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The Wnt/β-catenin signaling pathway plays a crucial role in early embryonic development. Wnt/β-catenin signaling is a major regulator of cell proliferation and keeps embryonic stem cells (ESCs) in the pluripotent state. Dysregulation of Wnt signaling in the early developmental stages causes several hereditary diseases that lead to embryonic abnormalities. Several other signaling molecules are directly or indirectly activated in response to Wnt/β-catenin stimulation. The crosstalk of these signaling factors either synergizes or opposes the transcriptional activation of β-catenin/Tcf4-mediated target gene expression. Recently, the crosstalk between the peroxisome proliferator-activated receptor delta (PPARδ), which belongs to the steroid superfamily, and Wnt/β-catenin signaling has been reported to take place during several aspects of embryonic development. However, numerous questions need to be answered regarding the function and regulation of PPARδ in coordination with the Wnt/β-catenin pathway. Here, we have summarized the functional activation of the PPARδ in co-ordination with the Wnt/β-catenin pathway during the regulation of several aspects of embryonic development, stem cell regulation and maintenance, as well as during the progression of several metabolic disorders.

The intent of this review is to critically consider the data that support the concept of programming and its implications. Birth weight and growth trajectories during childhood are associated with cardiometabolic disease in adult life. Both extremes, low and high birth weight coupled with postnatal growth increase the early presence of cardiometabolic risk factors and vascular imprinting, crucial elements of this framework. Data coming from epigenetics, proteomics, metabolomics, and microbiota added relevant information and contribute to better understanding of mechanisms as well as development of biomarkers helping to move forward to take actions. Research has reached a stage in which sufficiently robust data calls for new initiatives focused on early life. Prevention starting early in life is likely to have a very large impact on reducing disease incidence and its associated effects at the personal, economic, and social levels.

In a previous study, we proposed that age-related mitochondrial respiration defects observed in elderly subjects are partially due to age-associated downregulation of nuclear-encoded genes, including serine hydroxymethyltransferase 2 (SHMT2), which is involved in mitochondrial one-carbon (1C) metabolism. This assertion is supported by evidence that the disruption of mouse Shmt2 induces mitochondrial respiration defects in mouse embryonic fibroblasts generated from Shmt2-knockout E13.5 embryos experiencing anaemia and lethality. Here, we elucidated the potential mechanisms by which the disruption of this gene induces mitochondrial respiration defects and embryonic anaemia using Shmt2-knockout E13.5 embryos. The livers but not the brains of Shmt2-knockout E13.5 embryos presented mitochondrial respiration defects and growth retardation. Metabolomic profiling revealed that Shmt2 deficiency induced foetal liver-specific downregulation of 1C-metabolic pathways that create taurine and nucleotides required for mitochondrial respiratory function and cell division, respectively, resulting in the manifestation of mitochondrial respiration defects and growth retardation. Given that foetal livers function to produce erythroblasts in mouse embryos, growth retardation in foetal livers directly induced depletion of erythroblasts. By contrast, mitochondrial respiration defects in foetal livers also induced depletion of erythroblasts as a consequence of the inhibition of erythroblast differentiation, resulting in the manifestation of anaemia in Shmt2-knockout E13.5 embryos.

Transmission of metabolic diseases from mother to child is multifactorial and includes genetic, epigenetic and environmental influences. Evidence in rodents, humans and non-human primates support the scientific premise that exposure to maternal obesity or high-fat diet during pregnancy creates a long-lasting metabolic signature on the infant innate immune system and the juvenile microbiota, which predisposes the offspring to obesity and metabolic diseases. In neonates, gastrointestinal microbes introduced through the mother are noted for their ability to serve as direct inducers/regulators of the infant immune system. Neonates have a limited capacity to initiate an immune response. Thus, disruption of microbial colonization during the early neonatal period results in disrupted postnatal immune responses that highlight the neonatal period as a critical developmental window. Although the mechanisms are poorly understood, increasing evidence suggests that maternal obesity or poor diet influences the development and modulation of the infant liver and other end organs through direct communication via the portal system, metabolite production, alterations in gut barrier integrity and the hematopoietic immune cell axis. This review will focus on how maternal obesity and dietary intake influence the composition of the infant gut microbiota and how an imbalance or maladaptation in the microbiota, including changes in early pioneering microbes, might contribute to the programming of offspring metabolism with special emphasis on mechanisms that promote chronic inflammation in the liver. Comprehension of these pathways and mechanisms will elucidate our understanding of developmental programming and may expand the avenue of opportunities for novel therapeutics., (© 2017 Society for Endocrinology.)

