Hungry in the womb: what are the consequences? Lessons from the Dutch famine.
TL;DR: The finding that the effects of prenatal famine exposure may reach down across generations, possibly through epigenetic mechanisms, may be a promising strategy in preventing chronic diseases worldwide.
About: This article is published in Maturitas.The article was published on 2011-10-01. It has received 400 citations till now. The article focuses on the topics: Famine.
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TL;DR: Given the substantial burden of obesity and diabetes mellitus, future research efforts should adopt a translational approach to find sustainable and holistic solutions in preventing these costly diseases.
Abstract: Obesity and diabetes mellitus have reached epidemic proportions in the past few years. During 2011 to 2012, more than one-third of the US population was obese. Although recent trend data indicate that the epidemic has leveled off, prevalence of abdominal obesity continues to rise, especially among adults. As seen for obesity, the past few decades have seen a doubling of the diabetes mellitus incidence with an increasing number of type 2 diabetes mellitus cases being diagnosed in children. Significant racial and ethnic disparities exist in the prevalence and trends of obesity and diabetes mellitus. In general, in both adults and children, non-Hispanic blacks and Mexican Americans seem to be at a high risk than their non-Hispanic white counterparts. Secular changes in agricultural policies, diet, food environment, physical activity, and sleep have all contributed to the upward trends in the diabesity epidemic. Despite marginal improvements in physical activity and the US diet, the food environment has changed drastically to an obesogenic one with increased portion sizes and limited access to healthy food choices especially for disadvantaged populations. Interventions that improve the food environment are critical as both obesity and diabetes mellitus raise the risk of cardiovascular disease by ≈2-fold. Among those with type 2 diabetes mellitus, significant sex differences occur in the risk of cardiovascular disease such that diabetes mellitus completely eliminates or attenuates the advantages of being female. Given the substantial burden of obesity and diabetes mellitus, future research efforts should adopt a translational approach to find sustainable and holistic solutions in preventing these costly diseases.
590 citations
TL;DR: The role of the gut microbiota in energy harvest and fat storage is explored, as well as differences in the microbiota in obesity and undernutrition are explored.
Abstract: Malnutrition may manifest as either obesity or undernutrition. Accumulating evidence suggests that the gut microbiota plays an important role in the harvest, storage, and expenditure of energy obtained from the diet. The composition of the gut microbiota has been shown to differ between lean and obese humans and mice; however, the specific roles that individual gut microbes play in energy harvest remain uncertain. The gut microbiota may also influence the development of conditions characterized by chronic low-level inflammation, such as obesity, through systemic exposure to bacterial lipopolysaccharide derived from the gut microbiota. In this review, the role of the gut microbiota in energy harvest and fat storage is explored, as well as differences in the microbiota in obesity and undernutrition.
550 citations
Cites background from "Hungry in the womb: what are the co..."
...Furthermore, the exposure to undernutrition in utero may lead to large and long-term negative mental and physical sequelae.(88) Although food availability, socioeconomic factors, and genetics influence the development of undernutrition, the underlying mechanisms remain poorly defined....
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TL;DR: An overview of the evidence-base showing that indicators of nutritional deficit in pregnancy are associated with a greater risk of type-2 diabetes and cardiovascular mortality is provided and the observation that traits programmed by nutritional exposures in foetal life can be transmitted to further generations adds weight the argument that heritable epigenetic modifications play a critical role in nutritional programming.
Abstract: Foetal development and infancy are life stages that are characterised by rapid growth, development and maturation of organs and systems. Variation in the quality or quantity of nutrients consumed by mothers during pregnancy, or infants during the first year of life, can exert permanent and powerful effects upon developing tissues. These effects are termed 'programming' and represent an important risk factor for noncommunicable diseases of adulthood, including the metabolic syndrome and coronary heart disease. This narrative review provides an overview of the evidence-base showing that indicators of nutritional deficit in pregnancy are associated with a greater risk of type-2 diabetes and cardiovascular mortality. There is also a limited evidence-base that suggests some relationship between breastfeeding and the timing and type of foods used in weaning, and disease in later life. Many of the associations reported between indicators of early growth and adult disease appear to interact with specific genotypes. This supports the idea that programming is one of several cumulative influences upon health and disease acting across the lifespan. Experimental studies have provided important clues to the mechanisms that link nutritional challenges in early life to disease in adulthood. It is suggested that nutritional programming is a product of the altered expression of genes that regulate the cell cycle, resulting in effective remodelling of tissue structure and functionality. The observation that traits programmed by nutritional exposures in foetal life can be transmitted to further generations adds weight the argument that heritable epigenetic modifications play a critical role in nutritional programming.
