Nutritional programming of insulin resistance: causes and ...

Review

Feature Review

Nutritional programming of insulin resistance: causes and consequences Daniella E. Duque-Guimara˜es and Susan E. Ozanne University of Cambridge Metabolic Research Laboratories and Medical Research Council (MRC) Metabolic Disease Unit, Institute of Metabolic Sciences, Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK

Strong evidence indicates that adverse prenatal and early postnatal environments have a significant long-term influence on risk factors that result in insulin resistance, type 2 diabetes (T2D), and cardiovascular disease later in life. Here we discuss current knowledge of how maternal and neonatal nutrition influence early growth and the long-term risk of developing insulin resistance in different organs and at the whole-body level. Accumulating evidence supports a role for epigenetic mechanisms underlying this nutritional programming, consisting of heritable changes that regulate gene expression which in turn shapes the phenotype across generations. Deciphering these molecular mechanisms in key tissues and discovering key biological markers may provide valuable insight towards the development of effective intervention strategies. Insulin resistance and nutritional programming Insulin resistance is a well-recognized factor in the development and progression of metabolic syndrome (MetS), a constellation of disorders including obesity, T2D, hypertension, dyslipidemia, and cardiovascular disease [1]. In recent decades the prevalence of MetS has increased dramatically throughout the developed and developing world [2]. The primary function of insulin, a key anabolic hormone secreted by the pancreatic b cell, is to remove glucose from the circulation, when levels become too high, to help maintain optimal blood glucose levels. In situations of insulin resistance, defects in insulin action impair glucose uptake in peripheral tissues and result in overproduction of glucose by the liver, contributing to the development of hyperglycemia and/or compensatory hyperinsulinemia [3]. These effects trigger several metabolic disorders affecting different organs and tissues of the body [4]. The etiology of insulin resistance has multifactorial origins which include genetic and environment factors. It has been known for many years that current diet influences insulin sensitivity. However, it has recently been recognized that nutrition during very early life is crucial because it can permanently influence the risk of an individual developing insulin resistance, a phenomenon termed nutritional programming [5] (Box 1). In this article we review how maternal nutrition Corresponding author: Ozanne, S.E. ([email protected]). Keywords: nutritional programming; insulin resistance; epigenetics; metabolic diseases. 1043-2760/$ – see front matter ß 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tem.2013.05.006

influences the risk of developing insulin resistance in the offspring, and consequently metabolic diseases later in life (Figure 1). Because the early life environment plays an imperative role in adult onset of chronic diseases, interventions during this critical developmental window might provide opportunities to decrease the burden of metabolic diseases later in life [6]. Pre- and postnatal nutritional environment and disease The pre- and postnatal nutritional environment crucially shapes the ultimate phenotype of the organism. Nutritional programming during the perinatal period significantly influences risk factors that promote the development of insulin resistance and associated complications in the fetus [7,8] (Box 2). This evidence comes from studies both in humans and in animal models using four main types of nutritional modulation, as outlined below. Maternal undernutrition Human and animal studies have documented that maternal nutritional deprivation during gestation impairs maternal nutrient supply to the fetus, thereby causing intrauterine growth restriction (IUGR) and low birth-weight [9], thus leading to increased risk of insulin resistance and T2D in the offspring in later life [10]. Data from five cohort studies in different countries including Brazil, Guatemala, India, South Africa, and the Philippines showed that maternal undernutrition was strongly associated with lower offspring birth-weight [11]. Moreover, the Hertfordshire (UK) study from which the thrifty phenotype hypothesis (Box 1) emerged, and which has been replicated in many other cohort studies, has demonstrated a direct link between low birth-weight and increased risk of developing insulin resistance and T2D later in life [12]. Studies in humans and animals have demonstrated that suboptimal fetal growth and/or suboptimal maternal nutrition are associated with permanent and progressive changes in insulin signaling proteins that may contribute to the loss of glucose tolerance and development of T2D [13,14]. Apart from the classical Dutch Hunger Winter study (Box 1), at least two more human studies have investigated the direct association between exposure to famine in utero and subsequent glucose intolerance [15–17]. The Chinese famine study demonstrated, as did the Dutch study, that exposure to severe famine in fetal life increases the risk of hyperglycemia in adulthood, which is aggravated by an unhealthy diet and obesity in adulthood [16]. However, the Leningrad Siege study that Trends in Endocrinology and Metabolism, October 2013, Vol. 24, No. 10

525

Review Box 1. The concept of nutritional programming Early life is a critical period of developmental plasticity. During this time an organism has the ability to develop in various ways, depending on the particular environment or setting experienced. Any event that occurs during this period can therefore permanently influence the metabolism and physiology of the organism, and this process has been termed ‘fetal programming’ or more recently ‘developmental programming’ [130]. Strong evidence supports the idea that nutrition during fetal life is a crucial stimulus for such programming [131]. This was initially proposed within the ‘Barker hypothesis’, or the ‘thrifty phenotype hypothesis’, which proposed that in utero undernourishment resulted in two major responses by the fetus. Firstly, it led to sparing of growth of key tissues, such as the brain at the expense of others, such as skeletal muscle and the endocrine pancreas. Secondly, the fetus programmed its metabolism to be thrifty (i.e., very efficient at storing nutrients when they were available). These permanent changes, although beneficial in postnatal conditions of continued undernutrition, become detrimental in conditions of adequate or overnutrition postnatally, leading to the development of diseases later in life [132–135]. This hypothesis arose from epidemiological studies demonstrating that low birth-weight and ponderal index (proposed to be proxy measures of a suboptimal in utero environment), were strongly related to later prevalence of metabolic diseases such as coronary heart disease, T2D, and insulin resistance [136–138]. The Dutch Hunger Winter study is a classic and good example in humans that supports the idea of programming by early nutrition. This study showed that women exposed during pregnancy to the nutritional limitation imposed by severe famine have offspring with reduced birth-size and an increased risk of glucose intolerance in adult life [15]. Further evidence in support of the early environment is mediating the relationship between birth weight and T2D has come from the study of monozygotic (identical) twins. Poulsen and colleagues showed that, in middle-aged monozygotic twins who were discordant for T2D, the diabetic twin had the lower birthweight [139]. Animal studies have also provided strong evidence that early-life nutrition is an important factor in determining the long-term health of an individual.