Growth and development in utero is a complex and dynamic process that requires interaction between the mother organism and the fetus. The delivery of macro--and micronutrients, oxygen and endocrine signals has crucial importance for providing a high level of proliferation, growth and differentiation of cells, and a disruption in food intake not only has an influence on the growth of the fetus, but also has negative consequences for the offspring’s health in the future. Diseases that traditionally are linked to inappropriate life style of adults, such as type 2 diabetes, obesity, and arterial hypertension, can be "programmed" in the early stage of life and the disturbed growth of the fetus leads to the symptoms of the metabolic syndrome. The structural changes of some organs, such as the brain, pancreas and kidney, modifications of the signaling and metabolic pathways in skeletal muscles and in fatty tissue, epigenetic mechanisms and mitochondrial dysfunction are the basis of the metabolic disruptions. The programming of the metabolic disturbances is connected with the disruption in the intrauterine environment experienced in the early and late gestation period. It causes the changes in deposition of triglycerides, activation of the hormonal "stress axis" and disturbances in the offspring’s glucose tolerance. The present review summarizes experimental results that led to the identification of the above-mentioned links and it underlines the role of animal models in the studies of this important concept.

The contribution of inherited non-genetic factors to complex diseases is of great current interest. The ways in which mothers and fathers can affect their offspring's health clearly differ as a result of the intimate interactions between mother and offspring during pre- and postnatal life. There is, however, potential for some overlap in mechanisms, particularly epigenetic mechanisms. A small number of epidemiological studies and animal models have investigated the non-genetic contribution of the parents to offspring health. Discovering new mechanisms of disease inheritance is technically difficult, especially in genetically, socially and environmentally heterogeneous human populations. Therefore, rigorous experimental design, appropriate sample numbers and the use of high-throughput technologies are necessary to provide convincing evidence. Based on recent examples from the literature, here we propose several ways to improve human studies that aim to identify the underlying mechanisms of transgenerational inheritance of metabolic disease., (© 2013 WILEY Periodicals, Inc.)

Adult health is dependent, in part, on maternal nutrition and growth during early life, which may independently affect insulin sensitivity, body composition, and overall energy homeostasis. Since the publication of the "thrifty phenotype hypothesis" by Hales and Barker (Diabetologia 1992;35:595-601), animal experiments have focused on establishing the mechanisms involved, which include changes in fetal cortisol, insulin, and leptin secretion or sensitivity. Intrauterine growth retardation can be induced by either prolonged modest changes in maternal diet or by more severe changes in uterine blood supply near to term. These contrasting challenges result in different amounts of cellular stress in the offspring. In addition, shifts in the transcriptional activity of DNA may produce sustained metabolic adaptations. Within tissues and organs that control metabolic homeostasis (eg, hypothalamus, adipose tissue, stomach, skeletal muscle, and heart), a range of phenotypes can be induced by sustained changes in maternal diet via modulation of genes that control DNA methylation and by histone acetylation, which suggests epigenetic programming. We now need to understand how changes in maternal diet affect DNA and how they are conserved on exposure to oxidative stress. A main challenge will be to establish how the dietary environment interacts with the programmed phenotype to trigger the development of metabolic disease. This may aid in the establishment of nutrigenomic strategies to prevent the metabolic syndrome.

Research investigating the early programming of adult metabolic disease has in recent years provided much mechanistic insight into how the early environment impacts on long-term health. It includes studies addressing the roles of intrauterine nutrient availability, which is determined by maternal nutrition, maternal exposure to oxygen, toxic events, and infection; the placental interface; and also the early postnatal environment. This review will explore the epidemiological evidence for programming of metabolic disease and provide an overview of the various studies using animals to model metabolic phenotypic outcome. It will also discuss evidence for the proposed molecular mechanisms and the potential for intervention., (© 2010 New York Academy of Sciences.)

