Individuals exposed to high-fat, high-sugar diets before birth have an increased risk of obesity in later life. Recent studies have shown that these offspring exhibit increased preference for fat, leading to suggestions that perinatal exposure to high-fat, high-sugar foods results in permanent changes within the central reward system that increase the subsequent drive to overconsume palatable foods. The present study has determined the effect of a maternal "junk-food" diet on the expression of key components of the mesolimbic reward pathway in the offspring of rat dams at 6 wk and 3 mo of age. We show that offspring of junk-food-fed (JF) dams exhibit higher fat intake from weaning until at least 3 mo of age (males: 16 ± 0.6 vs. 11 ± 0.8 g/kg/d; females: 19 ± 1.3 vs. 13 ± 0.4 g/kg/d; P<0.01). mRNA expression of μ-opioid receptor (Mu) was 1.6-fold higher (P<0.01) and dopamine active transporter (DAT) was 2-fold lower (P<0.05) in JF offspring at 6 wk of age. By 3 mo, these differences were reversed, and Mu mRNA expression was 2.8-fold lower (P<0.01) and DAT mRNA expression was 1.9-fold higher (P<0.01) in the JF offspring. These findings suggest that perinatal exposure to high-fat, high-sugar diets results in altered development of the central reward system, resulting in increased fat intake and altered response of the reward system to excessive junk-food intake in postnatal life.

Individuals exposed to an increased nutrient supply before birth have a high risk of becoming obese children and adults. It has been proposed that exposure of the fetus to high maternal nutrient intake results in permanent changes within the central appetite regulatory network. No studies, however, have investigated the impact of increased maternal nutrition on the appetite regulatory network in species in which this network develops before birth, as in the human. In the present study, pregnant ewes were fed a diet which provided 100% (control, n = 8) or approximately 160% (well-fed, n = 8) of metabolizable energy requirements. Ewes were allowed to lamb spontaneously, and lambs were sacrificed at 30 days of postnatal age. All fat depots were dissected and weighed, and expression of the appetite-regulating neuropeptides and the leptin receptor (OBRb) were determined by in situ hybridization. Lambs of well-fed ewes had higher glucose (Glc) concentrations during early postnatal life (F = 5.93, P<0.01) and a higher relative subcutaneous (s.c.) fat mass at 30 days of age (34.9+/-4.7 g/kg vs. 22.8+/-3.3 g/kg; P<0.05). The hypothalamic expression of pro-opiomelanocortin was higher in lambs of well-fed ewes (0.48+/-0.09 vs. 0.28+/-0.04, P<0.05). In lambs of overnourished mothers, but not in controls, the expression of OBRb was inversely related to total relative fat mass (r2 = 0.50, P = 0.05, n = 8), and the direct relationship between the expression of the central appetite inhibitor CART and fat mass was lost. The expression of neuropeptide Y and AGRP was inversely related to total relative fat mass (NPY, r2 = 0.28, P<0.05; agouti-related peptide, r2 = 0.39, P<0.01). These findings suggest that exposure to increased nutrition before birth alters the responses of the central appetite regulatory system to signals of increased adiposity after birth.

Over the past two decades, there has been a marked shift in the fatty acid composition of the diets of industrialized nations towards increased intake of the n-6 fatty acid linoleic acid (LA, 18:2n-6), largely as a result of the replacement of saturated fats with plant-based polyunsaturated fatty acid (PUFA). While health agencies internationally continue to advocate for high n-6 PUFA intake combined with increased intakes of preformed n-3 long-chain PUFAs (LCPUFA) docosahexaenoic acid (DHA, 22:6n-3) and eicosapentaenoic acid (EPA, 20:5n-3) to reduce the incidence of cardiovascular disease (CVD), there are questions as to whether this is the best approach. LA competes with alpha-linolenic acid (18:3n-3) for endogenous conversion to the LC derivatives EPA and DHA, and LA also inhibits incorporation of DHA and EPA into tissues. Thus, high-LA levels in the diet generally result in low n-3 LCPUFA status. Pregnancy and infancy are developmental periods during which the fatty acid supply is particularly critical. The importance of an adequate supply of n-3 LCPUFA for ensuring optimal development of infant brain and visual systems is well established, and there is now evidence that the supply of n-3 LCPUFA also influences a range of growth, metabolic and immune outcomes in childhood. This review will re-evaluate the health benefits of modern Western diets and pose the question of whether the introduction of similar diets to nations with emerging economies is the most prudent public health strategy for improving health in these populations.