included fewer subjects did not find a significant association between intrauterine starvation and glucose intolerance in adult life [17]. As well as likely being underpowered, the lack of significant effect of maternal starvation in the Leningrad Siege study may be because the period of famine extended into childhood. This highlights the potential importance of the interaction between the fetal and postnatal nutritional environment on developmental programming. Maternal low-protein (LP) diet The maternal LP diet model, which resembles the phenotypic outcome of low birth-weight in humans, is one of the most studied in the developmental programming field [18]. This model is based on the ingestion of a LP (8% protein) diet throughout pregnancy and/or lactation followed by weaning onto a standard (20% protein) chow diet. Although the protein level of this diet is reduced, the carbohydrate level is increased to maintain the diet as isocaloric. The male offspring aged 20 weeks of LP-fed rat dams during pregnancy and lactation are insulin-resistant and hyperinsulinemic. At 15 months of age LP offspring have impaired glucose tolerance and by 17 months have developed frank diabetes. This process is delayed in female offspring, with insulin resistance only becoming apparent at 21 months of age [13,19]. Pancreatic islets from both male and female offspring aged 3 months demonstrate a lower response to glucose, suggesting the presence of b cell 526

Trends in Endocrinology and Metabolism October 2013, Vol. 24, No. 10

Box 2. Critical time-windows shaping risk for future disease in the offspring or across generations Critical time-points: in addition to the type of diet, the timing of the insult is also a critical factor in determining its effect on the risk of developing insulin resistance in the offspring. Fetal and suckling period have been shown to be critical time-windows in determining long-term metabolic heath. In terms of insulin resistance associated with obesity, the early postnatal period has been demonstrated to be particularly important. This is primarily based on animal studies employing early weaning, cross-fostering, or nutritional manipulation during the lactation period only [140–142]. It has also been demonstrated that, in animal models, the periconceptual nutritional status of the dam (i.e., the early stages of development including oocyte maturation, follicular development, conception, and embryo growth until implantation) has the capacity to program insulin action and other metabolic alterations in the offspring [143]. The adolescence period appears to represent yet another important window during which suboptimal exposures can induce the development of metabolic abnormalities. For example, Oliveira and colleagues showed that protein restriction during only the pubertal period caused b cell dysfunction and adiposity in adult rats [144]. Transgenerational effects: there is now evidence that maternal diet-induced epigenetic alterations can be transmitted through generations, and represents a vicious cycle that could lead to future generations becoming insulin-resistant without any exposure to suboptimal early nutrition. To be considered a true transgenerational phenotype transmitted by epigenetic modification of the germline, the phenotype must be present in the F3 generation, which is the first non-exposed generation [145]. There is some evidence that maternal malnutrition can adversely affect glucoseinsulin metabolism in the F3 generation. Hoile and colleagues investigated alterations in expression of the liver transcriptome transmitted through generations after feeding F0 rodent dams a protein-restricted diet during pregnancy. They found that protein restriction in the F0 females affected the expression of 1684 genes at F1, 1680 genes at F2, and 2062 genes at F3. However, 63/113 genes that were altered in all three subsequent generations demonstrated opposite differences between generations [146]. This variation might indicate that the maternal environment during development between generations provokes different signals to the developing offspring in each generation. Consistent with this, another study showed that transgenerational effects on phenotype were associated with altered DNA methylation of specific genes, in agreement with induction de novo of epigenetic marks in each generation [147].

dysfunction. However, only male LP offspring demonstrate increased reactive oxygen species (ROS) and reduced b cell mass [20]. These differences between islets from male and female LP offspring may contribute to the different timecourses in development of impaired glucose tolerance. Recently, Vo and colleagues demonstrated that male LP offspring had reduced liver X receptor-a (LXRa) expression, and increased glucose-6-phosphatase (G6Pase) and 11b-hydroxysteroid dehydrogenase type 1 (11BHSD1) in liver, indicative of increased gluconeogenesis which may contribute to the impaired glucose tolerance [21]. Global caloric restriction (CR) models There are different conditions for models of maternal CR in the literature. Different time-windows and percent of the diet restriction are the variables more usually changed. Recently, in a model of severe CR (70%), Mayeur and colleagues demonstrated that rat placentas from food-restricted mothers were smaller and had mitochondrial abnormalities as well as reduced ATP levels [22]. Considering the importance of the placenta for fetal growth, these alterations are likely to be highly detrimental to the offspring.