The prevalence of obesity among pregnant women is increasing. In addition to the short-term complications of obesity during pregnancy in both mother and child, it is now recognised that maternal obesity has long-term adverse outcomes for the health of her offspring in later life. Evidence from both animal and human studies indicates that maternal obesity increases the risk for the offspring in developing obesity and altering body composition in child- and adulthood and, additionally, it also has an impact on the offspring's cardiometabolic health with dysregulation of metabolism including glucose/insulin homoeostasis, and development of hypertension and vascular dysfunction. Potential mechanisms include effects on the development and function of adipose tissue, pancreas, muscle, liver, the vasculature and the brain. Further studies are required to elucidate the mechanisms underpinning the programming of disease risk in the offspring as a consequence of maternal obesity. The ultimate aim is to identify potential targets, which may be amenable to prevention or early intervention in order to improve the health of this and future generations.

There is considerable evidence for induction of differential risk of noncommunicable diseases in humans by variation in the quality of the early life environment. Studies in animal models show that induction and stability of induced changes in the phenotype of the offspring involve altered epigenetic regulation by DNA methylation and covalent modifications of histones. These findings indicate that such epigenetic changes are highly gene specific and function at the level of individual CpG dinucleotides. Interventions using supplementation with folic acid or methyl donors during pregnancy, or folic acid after weaning, alter the phenotype and epigenotype induced by maternal dietary constraint during gestation. This suggests a possible means for reducing risk of induced noncommunicable disease, although the design and conduct of such interventions may require caution. The purpose of this review is to discuss recent advances in understanding the mechanism that underlies the early life origins of disease and to place these studies in a broader life-course context.

Purpose of Review: Intrauterine growth restriction (IUGR) is associated with an increased propensity to develop adult-onset disease and is described by the developmental origins of adult disease hypothesis. Sequelae of fetal growth restriction include metabolic disease as well as nonmetabolic disorders. Although it has become clear that the morbidities associated with IUGR are complex and result from disruptions to multiple pathways and multiple organs, the mechanisms driving the long-term effects are only just beginning to be understood., Recent Findings: IUGR affects most organ systems by either interrupting developmental processes such as apoptosis or producing lasting changes to levels of key regulatory factors. Both of these are associated with an often persistent change in gene expression. Epigenetic modulation of transcription is a mechanism that is at least partially responsible for this. IUGR is accompanied by changes in the quantity and activity of enzymes responsible for making modifications to chromatin as well as global and gene-specific modifications of chromatin., Summary: The subtle adjustments needed to ensure developmental plasticity in IUGR are provided by epigenetic modulation of critical genes. Translating the messages of the epigenetic profile and identifying the players that mediate the effects remains one of the major challenges in the field. An understanding of the mechanisms driving the epigenetic changes will facilitate identification of dietary and pharmaceutical approaches that can be applied in the postnatal period.

There is substantial evidence which shows that constraints in the early life environment are an important determinant of risk of metabolic disease and CVD. There is emerging evidence that higher birth weight, which reflects a more abundant prenatal environment, is associated with increased risk of cancer, in particular breast cancer and childhood leukaemia. Using specific examples from epidemiology and experimental studies, this review discusses the hypothesis that increased susceptibility to CVD, metabolic disease and cancer have a common origin in developmental changes induced in the developing fetus by aspects of the intra-uterine environment including nutrition which involve stable changes to the epigenetic regulation of specific genes. However, the induction of specific disease risk is dependent upon the nature of the environmental challenge and interactions between the susceptibility set by the altered epigenome and the environment throughout the life course.

Mutations in the d-3-phosphoglycerate dehydrogenase (PHGDH; EC 1.1.1.95) gene, which encodes an enzyme involved in de novol-serine biosynthesis, are shown to cause human serine deficiency disorder. This disorder has been characterized by severe neurological symptoms including congenital microcephaly and psychomotor retardation. Our previous work demonstrated that targeted disruption of mouse Phgdh leads to a marked decrease in serine and glycine, severe growth retardation of the central nervous system, and lethality after embryonic day 13.5. To clarify how a serine deficiency causes neurodevelopmental defects, we characterized changes in metabolites, gene expression and morphological alterations in the spinal cord of Phgdh knockout mice. BeadChip microarray analysis revealed significant dysregulation of genes involved in the cell cycle. Ingenuity Pathway Analysis also revealed a significant perturbation of regulatory networks that operate in the cell cycle progression. Moreover, morphological examinations of the knockout spinal cord demonstrated a marked deficit in dorsal horn neurons. Radial glia cells, native neural stem/progenitor cells, accumulated in the dorsal ventricular zone, but they did not proceed to a G(0)-like quiescent state. The present integrative study provides in vivo evidence that normal cell cycle progression and subsequent neurogenesis of radial glia cells are severely impaired by serine deficiency.

