The global obesity pandemic is often causally linked to marked changes in diet and lifestyle, namely marked increases in dietary intakes of high-energy diets and concomitant reductions in physical activity levels. However, far less attention has been paid to the role of developmental plasticity and alterations in phenotypic outcomes resulting from environmental perturbations during the early-life period. Human and animal studies have highlighted the link between alterations in the early-life environment and increased susceptibility to obesity and related metabolic disorders in later life. In particular, altered maternal nutrition, including both undernutrition and maternal obesity, has been shown to lead to transgenerational transmission of metabolic disorders. This association has been conceptualised as the developmental programming hypothesis whereby the impact of environmental influences during critical periods of developmental plasticity can elicit lifelong effects on the physiology of the offspring. Further, evidence to date suggests that this developmental programming is a transgenerational phenomenon, with a number of studies showing transmission of programming effects to subsequent generations, even in the absence of continued environmental stressors, thus perpetuating a cycle of obesity and metabolic disorders. The mechanisms responsible for these transgenerational effects remain poorly understood; evidence to date suggests a number of potential mechanisms underpinning the transgenerational transmission of the developmentally programmed phenotype through both the maternal and paternal
lineage. Transgenerational phenotype transmission is often seen as a form of epigenetic inheritance with evidence showing both germline and somatic inheritance of epigenetic modifications leading to phenotype changes across generations. However, there is also evidence for non-genomic components as well as an interaction between the developing fetus with the in utero environment in the perpetuation of programmed phenotypes. A better understanding of how developmental programming effects are transmitted is essential for the implementation of initiatives aimed at curbing the current obesity crisis.
Obesity is often attributed to a Western lifestyle, a high-fat diet and decreased activity. While these factors certainly contribute to adult obesity, compelling data from our laboratory and others indicate that this explanation is oversimplified. Recent studies strongly argue that maternal/fetal under- or overnutrition predisposes the offspring to become hyperphagic and increases the risk of later obesity. Both infants small for gestational age (SGA) or infants born to obese mothers who consume a high-fat diet are at a markedly increased risk of adult obesity. Specific alterations in the fetal metabolic/energy environment directly influence the development of appetite regulatory pathways. Specifically, SGA infants demonstrate (1) impaired satiety and anorexigenic cell signaling, (2) enhanced cellular orexigenic responses, (3) programmed dysfunction of neuroprogenitor cell proliferation/ differentiation, and (4) increased expression of appetite (NPY) versus satiety (POMC) neurons. In both hypothalamic tissue and ex vivo culture, SGA newborns exhibit increased levels of the nutrient sensor SIRT1, signifying reduced energy, whereas maternal high-fat-exposed newborns exhibit reduced levels of pAMPK, signifying energy excess. Via downstream regulation of bHLH neuroproliferation (Hes1) and neurodifferentiation factors (Mash1, Ngn3), neurogenesis is biased toward orexigenic and away from anorexigenic neurons, resulting in excess appetite, reduced satiety and development of obesity. Despite the developmental programming of appetite neurogenesis, the potential for neuronal remodeling raises the opportunity for novel interventions.
Data from 3 recently completed studies were pooled and analyzed to answer the question whether breastfed infants of overweight/obese mothers show accelerated growth. It was shown that these infants gain weight faster than indicated by the WHO standards and that they grow significantly faster than infants of lean mothers. The question whether fast infant growth can be slowed down by lowering the protein content of formulas was examined. It was shown that formulas with a protein content that is just moderately above that of human milk support normal growth while significantly slowing down fast growth.
The conventional aetiological model of obesity and diabetes proposes a genetic predisposition and a precipitation by an unhealthy adult lifestyle. This hypothesis was challenged by David Barker who proposed that the intrauterine environment influences the risk of non-communicable diseases (NCDs). The original idea was based on fetal undernutrition because lower birth weight was associated with a higher risk of diabetes and heart disease. However, soon it was clear that the association was U shaped, and that the increased risk in large babies was driven by maternal obesity and diabetes. A number of human and animal studies have refined our ideas of ‘fetal programming’, which is now thought to be related to acquired chemical changes in DNA (methylation), histones (acetylation and other) and the role of non-coding miRNAs. Maternal nutritional disturbances are the major programming stimulus, in addition to a deranged metabolism, infections, maternal stress, extreme atmospheric temperature, etc. The first demonstration of a link between fetal ‘starvation’ and future ill-health was in the Dutch Hunger Winter studies. In the prospective Pune Maternal Nutrition Study, we found that small and thin Indian babies were more adipose compared to larger English babies, and their higher risk of future diabetes was reflected in higher insulin and leptin and lower adiponectin concentrations in the cord blood. This phenotype was partly related to a deranged 1-carbon metabolism due to an imbalance in vitamin B 12 (low) and folate (high) nutrition, which was also related to insulin resistance in the offspring. Maternal obesity and diabetes have made an increasing contribution to childhood obesity and diabetes at a young age. This was prominently shown in Pima Indians but is now obvious in all other populations. The best window of opportunity to prevent fetal programming of NCDs is in the periconceptional period. This is the period when gametogenesis, fertilisation, implantation, embryogenesis and placentation occur. Improving the nutrition and the health of young girls could make a substantial contribution to reducing the rapidly rising epidemic of NCDs in the world. This is referred to as ‘primordial’ prevention.