubMed  Google Scholar 

  • Ravelli AC, van der Meulen JH, Michels RP, Osmond C, Barker DJ, Hales CN, Bleker OP (1998) Glucose tolerance in adults after prenatal exposure to famine. Lancet 351:173–177

    Article  CAS  Google Scholar 

  • Simmons RA, Gounis AS, Bangalore SA, Ogata ES (1992) Intrauterine growth retardation: fetal glucose transport is diminished in lung but spared in brain. Pediatr Res 31:59–63

    Article  CAS  PubMed  Google Scholar 

  • Sohi G, Weese K, Revesz A, Arany E, Hardy DB (2011) Maternal protein restriction elevates cholesterol in adult rat offspring due to repressive changes in histone modifications at the cholesterol 7α-hydroxylase promoter. Mol Endocrinol 25(5):785–798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sohi G, Revesz A, Hardy DB (2013) Nutritional mismatch in postnatal life of low birth weight rat offspring leads to increased phosphorylation of hepatic eukaryotic initiation factor 2α in adulthood. Metabolism 62(10):1367–1374

    Article  CAS  PubMed  Google Scholar 

  • Sohi G, Barry E, Velenosi TJ, Urquhart BL, Hardy DB (2014) Nutritional mismatch in postnatal life of low birth weight rat offspring leads to elevated hepatic Cyp3a and Cyp2c activity in adulthood. Drug Metab Dispos 42:221–228

    Article  CAS  PubMed  Google Scholar 

  • Sohi G, Revesz A, Ramkumar J, Hardy DB (2015) Higher hepatic miR-29 expression in undernourished male rats during the postnatal period targets the long-term repression of IGF-1. Endocrinology 156:3069–3076

    Article  CAS  PubMed  Google Scholar 

  • Spoelstra MN, Mari A, Mendel M, Senga E, van Rheenen P, van Dijk TH, Reijngoud D-J, Zegers RGT, Heikens GT, Bandsma RHJ (2012) Kwashiorkor and marasmus are both associated with impaired glucose clearance related to pancreatic β-cell dysfunction. Metabolism 61:1224–1230

    Article  CAS  PubMed  Google Scholar 

  • Su Y, Jiang X, Li Y, Li F, Cheng Y, Peng Y, Song D, Hong J, Ning G, Cao Y et al (2016) Maternal low protein isocaloric diet suppresses pancreatic β-cell proliferation in mouse offspring via miR-15b. Endocrinology 157:4782–4793

    Article  CAS  PubMed  Google Scholar 

  • Tarry-Adkins JL, Chen JH, Smith NS, Jones RH, Cherif H, Ozanne SE (2009) Poor maternal nutrition followed by accelerated postnatal growth leads to telomere shortening and increased markers of cell senescence in rat islets. FASEB J 23:1521–1528

    Article  CAS  PubMed  Google Scholar 

  • Vo T, Revesz A, Ma N, Hardy DB (2013) Maternal protein restriction leads to enhanced hepatic gluconeogenic gene expression in adult male rat offspring due to impaired expression of the liver x receptor. J Endocrinol 218:85–97

    Article  CAS  PubMed  Google Scholar 

  • Williams SJ, Campbell ME, McMillen IC, Davidge ST (2005) Differential effects of maternal hypoxia or nutrient restriction on carotid and femoral vascular function in neonatal rats. Am J Physiol Integr Comp Physiol 288:R360–R367

    Article  CAS  Google Scholar 

  • Zhang T, Guan H, Arany E, Hill DJ, Yang K (2007) Maternal protein restriction permanently programs adipocyte growth and development in adult male rat offspring. J Cell Biochem 101:381–388

    Article  CAS  PubMed  Google Scholar 

  • Zheng S, Rollet M, Pan Y-X (2012) Protein restriction during gestation alters histone modifications at the glucose transporter 4 (GLUT4) promoter region and induces GLUT4 expression in skeletal muscle of female rat offspring. J Nutr Biochem 23:1064–1071

    Article  CAS  Google Scholar 

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Acknowledgements

Canadian Institutes for Health Research Operating Grant and Natural Sciences and Engineering Research Council of Canada Operating Grant.

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Authors and Affiliations

  1. The Department of Physiology and Pharmacology, The University of Western Ontario, London, ON, N6A 5C1, Canada

    Shelby L. Oke

  2. The Departments of Obstetrics and Gynecology and Physiology and Pharmacology, The Children’s Health Research Institute and the Lawson Health Research Institute, The University of Western Ontario, London, ON, N6A 5C1, Canada

    Daniel B. Hardy

Authors
  1. Shelby L. Oke
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Correspondence to Daniel B. Hardy .

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Editors and Affiliations

  1. Diabetes & Nutritional Sci Div Sch, King's College London, London, United Kingdom

    Victor Preedy

  2. Clinical Biochemistry, University of Westminster, Westminster, United Kingdom

    Vinood B. Patel

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Oke, S.L., Hardy, D.B. (2017). Effects of Protein Deficiency on Perinatal and Postnatal Health Outcomes. In: Preedy, V., Patel, V. (eds) Handbook of Famine, Starvation, and Nutrient Deprivation. Springer, Cham. https://doi.org/10.1007/978-3-319-40007-5_61-1

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  • DOI: https://doi.org/10.1007/978-3-319-40007-5_61-1

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  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-40007-5

  • Online ISBN: 978-3-319-40007-5

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