Review


Placenta Subopmal early postnatal nutrion

Pancreas

Adipose ssue

Gut

• Altered • Placenta • Impaired • Adiposity dysregulaon • Proinflammatory microbiota β cell composion • Mitochondrial response development • Decreased dysfuncon • Altered • Mitochondrial funconal • Proinflammatory adipokine dysfuncon maturaon response secreon • Increased • ER stress oxidave stress

Type 2 diabetes

Maternal undernutrion

Nutrional programming

Insulin resistance

Metabolic syndrome

Maternal overnutrion

Maternal dietary imbalance

Brain Skeletal muscle Liver • Proinflammatory • Increased expression of • Increased orexigenic regulators response gluconeogenesis • Impaired response of • Lipotoxicity • Proinflammatory anorexigenic regulators • Impaired response • Proinflammatory response • Mitochondrial myogenesis • Lepn resistance • Compromised dysfuncon • Altered hypothalamic glucose and lipid • Increased ROS structure and funcon metabolism • Lipotoxicity

Cardiovascular disease

TRENDS in Endocrinology & Metabolism

Figure 1. Causes and consequences of insulin resistance in nutritional programming. Different types of maternal nutrition cause systemic insulin resistance in the offspring through several molecular mechanisms in different organs and tissues. Consequently, the systemic insulin resistance triggers the offspring to have metabolic syndrome (MetS) or metabolic diseases such as type 2 diabetes (T2D) and cardiovascular disease. ER, endoplasmic reticulum; ROS, reactive oxygen species.

Another maternal CR study in rats, employing a more modest reduction in caloric intake (20%), demonstrated that this resulted in lower insulin-receptor expression in the hypothalamus, adipose tissue, and liver, and led to the development of insulin resistance and hyperleptinemia by 6 months of age [23]. These finding suggest that moderate maternal CR programs insulin and leptin resistance, which could promote obesity and T2D later in life. Maternal micronutrient deficiency The inadequate maternal dietary intake of micronutrients has also been associated with the development of insulin resistance in the offspring later in life. In addition to iron, that has been one of the most thoroughly studied in this context [24], maternal deficiency for several other minerals and vitamins is crucial for the health of the offspring. Indeed, exposure to low maternal zinc (initiated 3 weeks preconception) throughout gestation and lactation in the rat led to increased body-weight, as well as increased insulin and leptin concentrations, in offspring aged 15 weeks [25]. A maternal vitamin B12-deficient diet has also been demonstrated to have detrimental effects on metabolism in offspring [26]. Rat offspring of dams fed a vitamin B12-deficient diet had lower birth-weight, higher visceral fat, and dyslipidemia. They also had low circulating and adipose tissue levels of adiponectin and interleukin-1b (IL1b), and higher levels of tumor necrosis factor a (TNF-a), leptin, and interleukin-6 (IL-6), suggestive of an increased inflammatory state that could contribute to the development of insulin resistance in later life [27]. In agreement, a human study has showed that children whose mothers

were deficient in vitamin B12 during early pregnancy had increased risk of insulin resistance [as defined by the homeostasis model assessment (HOMA-IR)] [28]. An association between maternal vitamin D deficiency and development of insulin resistance in the offspring has also gained attention recently. In one study, children from vitamin D-deficient mothers had lower fat mass at birth but greater fat mass at 6 years of age [29]. The specific mechanism explaining the relationship between maternal vitamin D deficiency and insulin resistance in the offspring has yet to be established. Early postnatal overnutrition and catch-up growth In humans, attempts to recover growth of children born with IUGR by improving their postnatal nutrition does not necessarily reverse the adverse effects of IUGR, and can in fact often trigger even worst metabolic disturbances in the offspring. Postnatal exposure to an environment with plentiful food following intrauterine deprivation has been demonstrated to increase the risk of insulin resistance in individuals from both low-income and high-income countries [30]. A large study of Chinese adults demonstrated that the association between fetal famine exposure and risk of hyperglycemia later in life was stronger when the subjects consumed a Western diet postnatally (i.e., a nutritionally rich environment) [16]. Several mechanisms have been implicated in mediating the effects of accelerated early postnatal growth on insulin resistance. Using a rat model in which the dams received a LP diet (8%) during gestation followed by a 20% protein diet during suckling, Berends and colleagues found that 527

Review catch-up growth following IUGR led to an insulin-resistant phenotype in adipose tissue. The offspring had larger adipocytes at 22 days and 3 months of age after weaning onto a standard laboratory chow. Moreover, they had reduced adipose tissue insulin receptor substrate 1 (IRS1) and phosphatidylinositol 3-kinase (PI3K) p110b catalytic subunit as well as protein kinase B (AKT) phosphorylation and protein levels of AKT2. The mRNA expression of these genes was not different, suggesting that post-transcriptional mechanisms mediate these programmed changes in gene expression [31]. These findings support the idea that insulin resistance in the adipocyte might be one of the first metabolic adaptations that triggers the risk of T2D development during adulthood following accelerated early postnatal growth. Some studies have suggested that the insulin resistance triggered by catch-up growth is linked with an increased rate of gaining body fat rather than muscle tissue. For example, a Finnish study demonstrated that human subjects born small for gestational age (SGA) had 3–5 kg less lean tissue and more fat mass than those born with a normal birth-weight [32]. This finding was confirmed in another study that observed that young men born SGA had less muscular tissue and higher visceral fat mass [33]. Moreover, this study also showed that the catch-up group demonstrated reduced glucose uptake and impaired insulin signaling in skeletal muscle that may lead to preferential glucose uptake into adipose tissue during catch-up growth. Maternal overnutrition The rise in obesity around the world is occurring in all age groups, including women of childbearing age [34]. Strong data support the notion that maternal obesity influences the development of insulin resistance and adiposity in the offspring (reviewed in [35]). Women who are overweight and/or obese in early pregnancy, or who have a greater weight gain during pregnancy, have offspring with a greater body-mass index (BMI) at age 18 years [36]. In addition, according to a recent systematic review, pre-pregnancy overweight or obesity increases the risk of being born large for gestational age (LGA) and subsequently being overweight/obese in later life [37]. This is consistent with obese mothers being at higher risk of developing gestational diabetes than women with normal weight during pregnancy [38]. However, greater pre-pregnancy adiposity and pregnancy weight gain were independently associated with a high risk of giving birth to an LGA infant across all races in normal-weight women, suggesting that this is not only a condition that occurs in obese women [39]. The parameters associated with maternal obesity that mediate the detrimental effects on the offspring remain to be fully established. However, hyperinsulinemia is thought to play an important role [40]. Catalano and colleagues were the first to demonstrate that the human fetuses of obese mothers become insulin-resistant in utero, indicating that the development of insulin resistance starts in the very early stages of life [41]. Furthermore, children of overweight and obese mothers during the first 6 months of life have a lower rate of energy expenditure as well as higher BMI and increased adiposity, compared with children of lean mothers, indicating a higher risk for 528