349 citations
TL;DR: Ten genetically elucidated obesity syndromes are summarized and suggestions on how high-throughput '-omic' data can be integrated in order to get closer to the new age of personalized medicine are provided.
Abstract: In high-, middle- and low-income countries, the rising prevalence of obesity is the underlying cause of numerous health complications and increased mortality. Being a complex and heritable disorder, obesity results from the interplay between genetic susceptibility, epigenetics, metagenomics and the environment. Attempts at understanding the genetic basis of obesity have identified numerous genes associated with syndromic monogenic, non-syndromic monogenic, oligogenic and polygenic obesity. The genetics of leanness are also considered relevant as it mirrors some of obesity's aetiologies. In this report, we summarize ten genetically elucidated obesity syndromes, some of which are involved in ciliary functioning. We comprehensively review 11 monogenic obesity genes identified to date and their role in energy maintenance as part of the leptin-melanocortin pathway. With the emergence of genome-wide association studies over the last decade, 227 genetic variants involved in different biological pathways (central nervous system, food sensing and digestion, adipocyte differentiation, insulin signalling, lipid metabolism, muscle and liver biology, gut microbiota) have been associated with polygenic obesity. Advances in obligatory and facilitated epigenetic variation, and gene-environment interaction studies have partly accounted for the missing heritability of obesity and provided additional insight into its aetiology. The role of gut microbiota in obesity pathophysiology, as well as the 12 genes associated with lipodystrophies is discussed. Furthermore, in an attempt to improve future studies and merge the gap between research and clinical practice, we provide suggestions on how high-throughput '-omic' data can be integrated in order to get closer to the new age of personalized medicine.
289 citations
TL;DR: It is demonstrated that maternal BPA exposure during late stages of oocyte development and early stages of embryonic development significantly disrupted imprinted gene expression in embryonic day 9.5 and 12.5 embryos and placentas, and epigenetic defects were associated with abnormal placental development.
Abstract: Exposure to endocrine disruptors is associated with developmental defects. One compound of concern, to which humans are widely exposed, is bisphenol A (BPA). In model organisms, BPA exposure is linked to metabolic disorders, infertility, cancer, and behavior anomalies. Recently, BPA exposure has been linked to DNA methylation changes, indicating that epigenetic mechanisms may be relevant. We investigated effects of exposure on genomic imprinting in the mouse as imprinted genes are regulated by differential DNA methylation and aberrant imprinting disrupts fetal, placental, and postnatal development. Through allele-specific and quantitative real-time PCR analysis, we demonstrated that maternal BPA exposure during late stages of oocyte development and early stages of embryonic development significantly disrupted imprinted gene expression in embryonic day (E) 9.5 and 12.5 embryos and placentas. The affected genes included Snrpn, Ube3a, Igf2, Kcnq1ot1, Cdkn1c, and Ascl2; mutations and aberrant regulation of these genes are associated with imprinting disorders in humans. Furthermore, the majority of affected genes were expressed abnormally in the placenta. DNA methylation studies showed that BPA exposure significantly altered the methylation levels of differentially methylated regions (DMRs) including the Snrpn imprinting control region (ICR) and Igf2 DMR1. Moreover, exposure significantly reduced genome-wide methylation levels in the placenta, but not the embryo. Histological and immunohistochemical examinations revealed that these epigenetic defects were associated with abnormal placental development. In contrast to this early exposure paradigm, exposure outside of the epigenetic reprogramming window did not cause significant imprinting perturbations. Our data suggest that early exposure to common environmental compounds has the potential to disrupt fetal and postnatal health through epigenetic changes in the embryo and abnormal development of the placenta.
