**3. Metabolic pathways and epigenetics**

During their lifetime, cells receive several external signals, like hormones, growth factors, cytokines, and other extracellular factors. This flow of metabolites, through complex metabolic networks, acts optimizing diverse epigenetic cofactors, thus relating nutrition and diet changes into cytoplasmic signaling and chromatin remodeling. Histone modifications—as DNA methylation, RNA interference, and non-coding RNA—inserted by the term epigenetics represent diverted ways by which cells control the expression of genes without any alteration in the underlying genetic material [32].

The produced metabolites remain the same for a given cell, but tissue function and nutrient availability will determine the metabolite requirements. In addition, metabolic challenges, such as calorie or oxygen restriction or even a high-fat diet, drive decisions about cell fate. Consistently, dramatic epigenetic changes have been associated with metabolic disorders, such as obesity, insulin resistance, type 2 diabetes, and cancer [32, 33].

The changes on the cellular and tissue level are followed by alterations in epigenetic regulation of gene expression. Epigenetic modifications refer to heritable changes in gene expression occurring without changes in DNA sequence. The epigenetic code is changed dramatically in the course of embryonic development to initiate varying patterns of gene expression in different developing tissues. This code consists of modifications of chromatin histones and DNA playing a central role in packing DNA by forming nucleosomes. Mechanisms of epigenetic regulation are DNA methylation at cytosine residues in promoter or enhancer gene regions, intragenic DNA methylation usually leading to transcriptional silencing, and posttranslational modifications of core histone proteins, such as acetylation usually resulting in transcriptional activation. Non-coding microRNAs which can govern gene activity at both transcriptional and posttranscriptional levels are one more recently discovered key component of epigenetic control. Another important factor is the microRNA expression that may be modulated by histone modifications or DNA methylation and vice versa, thereby causing feedback loops in epigenetic regulation [30, 34, 35].

The ability of the genotype to produce different phenotypes in response to different environments is termed "plasticity." The time of maximal plasticity appears to be during development. Nonetheless, heritable phenotypic variation at a later stage is also possible because of the individual's capability to respond to environmental conditions. Plasticity in developmental programming has evolved to provide the best chances of survival and reproductive success to the organism. When reflecting this theory to developmental data, adaptive growth and metabolic-related strategies for transition from one life history phase to the next and the timing of such transitions (inherent adaptive plasticity) have evolved [36, 37].

**177**

*Metabolic Programming and Nutrition DOI: http://dx.doi.org/10.5772/intechopen.92201*

long-term impact [7, 36].

affect health and longevity [38].

the onset of disease/health in later life.

Adaptive plasticity enables a species to respond to an environmental change to survive and reproduce and may manifest itself as polyphenism or as a continuous variation in traits. In evolutionary terms, plastic and developmental responses in early life enable an organism to adjust its phenotype so that it can survive in the environment in which it will grow and reproduce. However, the adaptation is not always positive, and the outcome may be harmful and may result in teratogenesis, diseases, or death [36]. There are two types of adaptive responses (plasticity). The first type is the anticipatory or predictive adaptive responses, where the developing organism forecasts the future environment and then adjusts its phenotypic trajectory accordingly. The second type is the immediate adaptive responses that promote short-term maternal or fetal survival with some advantages in later life (developmental plasticity). These adaptive responses have a significant cost, and a cost-benefit analysis is performed to determine the true value of the adaptive response. The links between epigenetics, developmental programming, and plasticity in early growth and nutrition provide subsidies to understand aspects involved in child growth and development and their

The nutrition is one of the most studied environmental epigenetic factors, and already associations have been observed between adverse prenatal nutritional conditions, postnatal health, and increased risk of disease. It is known that maternal and paternal diets influence metabolic phenotypes in offspring through epigenetic information transmission. Over molecular mechanisms with respect to the fetal origins of adult disease have been suggested including mitochondrial dysfunction and oxidative stress as among the earliest events described in offspring exposed to nutrient restriction. This in turn modifies the expression of critical genes and can