obesity in adulthood [42]. Hedderson and colleagues have showed that women with a high rate of weight gain during the 5 years before pregnancy are also more likely to develop gestational diabetes than are women with stable weight [43]. Increased weight and insulin resistance before pregnancy are the strongest predictors of the degree of insulin resistance during late gestation. A high level of insulin resistance during this period is closely related to the development of gestational diabetes, and correlates strongly with fetal growth and fat mass at birth [44]. The underlying mechanisms that differentiate the effects of maternal pregravid obesity and excessive gestational weight gain on the development of insulin resistance in the offspring have not been fully elucidated. Studies in animal models support the results of human cohort studies and have provided direct evidence for the detrimental effects of maternal obesity on metabolic health in offspring [45,46]. A recent systematic review of rodent models demonstrated that, despite the considerable differences in study design, a maternal high-fat diet (HFD) was associated with poor glycemic control and thus development of T2D in the offspring [47]. Recent models have adopted the use of highly palatable diets to induce maternal obesity. By feeding dams a highly palatable obesogenic diet (rich in fat and simple sugars), Samuelsson and colleagues demonstrated the development of insulin resistance, glucose intolerance, hyperphagia, increased abdominal adiposity, and hypertension in the offspring [48]. Animal models have also helped to dissect out the importance of pre-pregnancy adiposity versus overnutrition during pregnancy. Using a HFD rodent model, Howie and colleagues demonstrated that regardless of whether the mother had experienced a lifetime of HFD, or if it was initiated at the time of conception, the offspring developed hyperinsulinemia, hyperleptinemia, and increased adiposity compared to control offspring [49]. Paternal diet The idea that the diet of the father can also affect the health of offspring has been suggested recently. One of the main studies supporting this concept demonstrated that male mice with a history of IUGR could influence metabolism of their offspring [50]. Alterations in current paternal diet have also been implicated in the determination of offspring health [51]. Male mice fed a HFD generated daughters that, although of normal body-weight and composition, were insulin-resistant and had altered pancreatic islet cell gene expression in adulthood. It has been suggested that these effects could be mediated via epigenetic alterations in germ cells [52]. Contribution of different organs and tissues to the process To understand how nutritional programming causes insulin resistance in the offspring it is necessary to consider the key tissues that regulate fetal nutrient supply as well as those that respond to changes in circulating insulin (Figure 1). Tissues affected by maternal under- or overnutrition Placenta. This organ is responsible for the communication between mother and fetus, representing the key interface

Review for the transport of nutrients and gases from the mother to the fetus. Therefore, perturbation in placental function will clearly impact upon fetal nutrient supply and thus influence long-term metabolic health [53]. During a healthy pregnancy, inflammatory pathways are activated to assist the development of insulin resistance [54]. Decreased maternal insulin-stimulated tissue glucose uptake is a natural and beneficial occurrence during pregnancy, and helps to ensure maximum glucose availability to the fetus. Maternal nutrition could therefore affect placenta and fetal development through modification of maternal and fetal concentrations of several hormones, cytokines, and growth factors [55]. Maternal overnutrition has been shown to exacerbate the placental inflammatory state, leading to an increased accumulation of macrophages and proinflammatory cytokines [56]. Studies in an ovine model have also demonstrated that increased circulating lipids in obese pregnancies lead to upregulation of the nuclear factor kB (NF-kB) and c-Jun N-terminal kinase (JNK) signaling pathways, and increased toll like receptor 4 (TLR4) expression in the placenta [57]. These findings demonstrate that maternal obesity induces a placental inflammatory response, therefore increasing the risk for systemic fetal inflammation which could adversely affect fetal development. Maternal undernutrition has also been shown to impact upon placental function. For example, maternal undernutrition induced placental mitochondrial abnormalities and consequently reduced ATP production in a rodent model [58]. Brain and the hypothalamus. The central nervous system (CNS) plays an essential role in controlling energy homeostasis by responding to changes in circulating hormones such as insulin and leptin, key regulators of energy balance and food intake. This takes place primarily through the coordinate regulation of expression of several orexigenic (e.g., neuropeptide Y/NPY) and anorexigenic (e.g., proopiomelanocortin, POMC) neuropeptides that collectively control food intake but can also regulate peripheral metabolism [59]. Hill and colleagues, in a study with mice lacking insulin and leptin receptors in POMC neurons, showed that these mice developed systemic insulin resistance [60]. Moreover, mice with neuron-specific disruption of the insulin receptor (IR) (Nirko mice) developed obesity and mild insulin resistance and hypertriglyceridemia [61]. The hypothalamus undergoes an extensive period of development, starting during embryonic life and continuing into early postnatal life, and is very sensitive to environment factors such as perinatal nutrition during this critical time-window of development [62,63]. For example, pups of rodent dams that were fed a HFD demonstrated at birth decreased mRNA expression of neuropeptides NPY and POMC, as well as leptin receptor and signal transducer and activator of transcription 3 (STAT3) expression, which are associated with hyperphagic behavior [64]. These findings suggest that a maternal HFD leads to dysregulation of central appetite control in very early life, and this could contribute to the development of obesity in later life. Furthermore, offspring from dams fed a HFD during gestation and lactation demonstrated hypothalamic inflammation at weaning characterized by an upregulation of the


