Since the first mention of fetal programming of adult health and disease, a plethora of programming events in early life has been suggested. These have included intrauterine and postnatal events, but limited attention has been given to the potential contribution of the birth process to normal physiology and long-term health. Over the last 30 years a growing number of studies have demonstrated that babies born at term by vaginal delivery (VD) have significantly different physiology at birth to those born by Caesarean section (CS), particularly when there has been no exposure to labour, i.e. pre-labour CS (PLCS). This literature is reviewed here and the processes involved in VD that might programme post-natal development are discussed. Some of the effects of CS are short term, but longer term problems are also apparent. We suggest that VD initiates important physiological trajectories and the absence of this stimulus in CS has implications for adult health. There are a number of factors that might plausibly contribute to this programming, one of which is the hormonal surge or "stress response" of VD. Given the increasing incidence of elective PLCS, an understanding of the effects of VD on normal development is crucial.

In the fetus, adipose tissue comprises both brown and white adipocytes for which brown fat is characterised as possessing the unique uncoupling protein (UCP)1. The dual characteristics of fetal fat reflect its critical role at birth in providing lipid that is mobilised rapidly following activation of UCP1 upon cold exposure to the extrauterine environment. A key stage in the maturation of fetal fat is the gradual rise in the abundance of UCP1. For species with a mature hypothalamic-pituitary axis at birth there is a gradual increase in the amount and activity of UCP1 during late gestation, in conjunction with an increase in the plasma concentrations of catecholamines, thyroid hormones, cortisol, leptin and prolactin. These may act individually, or in combination, to promote UCP1 expression and, following the post-partum surge in each hormone, UCP1 abundance attains maximal amounts.Adipose tissue grows in the fetus at a much lower rate than in the postnatal period. However, its growth is under marked nutritional constraints and, in contrast to many other fetal organs that are unaffected by nutritional manipulation, fat mass can be significantly altered by changes in maternal and, therefore, fetal nutrition. Fat deposition in the fetus is enhanced during late gestation following a previous period of nutrient restriction up to mid gestation. This is accompanied by increased mRNA abundance for the receptors of IGF-I and IGF-II. In contrast, increasing maternal nutrition in late gestation results in less adipose tissue deposition but enhanced UCP1 abundance. The pronounced nutritional sensitivity of fetal adipose tissue to both increased and decreased maternal nutrition may explain why the consequences of an adverse nutritional environment persist into later life.

Increased glucocorticoid action and adipose tissue inflammation contribute to excess adiposity. These adaptations may be enhanced in offspring exposed to nutrient restriction (NR) in utero, thereby increasing their susceptibility to later obesity. We therefore determined the developmental ontogeny of glucocorticoid receptor (GR), 11beta-hydroxysteroid dehydrogenase (11betaHSD) types 1 and 2, and uncoupling protein (UCP)-2 mRNA in perirenal adipose tissue between late gestation and 6 mo after birth in the sheep, as well as the effect of maternal NR targeted between early to mid (28-80 days, term approximately 147 days)- or late (110-147 days) gestation. GR and 11betaHSD1 mRNA increased with fat mass and were all maximal within the 6-mo observation period. 11betaHSD2 mRNA abundance demonstrated a converse decline, whereas UCP2 peaked at 30 days. GR and 11betaHSD1 mRNA abundance were strongly correlated with total and relative perirenal adipose tissue weight, and UCP2 was strongly correlated with GR and 11betaHSD1 mRNA. Early- to midgestational NR increased GR, 11betaHSD1, and UCP2 mRNA, but decreased 11betaHSD2 mRNA abundance, an adaptation reversed with late-gestational NR. We conclude that the continual rise in glucocorticoid action and fat mass after birth may underlie the development of later obesity. The magnitude of this adaptation is partly dependent on maternal food intake through pregnancy.

The present study examined the ontogeny of mitochondrial protein abundance in adipose tissue and lungs over the first month of life in the sheep and the extent to which this may be altered by maternal undernutrition during the final month of gestation. The ontogeny of uncoupling protein (UCP), voltage-dependent anion channel (VDAC) and cytochrome c abundance were determined in adipose tissue and lungs sampled from near-term fetuses and young sheep aged 4 h, 1, 7 and 30 d. In adipose tissue, the abundance of UCP1, VDAC and cytochrome c all peaked at 1 d of age and then decreased by 30 d of age, at which stage the brown adipose tissue-specific UCP1 was no longer detectable but UCP2 was clearly abundant. For the lungs, however, UCP2 and VDAC abundance both peaked 7 d after birth and then decreased by 30 d of age. During postnatal development, therefore, a marked change in mitochondrial protein abundance occurs within both adipose tissue and lungs. Maternal nutrient restriction had no effect on lamb growth or tissue weights at 30 d of age but was associated with increased abundance of UCP2 and VDAC but not cytochrome c in both adipose tissue and lungs. These mitochondrial adaptations within both adipose tissue and the lungs of offspring born to previously nutrient-restricted mothers may compromise adipose tissue and lung function during periods of environmental stress.