251 citations
Cites background from "Hungry in the womb: what are the co..."
...The hypothesis has been supported by a growing number of human diseases associated with unfortunate events during pregnancy including drug exposure [2], chemical exposure [3], prenatal stress [4], and maternal caloric restriction [5]....
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References
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TL;DR: It is shown that individuals who were prenatally exposed to famine during the Dutch Hunger Winter in 1944–45 had, 6 decades later, less DNA methylation of the imprinted IGF2 gene compared with their unexposed, same-sex siblings.
Abstract: Extensive epidemiologic studies have suggested that adult disease risk is associated with adverse environmental conditions early in development. Although the mechanisms behind these relationships are unclear, an involvement of epigenetic dysregulation has been hypothesized. Here we show that individuals who were prenatally exposed to famine during the Dutch Hunger Winter in 1944-45 had, 6 decades later, less DNA methylation of the imprinted IGF2 gene compared with their unexposed, same-sex siblings. The association was specific for periconceptional exposure, reinforcing that very early mammalian development is a crucial period for establishing and maintaining epigenetic marks. These data are the first to contribute empirical support for the hypothesis that early-life environmental conditions can cause epigenetic changes in humans that persist throughout life.
2,723 citations
TL;DR: In national samples of 10 year olds and adults in Britain systolic blood pressure was inversely related to birth weight, which suggests that the intrauterine environment influences blood pressure during adult life.
Abstract: In national samples of 9921 10 year olds and 3259 adults in Britain systolic blood pressure was inversely related to birth weight. The association was independent of gestational age and may therefore be attributed to reduced fetal growth. This suggests that the intrauterine environment influences blood pressure during adult life. It is further evidence that the geographical differences in average blood pressure and mortality from cardiovascular disease in Britain partly reflect past differences in the intrauterine environment. Within England and Wales 10 year olds living in areas with high cardiovascular mortality were shorter and had higher resting pulse rates than those living in other areas. Their mothers were also shorter and had higher diastolic blood pressures. This suggests that there are persisting geographical differences in the childhood environment that predispose to differences in cardiovascular mortality.
2,233 citations
TL;DR: Testing the hypothesis that prenatal and early postnatal nutrition determines subsequent obesity found that exposure during the last trimester of pregnancy and the first months of life is consistent with the inference that nutritional deprivation affected a critical period of development for adipose-tissue cellularity.
Abstract: In a historical cohort study of 300,000 19-year-old men exposed to the Dutch famine of 1944-45 and examined at military induction, we tested the hypothesis that prenatal and early postnatal nutrition determines subsequent obesity. Outcomes were opposite depending on the time of exposure. During the last trimester of pregnancy and the first months of life, exposure produced significantly lower obesity rates (P less than 0.005). This result is consistent with the inference that nutritional deprivation affected a critical period of development for adipose-tissue cellularity. During the first half of pregnancy, however, exposure resulted in significantly higher obesity rates (P less than 0.0005). This observation is consistent with the inference that nutritional deprivation affected the differentiation of hypothalamic centers regulating food intake and growth, and that subsequent increased food availability produced an accumulation of excess fat in an organism growing to its predetermined maximum size.
1,548 citations
"Hungry in the womb: what are the co..." refers background in this paper
...However, men exposed to famine in early gestation were more likely to be obese, whereas those exposed in late gestation were less likely to be obese [6]....
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TL;DR: Prenatal exposure to famine, especially during late gestation, is linked to decreased glucose tolerance in adults, and this effect of famine on glucose tolerance is especially important in people who become obese as adults.
1,402 citations
TL;DR: Maternal malnutrition during early gestation was associated with higher BMI and waist circumference in 50-y-old women but not in men, and pertubations of central endocrine regulatory systems established in early gestation may contribute to the development of abdominal obesity in later life.
1,070 citations