TLR4 signaling cascade and activation of JNK-1 and IkB kinase-b (IKKB) pathways. These were associated with impaired glucose tolerance and increased hepatic gluconeogenesis [65]. Using a model of IUGR, Fukami and colleagues showed that impairment of hypothalamic insulin signaling contributes to hyperphagia in IUGR offspring. After an intracerebroventricular injection of insulin, the IUGR pups showed a persistent state of orexigenic stimulation (NPY neurons) in the arcuate (ARC) nucleus and relative resistance to anorexigenic (POMC neurons) effects [66]. Pups from rodent mothers who were moderately caloric-restricted during gestation also showed altered hypothalamic structure and function and leptin resistance [67]. The progressive loss of hypothalamic neuronal response to leptin and insulin appears to be a common mechanism linking a range of suboptimal early exposures (including both under- and overnutrition) to the development of central leptin and insulin resistance and increased risk of obesity and T2D later in life [68,69]. Skeletal muscle. Skeletal muscle is a key insulin-sensitive tissue and the major site of glucose disposal postprandially. Thus, skeletal muscle is strongly involved in the development of systemic insulin resistance [70]. Skeletal muscle development starts during the fetal period and it is believed that muscle fiber number is established by birth. Mesenchymal stem cells generate all the cells involved in fetal skeletal muscle development, which involves myogenesis, adipogenesis, and fibrogenesis processes. Any dysregulation of these processes could compromise the number and/or the composition of the muscle fibers, and this could negatively affect function including contractile activity, insulin sensitivity, oxidative capacity, and mitochondrial function [71]. For example, rats born to mothers fed a cafeteria diet during pregnancy and lactation had a 25% reduction in muscle cross-sectional area, with approximately 20% fewer fibers compared with control pups. Moreover, they had increased intramuscular lipid and reduced muscle cell proliferation and insulin receptor expression [72]. In an ovine model of maternal obesity during pregnancy, fetal muscle demonstrated insulin resistance, inflammation, ectopic lipid deposition, and alterations in fundamental proteins involved in glucose and lipid metabolism including AKT and AMP- activated protein kinase (AMPK) [73]. Consistent with these observations, female offspring of obese dams demonstrated decreased muscle expression of p110b (a catalytic subunit of P13K), as well as reduced IRS-1 content and AKT phosphorylation at serine residue 473, compared with control offspring at 3 months of age [74]. Furthermore, a study in rats demonstrated that a maternal HFD resulted in impaired myogenesis and reduced glucose transporter type 4 (GLUT4) (the major insulin-stimulated glucose transporter) in skeletal muscle. These effects were exaggerated if the offspring were weaned onto a HFD [75]. Ozanne and colleagues, in a study using skeletal muscle biopsies of young adult men with low birth-weight, demonstrated that protein kinase C z (PKCz), the p85a and p110b subunits of PI3K, and GLUT4 were reduced in low birth-weight men. These observations were similar to those observed in the maternal LP rat model [14]. This supports the use of the rodent 529

Review model as an accurate representation of the human situation and suggests that programming of insulin signaling protein expression is a fundamentally conserved process. Adipose tissue. Adipose tissue has emerged as an important endocrine organ, crucial in metabolic homeostasis. It contributes to whole-body insulin sensitivity both through taking up glucose in an insulin-dependent manner and influencing insulin sensitivity of other tissues by releasing free fatty acids and adipokines [76,77]. A suboptimal in utero nutritional environment that results in adipocyte dysfunction could therefore lead to development of increased adiposity, inflammation, and altered secretion of adipokines, all of which would predispose the offspring to the development of an insulin-resistant phenotype [78]. In a sheep model of early- to mid-gestational nutrient restriction (NR) followed by a postnatal obesogenic environment, NR offspring had adipose tissue dysfunction characterized by endoplasmic reticulum (ER) stress, insulin resistance, and increased macrophage infiltration, leading to lipid accumulation in other organs such as skeletal muscle and liver [79]. The precise mechanisms underlying such alterations in adipose tissue remain unanswered. However, it has been suggested that the sympathetic nervous system (SNS), which influences lipolysis and adipocyte proliferation, may be involved, at least in part, in mediating the effects of nutritional programming on adipose tissue [80]. Liver. This tissue is central in the maintenance of energy homeostasis, with several important functions in glucose and lipid metabolism. It is the main source of glucose during fasting and a major storage site for glycogen. Studies using several animal models have demonstrated that a maternal HFD can negatively affect liver metabolism and insulin sensitivity in the offspring, and increase the risk of non-alcoholic fatty liver disease, through several distinct mechanisms. These include an increase in ROS with concomitant decrease in antioxidant defenses, as well as decreased expression of mitochondrial genes involved in fatty acid oxidation [81]. Additional suggested mechanisms include elevated expression of gluconeogenic enzymes, decreased expression of proteins involved in insulin signaling, activation of inflammatory pathways, and lipotoxicity [82]. The development of fatty liver appears to be an early consequence of IUGR; a study using a rodent model of IUGR showed increased hepatic triglyceride and cholesterol content by 3 weeks of age [83]. Pancreas. Pancreatic b cells are the only cells in the body that can produce insulin and thus are crucial in the regulation of glucose homeostasis. Although b cells are not insulin-sensitive and therefore do not develop insulin resistance, they have the ability to compensate for the insulin-resistant state by secreting more insulin. However, in the case of chronic hyperglycemia, b cells suffer irreversible damage and lose their capacity to produce and secrete insulin, and this leads the organism to be dependent on exogenous insulin [84]. Many reports in a range of species have indicated that suboptimal maternal nutrition such as an obesogenic diet (rich in fat and simple carbohydrates 530