The foods contain nutrients and bioactive components that can modify epigenetic marks and alter the expression of genes. These compounds, including folate, vitamin B12, methionine, among others, can affect DNA methylation and histone, altering 1-carbon metabolism. The S-adenosylmethionine (AdoMet) and S-adenosylhomocysteine (AdoHcy), metabolites of 1-carbon metabolism, can alter the methylation of DNA and histones. Thus, nutrients and bioactive components, as well as conditions that may affect the levels of AdoMet or AdoHcy in the tissue,

In a study developed by our research group, we identified that the maternal intake of soybeans in lactation changed the lipid content of breast milk and programmed offspring for a phenotype of the lower metabolic risk. The difference in fat content of breast milk and the higher isoflavones content of soy diet are possible imprinting factors that could program the offspring [18]. This is particularly important because it highlights the dual role of nutritional alterations, whether as reprogramming strategies to prevent disease or leading to adult disease [40].

The metabolic mechanism linked to the programming induced by the adverse intrauterine environment is not completely clear, but fetal metabolic programming has already been indicated to contribute to changes in tissue development, number of cells, neural circuits, and so on. Epigenetic programming plays an important role in the differentiation and development of embryonic, tissue, and stem cells. The changes induced by epigenetic modification in cell or tissue function can be transmitted from fetuses to adults and induce the development of the metabolic syndrome in adult offspring. There is a vulnerable "window" for epigenetic programming when germ cells, embryos, and fetuses are in development [11, 41]. **Figure 2** presents a scheme of developmental origins of health and disease. Epigenetic marks can be modulated by environmental factors, are heritable, perpetuate gene-expression changes that underlie programming, and may contribute to

have the ability to modify the methylation of DNA and histones [11, 39].

#### *Metabolic Programming and Nutrition DOI: http://dx.doi.org/10.5772/intechopen.92201*

*New Insights into Metabolic Syndrome*

telomere biology system [30, 31].

underlying genetic material [32].

diabetes, and cancer [32, 33].

regulation [30, 34, 35].

**3. Metabolic pathways and epigenetics**

development. This predisposition to develop obesity is particularly clear in the offspring of calorie-restricted dams and is also exacerbated when animals are exposed to an obesogenic environment in adulthood. Mechanisms contained in the deregulation of food intake and energy balance, due to perinatal nutrition, could be related to hypothalamic alterations and a lower capacity to respond to insulin and leptin signaling [29]. One potential mechanism of developmental programming is through permanent structural alterations of different organs. Different stress exposures (oxidative, immune, and inflammatory stresses, as well as maternal-placental-fetal endocrine disturbances) during the prenatal development could reprogram the

During their lifetime, cells receive several external signals, like hormones, growth factors, cytokines, and other extracellular factors. This flow of metabolites, through complex metabolic networks, acts optimizing diverse epigenetic cofactors, thus relating nutrition and diet changes into cytoplasmic signaling and chromatin remodeling. Histone modifications—as DNA methylation, RNA interference, and non-coding RNA—inserted by the term epigenetics represent diverted ways by which cells control the expression of genes without any alteration in the

The produced metabolites remain the same for a given cell, but tissue function and nutrient availability will determine the metabolite requirements. In addition, metabolic challenges, such as calorie or oxygen restriction or even a high-fat diet, drive decisions about cell fate. Consistently, dramatic epigenetic changes have been associated with metabolic disorders, such as obesity, insulin resistance, type 2

The changes on the cellular and tissue level are followed by alterations in epigenetic regulation of gene expression. Epigenetic modifications refer to heritable changes in gene expression occurring without changes in DNA sequence. The epigenetic code is changed dramatically in the course of embryonic development to initiate varying patterns of gene expression in different developing tissues. This code consists of modifications of chromatin histones and DNA playing a central role in packing DNA by forming nucleosomes. Mechanisms of epigenetic regulation are DNA methylation at cytosine residues in promoter or enhancer gene regions, intragenic DNA methylation usually leading to transcriptional silencing, and posttranslational modifications of core histone proteins, such as acetylation usually resulting in transcriptional activation. Non-coding microRNAs which can govern gene activity at both transcriptional and posttranscriptional levels are one more recently discovered key component of epigenetic control. Another important factor is the microRNA expression that may be modulated by histone modifications or DNA methylation and vice versa, thereby causing feedback loops in epigenetic

