Elsevier

Physiology & Behavior

Volume 88, Issue 3, 30 June 2006, Pages 234-243
Physiology & Behavior

Mechanisms by which poor early growth programs type-2 diabetes, obesity and the metabolic syndrome

https://doi.org/10.1016/j.physbeh.2006.05.039Get rights and content

Abstract

Fetal programming is gaining momentum as a highly documented phenomenon which links poor early growth to adult disease. It is backed up by large cohorts in epidemiological studies worldwide and has been tested in various animal models. The root causes of programming link closely with maternal condition during pregnancy, and therefore the fetal environment. Suboptimal fetal environments due to poor or inadequate nutrition, infection, anemia, hypertension, inflammation, gestational diabetes or hypoxia in the mother expose the fetus to hormonal, growth factor, cytokine or adipokine cues. These in turn act to alter metabolic, immune system, vascular, hemodynamics, renal, growth and mitochondrial parameters respectively and most evidently in the later stages of life where they impact on the individual as poor glucose homeostasis, insulin resistance, type 2 diabetes, hypertension, cardiovascular disease, obesity and heart disease. These events are compounded by over-nutrition or lifestyle choices which are in conflict with the programming of the fetus. We and others have utilised various species to test the early life programming hypothesis and to identify key molecular mechanisms. With parallel studies of human cohorts, these molecular markers can be validated as realistic targets for intervention.

Introduction

With over 50 references cited in PubMed when “fetal programming” is used as a search descriptor, it is clearly evident that research in this field is burgeoning and the list of pathologies linked to it is ever increasing. The nature of fetal programming is such that it is involved in many disease phenotypes, both for the in-utero affected individual and, as is emerging, that of succeeding generations. Nevertheless, this review will attempt to summarise the extent of the problems encountered when an organism develops in a suboptimal environment, which it perceives it will meet ex-utero, but then goes on to grow in adequate or better conditions.

Section snippets

Epidemiological basis of fetal programming effects

Many studies have revealed links between poor early human growth and susceptibility to type 2 diabetes, insulin resistance, cardiovascular disease, obesity and cancer. For a long time, the markers used to define poor early growth have been relatively crude indices based on birth weight, length, abdominal and head circumference as well as placental weight and the various relative indices. However, there are still no means to measure if a newborn has attained its full growth potential in-utero.

Animal models

The modeling of fetal growth restriction and adult disease in animals has been employed to study the underlying mechanisms of disease at the molecular level. The majority of these are based on work with rodents, although larger species such as sheep and pigs have also been used. Recent studies in sheep have shown that maternal nutrient restriction over the period of maximal placental growth, i.e. between 28 and 80 days gestation, resulted in offspring with more adipose tissue. In this tissue,

Common mechanisms

The Thrifty Phenotype hypothesis and the vast experimental evidence supporting it has led to the search for a common mechanism by which all the disparate intrauterine insults go on to exert effects on various different physiological systems in the offspring. This has spawned two main mechanistic theories. Fowden et al. [112] reviewed from the literature a common postnatal outcome for the various experimental intrauterine conditions, i.e. alterations in cortiscosterone/cortisol and or ACTH

Future directions

A range of animal models have been used to dissect (i) the maternal milieu which directs fetal programming and (ii) the molecular mechanisms which are adversely altered in the metabolic syndrome. There is increasing opinion that phenotypic adjustments brought about by fetal programming are inherited. This is supported by inter-generational studies showing that the effects of an adverse fetal environment influence both the offsprings' birthweight and glucose tolerance and that of the next

Intervention strategies

Although it is undisputed that a suboptimal maternal diet, smoking and stress have adverse effects for the fetus, these are difficult to address successfully. One of the most immediate and intuitive measures would be to ensure adequate maternal nutrition throughout pregnancy and lactation; however, it is important that any dietary enhancement in the mother should promote lean and not fat mass. Fat intake during pregnancy has been shown to correlate with the incidence of gestational diabetes

References (127)

  • P. Haggarty et al.

    Placental nutrient transfer capacity and fetal growth

    Placenta

    (2002)
  • L.H. Allen

    Biological mechanisms that might underlie iron's effects on fetal growth and preterm birth

    J Nutr

    (2001)
  • R. Benediktsson et al.

    Glucocorticoid exposure in utero: new model for adult hypertension

    Lancet

    (1993)
  • S.A. Brown et al.

    Development of cholesterol homeostatic memory in the rat is influenced by maternal diets

    Metabolism

    (1990)
  • F. Guo et al.

    High-fat feeding during pregnancy and lactation affects offspring metabolism in rats

    Physiol Behav

    (1995)
  • A.J. Buckley et al.

    Altered body composition and metabolism in the male offspring of high fat-fed rats

    Metabolism

    (2005)
  • S.E. Ozanne et al.

    Ketosis resistance in the male offspring of protein-malnourished rat dams

    Metabolism

    (1998)
  • K.M. Godfrey et al.

    Fetal programming and adult health

    Public Health Nutr

    (2001)
  • D.J. Barker et al.

    Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth

    Diabetologia

    (1993)
  • J.G. Eriksson et al.

    Catch-up growth in childhood and death from coronary heart disease: longitudinal study

    BMJ

    (1999)
  • T. Forsen et al.

    Growth in utero and during childhood among women who develop coronary heart disease: longitudinal study

    BMJ

    (1999)
  • D.A. Leon et al.

    Reduced fetal growth rate and increased risk of death from ischaemic heart disease: cohort study of 15 000 Swedish men and women born 1915–29

    BMJ

    (1998)
  • J. Laitinen et al.

    Predictors of abdominal obesity among 31-y-old men and women born in Northern Finland in 1966

    Eur J Clin Nutr

    (2004)
  • N.M. Leong et al.

    Early life risk factors in cancer: the relation of birth weight to adult obesity

    Int J Cancer

    (2003)
  • K. Innes et al.

    Birth characteristics and subsequent risk for breast cancer in very young women

    Am J Epidemiol

    (2000)
  • M. Sanderson et al.

    Perinatal factors and risk of breast cancer

    Epidemiology

    (1996)
  • C.N. Hales et al.

    Fetal and infant growth and impaired glucose tolerance at age 64

    BMJ

    (1991)
  • C.N. Hales et al.

    Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis

    Diabetologia

    (1992)
  • C.N. Hales et al.

    The thrifty phenotype hypothesis

    Br Med Bull

    (2001)
  • S. Bo et al.

    Low birthweight and metabolic abnormalities in twins with increased susceptibility to Type 2 diabetes mellitus

    Diabet Med

    (2000)
  • P. Poulsen et al.

    Heritability of type II (non-insulin-dependent) diabetes mellitus and abnormal glucose tolerance—a population-based twin study

    Diabetologia

    (1999)
  • C.A. Newsome et al.

    Is birth weight related to later glucose and insulin metabolism?—A systematic review

    Diabet Med

    (2003)
  • R.S. Lindsay et al.

    Currently identified genes affecting insulin resistance are not associated with birth weight in the Pima population

    Diabet Med

    (2002)
  • J. Eriksson et al.

    The effects of the Pro12Ala polymorphism of the PPARgamma-2 gene on lipid metabolism interact with body size at birth

    Clin Genet

    (2003)
  • C.J. Petry et al.

    Common polymorphism in H19 associated with birthweight and cord blood IGF-II levels in humans

    BMC Genet

    (2005)
  • D. Habek et al.

    Fetal tobacco syndrome and perinatal outcome

    Fetal Diagn Ther

    (2002)
  • K.K. Ong et al.

    Size at birth and early childhood growth in relation to maternal smoking, parity and infant breast-feeding: longitudinal birth cohort study and analysis

    Pediatr Res

    (2002)
  • S.M. Montgomery et al.

    Smoking during pregnancy and diabetes mellitus in a British longitudinal birth cohort

    BMJ

    (2002)
  • A.M. Toschke et al.

    Maternal smoking during pregnancy and appetite control in offspring

    J Perinat Med

    (2003)
  • S.M. Montgomery et al.

    Smoking during pregnancy and bulimia nervosa in offspring

    J Perinat Med

    (2005)
  • T.O. Scholl et al.

    Anemia and iron-deficiency anemia: compilation of data on pregnancy outcome

    Am J Clin Nutr

    (1994)
  • G. Moreu et al.

    Relationship between maternal periodontal disease and low-birth-weight pre-term infants

    J Clin Periodontol

    (2005)
  • V.A. Dewyea et al.

    Asthma in pregnancy

    Allergy Asthma Proc

    (2005)
  • J. Bispham et al.

    Maternal nutritional programming of fetal adipose tissue development: differential effects on messenger ribonucleic acid abundance for uncoupling proteins and peroxisome proliferator-activated and prolactin receptors

    Endocrinology

    (2005)
  • B.S. Muhlhausler et al.

    Impact of glucose infusion on the structural and functional characteristics of adipose tissue and on hypothalamic gene expression for appetite regulatory neuropeptides in the sheep fetus during late gestation

    J Physiol

    (2005)
  • D.S. Gardner et al.

    Programming of glucose–insulin metabolism in adult sheep after maternal undernutrition

    Am J Physiol Regul Integr Comp Physiol

    (2005)
  • K.R. Poore et al.

    The effect of birth weight on hypothalamo–pituitary–adrenal axis function in juvenile and adult pigs

    J Physiol

    (2003)
  • K.R. Poore et al.

    The effect of birth weight on glucose tolerance in pigs at 3 and 12 months of age

    Diabetologia

    (2002)
  • K.R. Poore et al.

    Insulin sensitivity in juvenile and adult Large White pigs of low and high birthweight

    Diabetologia

    (2004)
  • H.B. Corstius et al.

    Effect of intrauterine growth restriction on the number of cardiomyocytes in rat hearts

    Pediatr Res

    (2005)
  • Cited by (0)

    View full text