and/or a hypercaloric diet) [85], HFD [86], moderate CR [87], and a LP diet [88] all compromise offspring pancreatic development by affecting structure (b cell mass) and function. In a study with rats exposed to intrauterine CR, the reduction in b cell mass was attributed to a decrease in the rate of b cell replication as well as a potential decrease in b cell neogenesis [89]. As with the liver, defects in the endocrine pancreas have been associated with mitochondrial dysfunction and increased ROS, leading to decreased ATP production [90,91]. Impaired pancreatic function can become particularly apparent when an increased demand for insulin occurs, leading to an increased risk of T2D in later life. Tarry-Adkins and colleagues demonstrated, using the rat LP offspring that underwent rapid postnatal catch-up growth, that a suboptimal early environment led to a premature aging phenotype in islets. This included accelerated telomere shortening that was accompanied by increased oxidative stress and impaired antioxidant defense capacity [92]. Gut. In recent years a growing literature has highlighted the link between gut microbiota composition, its metabolic capacity, and the risk of metabolic diseases such as T2D and obesity [93,94]. Recently, an analysis of human and animal experiments demonstrated that the gut microbiota are strongly involved in the natural development of insulin resistance during the third trimester of pregnancy [95]. Moreover, because colonization by microbiota is thought to start in utero [96], and it is known that the maternal microbiota, vaginal microbiota, and nutrition during breastfeeding may influence this process [97], the concept of programmed changes in gut microbiota is emerging as a novel mechanism underlying nutritional programming. It has been demonstrated that a maternal HFD decreased the functional maturation of the gut and altered its microbiota composition [98]. Studies in humans have also shown that maternal BMI, weight, and weight gain during pregnancy are important in determining the composition of the offspring gut microbiota [99]. These parameters are potentially modifiable by diet and therefore represent a potential therapeutic target. The role of epigenetics The term epigenetics refers to heritable changes in gene expression that are driven by extracellular stimuli and mechanisms that act on DNA but without changing the DNA sequence [100]. The main epigenetic mechanisms are DNA methylation, histone modification, and microRNAs [101]. Epigenetic regulation is crucial to the development and differentiation of various cell types, and offers organisms phenotypic plasticity to help them adapt their gene expression and function in response to the environment. One potential crucial environmental factor is early nutrition that can permanently influence the metabolism of the offspring in a fashion that is transmittable across generations (Box 2) [102]. Maternal suboptimal nutrition leads to a range of physiological and cellular adaptive responses in key organ systems (see above), therefore there must be a retained memory of the perturbed environment in early life. There is growing evidence that this cellular memory may be mediated by changes in the epigenome [103]. Some

Review of the earliest evidence for this came from studies by Waterland and colleagues. They demonstrated using agouti viable yellow mice (that contain a methylation-sensitive transposable element in the agouti gene), that by supplementing pregnant dams with folic acid, vitamin B12, choline, and betaine they could alter the phenotype (including coat color and body weight) of the offspring [102]. Since these studies a decade ago there is a growing literature demonstrating that exposure to a range of nutritional insults during fetal life leads to metabolic dysfunction which is associated with epigenetic changes. For example, modification of the histone H3K9 from methylation to acetylation in the adiponectin promoter region, and increased methylation of histone H4K20 in the leptin promoter region, were associated with reduced adiponectin expression and enhanced leptin expression, respectively, in adipose tissue from offspring exposed to a maternal HFD during gestation [104]. Furthermore, fetal livers of dams fed with a HFD showed higher mRNA content of gluconeogenic genes that were associated with modification of the phosphoenolpyruvate carboxykinase (Pck) histone marks [105]. There is also some evidence that epigenetic mechanisms may contribute to some of the sexually dimorphic effects observed in programming studies. It was demonstrated that a HFD during gestation led to sex-specific epigenetic alterations in DNA methylation across the genome as well as differences in placental, Y- and X-linked histone demethylase paralogs lysine (K)-specific demethylase 5C (Kdm5c) and lysine (K)-specific demethylase 5D (Kdm5d) [106]. Maternal protein restriction and CR during pregnancy can also affect the metabolism of the offspring via epigenetic regulation. Furthermore, transcription factors have emerged as key targets of nutritional programming through epigenetic mechanisms. Adult rat offspring of LP-fed dams had increased expression of peroxisomal proliferator-activated receptor (PPARa) in cardiac tissue, an important transcription factor involved in lipid metabolism, and a parallel decrease in its promoter methylation. These differences were present at birth [107]. The maternal LP diet can also increase the mRNA and protein expression of CCAAT/enhancer-binding protein (C/EBPb), a transcription factor that regulates the expression of genes involved in energy homeostasis, in skeletal muscle of female rodent offspring [108]. Sandovici and colleagues demonstrated that expression of hepatocyte nuclear factor 4a (Hnf4a), a key developmental transcription factor previously implicated in diabetes, was reduced in pancreatic islets following suboptimal nutrition in early life through programmed changes in DNA methylation and histone modifications [109]. Similar studies by Park and colleagues demonstrated the transcription factor Pancreatic and duodenal homeobox 1 (Pdx1) was also susceptible to chromatin remodeling and epigenetic-induced transcriptional silencing as a result of IUGR [110]. Recent studies have also shown that post-transcriptional regulation of gene expression through alterations in microRNAs (miRs) play a key role in mediating the effects of early nutrition on cellular memory. For example, maternal protein restriction in rodents led to a permanent increase in the expression of miR483-3p and reduced expression of its target,