The ability of the genotype to produce different phenotypes in response to different environments is termed "plasticity." The time of maximal plasticity appears to be during development. Nonetheless, heritable phenotypic variation at a later stage is also possible because of the individual's capability to respond to environmental conditions. Plasticity in developmental programming has evolved to provide the best chances of survival and reproductive success to the organism. When

reflecting this theory to developmental data, adaptive growth and metabolic-related strategies for transition from one life history phase to the next and the timing of

such transitions (inherent adaptive plasticity) have evolved [36, 37].

**176**

Adaptive plasticity enables a species to respond to an environmental change to survive and reproduce and may manifest itself as polyphenism or as a continuous variation in traits. In evolutionary terms, plastic and developmental responses in early life enable an organism to adjust its phenotype so that it can survive in the environment in which it will grow and reproduce. However, the adaptation is not always positive, and the outcome may be harmful and may result in teratogenesis, diseases, or death [36].

There are two types of adaptive responses (plasticity). The first type is the anticipatory or predictive adaptive responses, where the developing organism forecasts the future environment and then adjusts its phenotypic trajectory accordingly. The second type is the immediate adaptive responses that promote short-term maternal or fetal survival with some advantages in later life (developmental plasticity). These adaptive responses have a significant cost, and a cost-benefit analysis is performed to determine the true value of the adaptive response. The links between epigenetics, developmental programming, and plasticity in early growth and nutrition provide subsidies to understand aspects involved in child growth and development and their long-term impact [7, 36].

The nutrition is one of the most studied environmental epigenetic factors, and already associations have been observed between adverse prenatal nutritional conditions, postnatal health, and increased risk of disease. It is known that maternal and paternal diets influence metabolic phenotypes in offspring through epigenetic information transmission. Over molecular mechanisms with respect to the fetal origins of adult disease have been suggested including mitochondrial dysfunction and oxidative stress as among the earliest events described in offspring exposed to nutrient restriction. This in turn modifies the expression of critical genes and can affect health and longevity [38].

The foods contain nutrients and bioactive components that can modify epigenetic marks and alter the expression of genes. These compounds, including folate, vitamin B12, methionine, among others, can affect DNA methylation and histone, altering 1-carbon metabolism. The S-adenosylmethionine (AdoMet) and S-adenosylhomocysteine (AdoHcy), metabolites of 1-carbon metabolism, can alter the methylation of DNA and histones. Thus, nutrients and bioactive components, as well as conditions that may affect the levels of AdoMet or AdoHcy in the tissue, have the ability to modify the methylation of DNA and histones [11, 39].

In a study developed by our research group, we identified that the maternal intake of soybeans in lactation changed the lipid content of breast milk and programmed offspring for a phenotype of the lower metabolic risk. The difference in fat content of breast milk and the higher isoflavones content of soy diet are possible imprinting factors that could program the offspring [18]. This is particularly important because it highlights the dual role of nutritional alterations, whether as reprogramming strategies to prevent disease or leading to adult disease [40].

The metabolic mechanism linked to the programming induced by the adverse intrauterine environment is not completely clear, but fetal metabolic programming has already been indicated to contribute to changes in tissue development, number of cells, neural circuits, and so on. Epigenetic programming plays an important role in the differentiation and development of embryonic, tissue, and stem cells. The changes induced by epigenetic modification in cell or tissue function can be transmitted from fetuses to adults and induce the development of the metabolic syndrome in adult offspring. There is a vulnerable "window" for epigenetic programming when germ cells, embryos, and fetuses are in development [11, 41].

**Figure 2** presents a scheme of developmental origins of health and disease. Epigenetic marks can be modulated by environmental factors, are heritable, perpetuate gene-expression changes that underlie programming, and may contribute to the onset of disease/health in later life.

**Figure 2.**

*Scheme demonstrative of developmental origins of health and disease, during prenatal and early postnatal life, involved in the susceptibility to obesity and metabolic changes.*
