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