growth differentiation factor-3 (GDF-3), that could influence the ability of adipose tissue to store lipid. This effect was conserved between species, with similar differences being observed in adipose tissue from young men who had a low birth-weight [111]. Furthermore, in a recent study known and novel miRs were identified in human breast milk. It was demonstrated that a maternal HFD altered the expression of these miRs, providing a new potential mechanism underlying the effects of maternal nutrition on the offspring metabolism, and the importance of human breast milk for children [112]. Moreover, studies of individuals prenatally exposed to famine during the Dutch Hunger Winter demonstrated hypomethylation of insulinlike growth factor 2 (IGF-2) compared with their unexposed and same-sex siblings at age 60 [113]. Thus, these findings reinforce the idea of very early life being a crucial period where epigenetic changes are established and maintained throughout life. Future directions and intervention strategies Several reports suggest that insulin resistance plays central role in linking maternal nutrition to the development of several metabolic diseases [114]. Indeed, the development of insulin resistance and subsequent metabolic complications, such as increased glycemia, blood pressure, triglyceride, waist circumference, and decreased highdensity cholesterol, doubles the risk of heart disease and increases fivefold the risk of T2D [115]. Targeting factors that increase risk of developing insulin resistance therefore represents an important priority if we are to prevent some of the most common healthcare issues in the modern world. Although it is widely agreed that suboptimal maternal nutrition has a negative impact on the health of the offspring, effective intervention strategies to prevent the development of metabolic diseases, as a consequence of nutritional programming, is still a challenge. A limited number of intervention studies in rodents with different approaches, such as increased physical activity [116], dietary modulation [117], or pharmacologic interventions [118–120], are starting to emerge. For example, IUGR rodents exposed to postnatal CR show increased metabolic flexibility and leanness compared to those fed ad libitum postnatally [117]. Moreover, early postnatal supplementation with resveratrol, a compound that when ingested might mimic some of the biochemical effects of CR, improved glucose and lipid metabolism in offspring born with IUGR from HFD-fed mothers [121]. Such interventions have targeted the offspring; however, a few studies have focused on maternal interventions. In rodents, an improvement in glucose homeostasis in offspring is observed if maternal LP-fed dams are given water supplemented with the amino acid taurine [122]. Supplementation with n-3 fatty acids or vitamin D during pregnancy has been another strategy explored in animal and human studies; however, results have been mixed and conclusions drawn remain controversial [123,124]. One study in humans showed that regular multivitamin use around the time of conception led to decreased risk of SGA births [125]. In light of the evidence linking gut microbiota composition and metabolism, supplementation with probiotics has been explored as 531

Review a potential intervention. Such studies have shown that it is possible to improve maternal glucose metabolism and reduce the risk of central adiposity and gestational diabetes using probiotic supplements during pregnancy [126– 128]. The long-term metabolic effects of the supplementation on the health of offspring have not yet been established. Recent studies have also started to address the potential benefit of pharmacological interventions during pregnancy on the short- and long-term health of both the mother and child. A recent randomized trial by Rowan and colleagues compared the effects of insulin and metformin (an insulin-sensitizer) treatment of women with gestational diabetes. Although there were no differences in pregnancy outcome, at age 2 years the children born to the metformin-treated mothers had larger measures of subcutaneous body fat, but not overall body fat, compared to the offspring of insulin-treated mothers [129]. The potential long-term beneficial (or detrimental) effects of this remain to be established. More studies are therefore needed, in both humans and animal models, to establish the potential of pharmacological interventions to protect offspring of obese women against suboptimal nutritional programming. Concluding remarks In summary, insulin resistance is an important factor contributing to nutritional programming of T2D and/or cardiovascular disease. Considering the explosive increase in these metabolic diseases in recent years, several types of interventions are being explored in an attempt to prevent the development of insulin resistance in the context of nutritional programming, although more studies are needed to prove their efficacy. Moreover, the involvement of epigenetic mechanisms in this nutritional programming opens up a great potential for the discovery of novel biological markers that could be used to identify offspring at high risk of developing metabolic diseases. Furthermore, the elucidation of new epigenetic mechanisms becomes crucial for the understanding how the effects of nutritional programming could be transmitted across generations. Acknowledgments D.E.D.G. is a Science without Borders-CNPq (Brazil) Postdoctoral Fellow and S.E.O. is a British Heart Foundation Senior Fellow.