We investigated the influence of maternal dietary restriction between days 28 and 80 of gestation followed by re-feeding to the intake of well-fed ewes up to 140 days of gestation (term is 147 days) in sheep, on expression of mRNA for insulin-like growth factor (IGF)-I, IGF-II and growth hormone receptor (GHR) in fetal liver and skeletal muscle. Singleton bearing ewes either consumed 3·2-3·8 MJ/day of metabolisable energy (ME) (i.e. nutrient restricted -approximately 60% of ME requirements, taking into account requirements for both ewe maintenance and growth of the conceptus) or 8·7-9·9 MJ/day (i.e. well fed -approximately 150% of ME requirements) between days 28 and 80 of gestation. All ewes were then well fed (150% of ME requirements)

Human epidemiological studies have indicated that the risk of developing non-communicable diseases in later life may be related to exposures during the developmental period. Developmental life is a vulnerable period of the lifespan during which adverse environmental factors have the potential to disturb the processes of cell proliferation and differentiation or to alter patterns of epigenetic remodelling. Animal models have been instrumental in demonstrating the biological plausibility of the associations observed in human populations, providing proof of principle to the theory of the developmental origins of health and disease (DOHaD). A variety of large-and small-animal models have made important contributions to the field, providing strong evidence of a causal relationship between early-life exposures and metabolic risk factors in later life. Studies of animal models are continuing to contribute to improving the understanding of the mechanisms of the developmental origins of disease. All models have their advantages and disadvantages, and the model that is most appropriate for any particular study is hypotheses dependent. The present review aims to briefly summarise the contributions that animal models have made to the DOHaD field, before reviewing the strengths and weaknesses of these animal models. It is proposed that the integration of evidence from a variety of different models is required for the advancement of understanding within the field.

The present study examined the extent to which the late gestation rise in fetal plasma cortisol influenced adipose tissue development in the fetus. The effect of cortisol on the abundance of adipose tissue mitochondrial proteins on both the inner (i.e. uncoupling protein (UCP)1) and outer (i.e. voltage-dependent anion channel (VDAC)) mitochondrial membrane, together with the long and short forms of the prolactin receptor (PRLR) protein and leptin mRNA was determined. Perirenal adipose tissue was sampled from ovine fetuses to which (i) cortisol (2-3 mg/ day for 5 days) or saline was infused up to 127-130 days of gestation, and (ii) adrenalectomised and intact controls at between 142 and 145 days of gestation (term=148 days). UCP1 protein abundance was significantly lower in adrenalectomised fetuses compared with age-matched controls, and UCP1 was increased by cortisol infusion and with gestational age. Adrenalectomy reduced the concentration of the long form of PRLR, although this effect was only significant for the highest molecular weight isoform. In contrast, neither the short form of PRLR, VDAC protein abundance or leptin mRNA expression was significantly affected by gestational age or cortisol status. Fetal plasma triiodothyronine concentrations were increased by cortisol and with gestational age, an affect abolished by adrenalectomy. When all treatment groups were combined, both plasma cortisol and triiodothyronine concentrations were positively correlated with UCP1 protein abundance. In conclusion, an intact adrenal is necessary for the late gestation rise in UCP1 protein abundance but cortisol does not appear to have a major stimulatory role in promoting leptin expression in fetal adipose tissue. It remains to be established whether effects on UCP1 protein are directly regulated by cortisol alone or mediated by other anabolic fetal hormones such as triiodothyronine.

As the role of leptin in energy balance in neonate is unknown, we investigated the effect of acute (2 h) and chronic (7 days) administration of leptin (100 microg/day) on thermoregulation and mitochondrial protein abundance in adipose tissue. The concentration of uncoupling protein (UCP)1 and voltage-dependent anion channel (VDAC) located on the inner and outer mitochondrial membranes, respectively, were measured. Administration of leptin prevented the normal decline in colonic temperature over the first few hours and days after birth. It subsequently accelerated the loss of both mRNA and protein for UCP1 but had no effect on VDAC abundance. At seven days of age, colonic temperature was correlated strongly with both mRNA abundance and thermogenic potential of UCP1 in leptin-treated but not control lambs, indicating more effective use of UCP1 for heat production following leptin administration. Leptin had no effect on weight gain or adipose tissue deposition; at one day of age only, leptin mRNA was correlated positively with adipose tissue weight. In conclusion, leptin administration to neonatal lambs improves thermoregulation and promotes the loss of UCP1 in brown adipose tissue.