More than 60% of adults in the US are classified as overweight, with most developing associated metabolic problems. It is increasingly clear that the origins of obesity and metabolic disease are early in life, yet the physiological basis for this is not well understood. We propose that perturbations to nutrient supply in utero affect adipocyte development, altering functional properties and promoting excess body fat accumulation after birth. We also propose that excessive body fat accumulation leads to leptin and insulin resistance in these individuals, rendering them more susceptible to further weight gain and metabolic deterioration. Finally, we propose that interventions that inhibit this early increase in fat deposition have the potential to interrupt the pathway to obesity.

Human epidemiological and experimental animal studies have shown that suboptimal environments in the womb and during early neonatal life alter growth and may program offspring susceptibility to lifelong health problems. One of the most interesting and significant feature of developmental programming is the evidence that adverse consequences of altered intrauterine environments can be passed from first generation to second generation offspring. To obtain the transgenerational phenotype, a negative environment is required during fetal or early neonatal life, the physiologic phenotype or disease can be transmitted through the germ line and the subsequent generations are not directly exposed to the environmental factor. The hypothesis has become well accepted by compelling animal studies that define the outcome of specific challenges such as: 1) nutrient restriction or overfeeding during pregnancy and lactation; 2) uterine blood flow restriction; 3) fetal exposure to inappropriately high levels of glucocorticoids, and 4) experimental maternal diabetes. Maternal protein restriction in the rat adversely affects glucose metabolism of male and female second generation offspring in a gender and developmental time window-specific manner. Other studies have proved transgenerational passage of effects resulting from treatment of pregnant rats with dexamethasone by either maternal or paternal lines. First generation female diabetic offspring of F0 rats treated with streptozotocin during pregnancy had F2 offspring with altered glucose and carbohydrate metabolism. The studies suggest that the mechanisms involved in developmental programming are likely epigenetic rather than due to DNA sequence mutations. Many individuals all over the world experience undernutrition, stress, hyperglycemia and other negative environmental factors during pregnancy and/or lactation. Insult during this critical period of development may induce malprogramming and adversely alter not only the F1 generation but also future generations. Preventing or treating these conditions will help to minimize the risk of transmission of metabolic diseases to future generations.

Bcl-2 interacting cell death suppressor (Bis), also known as Bag3 or CAIR-1, is involved in antistress and antiapoptotic pathways. In addition to Bcl-2, Bis binds to several proteins, suggesting it has diverse functions in normal and pathological conditions. To better define the physiological function of Bis in vivo, we developed bis-deficient mice with a cre-loxP system. Targeted disruption of exon 4 of the bis gene was demonstrated by Southern blotting and PCR, and Western blotting showed that no intact or truncated Bis protein was synthesized in bis(-/-) mice. While heterozygotes were fertile and appeared normal, Bis-deficient mice showed growth retardation and died by 3 wk after birth. The relative weight of the thymus and spleen was reduced and the total numbers of white blood cells, splenocytes, and thymocytes were significantly reduced compared with wild-type littermates. Serum profiles indicated significant hypoglycemia as well as decrease in triglyceride and cholesterol levels. Expression profiles of metabolic genes indicated that gluconeogenesis and beta-oxidation are activated in the liver of bis(-/-) mice. This activation, as well as a decrease in peripheral fat and an induction of fatty liver, appears to be an adaptive response to hypoglycemia. Our study reveals that the absence of Bis has considerable influences on postnatal growth and survival, possibly due to a nutritional impairment.