The 'developmental origins of adult health and disease' hypothesis stated that environmental factors, particularly maternal undernutrition, act in early life to programme the risks for adverse health outcomes, such as cardiovascular disease, obesity and the metabolic syndrome in adult life. Early physiological tradeoffs, including activation of the foetal hypothalamo-pituitary-adrenal (HPA) axis, confer an early fitness advantage such as foetal survival, while incurring delayed health costs. We review the evidence that such tradeoffs are anticipated from conception and that the periconceptional nutritional environment can programme the developmental trajectory of the stress axis and the systems that maintain and regulate arterial blood pressure. There is also evidence that restriction of placental growth and function, results in an increased dependence of the maintenance of arterial blood pressure on the sequential recruitment of the sympathetic nervous system and HPA axis. While the 'early origins of adult disease' hypothesis has focussed on the impact of maternal undernutrition, an increase in maternal nutritional intake and in maternal body mass intake has become more prevalent in developed countries. Exposure to overnutrition in foetal life results in a series of central and peripheral neuroendocrine responses that in turn programme development of the fat cell and of the central appetite regulatory system. While the physiological responses to foetal undernutrition result in the physiological trade off between foetal survival and poor health outcomes that emerge after reproductive senescence, exposure to early overnutrition results in poor health outcomes that emerge in childhood and adolescence. Thus, the effects of early overnutrition can directly impact on reproductive fitness and on the health of the next generation. In this context, the physiological responses to relative overnutrition in early life may directly contribute to an intergenerational cycle of obesity.

During fetal life, adipose tissue is predominantly comprised of brown or thermogenic adipocytes and there is a transition to white, lipid-storing adipocytes after birth concomitant with the onset of suckling. In pregnancies complicated by gestational diabetes, the fetus is hyperglycemic, has an increased fat mass, and is at increased risk of obesity in later life. In the present study, we have investigated the hypothesis that exposure to increased maternal nutrition during late gestation results in increased expression of genes that regulate adipogenesis and lipogenesis in perirenal fat in fetal sheep. Pregnant ewes were fed either at or approximately 55% above maintenance energy requirements during late pregnancy and quantitative RT-PCR was used to measure peroxisome proliferator-activated receptor gamma, lipoprotein lipase, glycerol-3-phosphate dehydrogenase, adiponectin, and leptin mRNA expression. We report that exposure to metabolic and hormonal signals of increased nutrition before birth results in an increase in the expression of the adipogenic factor, peroxisome proliferator-activated receptor gamma, and in lipoprotein lipase, adiponectin, and leptin mRNA expression in fetal perirenal fat. We propose that an increase in maternal, and hence fetal, nutrition results in a precocial increase in adipogenic, lipogenic, and adipokine gene expression in adipose tissue and that these changes may be important in the development of obesity in later life.

Adverse conditions in early life result in increased activation of the hypothalamo-pituitary-adrenal axis and in stress responsiveness in offspring. We have developed a model in which "donor" ewes are either normally nourished or overnourished prior to a period of dietary restriction, before transfer of the embryo at 6-7 d after conception to a ewe of normal weight and nutritional history. A moderate restriction of energy intake during the periconceptional period in both normal weight and overweight ewes resulted in increased adrenal mass in male and female lambs and an increased cortisol response to stress in female lambs. The increase in adrenal weight in lambs exposed to periconceptional undernutrition was associated with a decrease in the adrenal mRNA expression of IGF2 and decreased methylation in the proximal CTCF-binding site in the differentially methylated region of the IGF2/H19 gene. Thus, weight loss in both normal and overweight mothers during the periconceptional period results in epigenetic modification of IGF2 in the adrenal gland, adrenal overgrowth, and increased vulnerability to stress in offspring. Determining the appropriate approach to weight loss in the periconceptional period may therefore be important in overweight or obese women seeking to become pregnant.

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There is an association between growing slowly before birth, accelerated growth in early postnatal life and the emergence of insulin resistance, visceral obesity and glucose intolerance in adult life. In this review we consider the pathway through which intrauterine growth restriction (IUGR) leads to the initial increase in insulin sensitivity and to catch-up growth. We also discuss the importance of the early insulin environment in determining later visceral adiposity and the intrahepatic mechanisms that may result in the emergence of glucose intolerance in a subset of IUGR infants. We present evidence that a key fetal adaptation to poor fetal nutrition is an upregulation of the abundance of the insulin receptor in the absence of an upregulation of insulin signalling in fetal skeletal muscle. After birth, however, there is an upregulation in the abundance of the insulin receptor and the insulin signalling pathway in the IUGR offspring. Thus, the origins of the accelerated postnatal growth rate experienced by IUGR infants lie in the fetal adaptations to a poor nutrient supply. We also discuss how the intracellular availability of free fatty acids and glucose within the visceral adipocyte and hepatocyte in fetal and neonatal life are critical in determining the subsequent metabolic phenotype of the IUGR offspring. It is clear that a better understanding of the relative contributions of the fetal and neonatal nutrient environment to the regulation of key insulin signalling pathways in muscle, visceral adipose tissue and the liver is required to support the development of evidence-based intervention strategies and better outcomes for the IUGR infant.