Objective: Maternal undernutrition during gestation is associated with increased metabolic and cardiovascular disease in the offspring. We investigated whether these effects may persist in subsequent generations., Design: Historical cohort study., Setting: Interview during a clinic or home visit or by telephone., Population: Men and women born in the Wilhelmina Gasthuis in Amsterdam between November 1943 and February 1947., Methods: We interviewed cohort members (F1) born around the time of the 1944-45 Dutch famine, who were exposed or unexposed to famine in utero, about their offspring (F2)., Main Outcome Measures: Birthweight, birth length, ponderal index and health in later life (as reported by F1) of the offspring (F2) of 855 participating cohort members, according to F1 famine exposure in utero., Results: F1 famine exposure in utero did not affect F2 (n = 1496) birthweight, but, among the offspring of famine-exposed F1 women, F2 birth length was decreased (-0.6 cm, P adjusted for F2 gender and birth order = 0.01) and F2 ponderal index was increased (+1.2 kg/m(3), P adjusted for F2 gender and birth order = 0.001). The association remained unaltered after adjusting for possible confounders. The offspring of F1 women who were exposed to famine in utero also had poor health 1.8 (95% CI 1.1-2.7) times more frequently in later life (due to miscellaneous causes) than that of F1 unexposed women., Conclusions: We did not find transgenerational effects of prenatal exposure to famine on birthweight nor on cardiovascular and metabolic disease rates. F1 famine exposure in utero was, however, associated with increased F2 neonatal adiposity and poor health in later life. Our findings may imply that the increase in chronic disease after famine exposure in utero is not limited to the F1 generation but persists in the F2 generation.

There is considerable evidence for the induction of different phenotypes by variations in the early life environment, including nutrition, which in man is associated with a graded risk of metabolic disease; fetal programming. It is likely that the induction of persistent changes to tissue structure and function by differences in the early life environment involves life-long alterations to the regulation of gene transcription. This view is supported by both studies of human subjects and animal models. The mechanism which underlies such changes to gene expression is now beginning to be understood. In the present review we discuss the role of changes in the epigenetic regulation of transcription, specifically DNA methylation and covalent modification of histones, in the induction of an altered phenotype by nutritional constraint in early life. The demonstration of altered epigenetic regulation of genes in phenotype induction suggests the possibility of interventions to modify long-term disease risk associated with unbalanced nutrition in early life.

The 'thrifty phenotype' hypothesis proposes that the fetus adapts to an adverse intrauterine milieu by optimizing the use of a reduced nutrient supply to ensure survival. However, favoring the development of some organs over that of others leads to persistent alterations in the growth and function of developing tissues. Although this concept has been somewhat controversial, recent epidemiological, clinical and animal studies provide support for the developmental origins of disease hypothesis. Underlying mechanisms include reprogramming of the hypothalamic-pituitary-adrenal axis, islet development and insulin-signaling pathways. Emerging data indicates that epigenetic regulation of gene expression might also play a crucial role in the pathogenesis of type 2 diabetes in individuals who are growth retarded at birth.

Alterations of the intrauterine and early postnatal nutritional, metabolic, and hormonal environment may cause predispositions to the development of disorders and diseases in later life. Mechanisms responsible for this perinatally acquired 'malprogramming' still remain unclear. It has long been known, however, that hormones are environment-dependent organizers of the developing 'neuroendocrine-immune network', which regulates all fundamental processes of life. When present in nonphysiological concentrations during critical ontogenetic periods, hormones can therefore also act as 'endogenous functional teratogens'. Fetal and neonatal hyperinsulinism is a pathognomic feature in the offspring of diabetic mothers. Perinatal hyperinsulinism also occurs due to early postnatal overfeeding. Data obtained by our group indicate that elevated insulin concentrations during critical periods of perinatal life may induce a lasting 'malprogramming' of neuroendocrine systems regulating body weight, food intake, and metabolism. Similar characteristics may occur due to perinatal hyperleptinism, hypercortisolism etc. Since mechanisms of early 'programming' of obesity, diabetes, and the metabolic syndrome X are unclear, a complex 'neuroendocrine malprogramming' of the regulation of body weight and metabolism may provide a general etiopathogenetic concept in this context, exemplarily revealing critical new implications for chances and challenges of perinatal preventive medicine in the future.

The Barker hypothesis of fetal programming for adult cardiovascular and metabolic diseases has attracted much interest over the past few years. In this review, we summarize the main studies in this field, give a brief outline of some of the laboratory models used to investigate this hypothesis and discuss potential mechanisms underlying these clinical observations that are amenable to future research.

A clinical and neuropathological study is presented of two cases each of which showed neuronal heterotopia. Microgyria was also present in one case. One patient was suffering from a degenerative disorder affecting the white matter. The other was a case of Menkes' disease. It is suggested that the antenatal damage may have been caused by an imbalance of the maternal metabolism, the predisposing factor being the mother's carrier state for a metabolic defect. This is the first report of teratogenesis in a case of Menkes' disease. It is also noted that in this case there is interference with the postnatal as well as the antenatal development of the brain.