References 1 DeFronzo, R.A. (2010) Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009. Diabetologia 53, 1270–1287 2 Cameron, A.J. et al. (2004) The metabolic syndrome: prevalence in worldwide populations. Endocrinol. Metab. Clin. North Am. 33, 351–375 3 DeFronzo, R.A. and Ferrannini, E. (1987) Regulation of hepatic glucose metabolism in humans. Diabetes Metab. Rev. 3, 415–459 4 Johnson, A.M. and Olefsky, J.M. (2013) The origins and drivers of insulin resistance. Cell 152, 673–684 5 Symonds, M.E. et al. (2009) Nutritional programming of the metabolic syndrome. Nat. Rev. Endocrinol. 5, 604–610 6 Burdge, G.C. and Lillycrop, K.A. (2010) Nutrition, epigenetics, and developmental plasticity: implications for understanding human disease. Annu. Rev. Nutr. 30, 315–339 7 Berends, L.M. and Ozanne, S.E. (2012) Early determinants of type-2 diabetes. Best Pract. Res. Clin. Endocrinol. Metab. 26, 569–580

532


8 Remacle, C. et al. (2011) Developmental programming of adult obesity and cardiovascular disease in rodents by maternal nutrition imbalance. Am. J. Clin. Nutr. 94, 1846S–1852S 9 Kind, K.L. et al. (2006) Diet around conception and during pregnancy – effects on fetal and neonatal outcomes. Reprod. Biomed. Online 12, 532– 541 10 Whincup, P.H. et al. (2008) Birth weight and risk of type 2 diabetes: a systematic review. JAMA 300, 2886–2897 11 Victora, C.G. et al. (2008) Maternal and child undernutrition: consequences for adult health and human capital. Lancet 371, 340–357 12 Hales, C.N. et al. (1991) Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 26303, 1019–1022 13 Petry, C.J. et al. (2001) Diabetes in old male offspring of rat dams fed a reduced protein diet. Int. J. Exp. Diabetes Res. 2, 139–143 14 Ozanne, S.E. et al. (2005) Low birth weight is associated with specific changes in muscle insulin-signalling protein expression. Diabetologia 48, 547–552 15 Roseboom, T. et al. (2006) The Dutch famine and its long-term consequences for adult health. Early Hum. Dev. 82, 485–491 16 Li, Y. et al. (2010) Exposure to the Chinese famine in early life and the risk of hyperglycemia and type 2 diabetes in adulthood. Diabetes 59, 2400–2406 17 Stanner, S.A. et al. (1997) Does malnutrition in utero determine diabetes and coronary heart disease in adulthood? Results from the Leningrad siege study, a cross sectional study. BMJ 315, 1342–1348 18 Ozanne, S.E. and Hales, C.N. (1999) The long term consequences of intra-uterine protein malnutrition on glucose metabolism. Proc. Nutr. Soc. 58, 615–619 19 Fernandez-Twinn, D.S. et al. (2005) Maternal protein restriction leads to hyperinsulinemia and reduced insulin signaling protein expression in 21-mo-old female rat offspring. Am. J. Physiol. Regul. Integr. Comp. Physiol. 288, R368–R373 20 Theys, N. et al. (2009) Maternal low-protein diet alters pancreatic islet mitochondrial function in a sex-specific manner in the adult rat. Am. J. Physiol. Regul. Integr. Comp. Physiol. 297, 1516–1525 21 Vo, T.X. et al. (2013) LXR mediates enhanced hepatic gluconeogenic gene expression in adult male rat MPR offspring. J. Endocrinol. http:// dx.doi.org/10.1530/JOE-13-0055 22 Mayeur, S. (2013) Maternal calorie restriction modulates placental mitochondrial biogenesis and bioenergetic efficiency: putative involvement in fetoplacental growth defects in rats. Am. J. Physiol. Endocrinol. Metab. 304, E14–E22 23 Palou, M. et al. (2012) Impaired insulin and leptin sensitivity in the offspring of moderate caloric-restricted dams during gestation is early programmed. J. Nutr. Biochem. 23, 1627–1639 24 Swali, A. et al. (2012) Processes underlying the nutritional programming of embryonic development by iron deficiency in the rat. PLoS ONE 7, e48133 25 Jou, M.Y. et al. (2010) Maternal zinc deficiency in rats affects growth and glucose metabolism in the offspring by inducing insulin resistance postnatally. J. Nutr. 140, 1621–1627 26 Rosenberg, I.H. (2008) Metabolic programming of offspring by vitamin B12/folate imbalance during pregnancy. Diabetologia 51, 6–7 27 Kumar, K.A. et al. (2013) Maternal dietary folate and/or vitamin B12 restrictions alter body composition (adiposity) and lipid metabolism in Wistar rat offspring. J. Nutr. Biochem. 24, 25–31 28 Stewart, C.P. et al. (2011) Low maternal vitamin B-12 status is associated with offspring insulin resistance regardless of antenatal micronutrient supplementation in rural Nepal. J. Nutr. 141, 1912–1917 29 Crozier, S.R. et al. (2012) Maternal vitamin D status in pregnancy is associated with adiposity in the offspring: findings from the Southampton Women’s Survey. Am. J. Clin. Nutr. 96, 57–63 30 Jain, V. and Singhal, A. (2012) Catch up growth in low birth weight infants: striking a healthy balance. Rev. Endocr. Metab. Disord. 13, 141–147 31 Berends, L.M. et al. (2012) Catch-up growth following intra-uterine growth-restriction programmes an insulin-resistant phenotype in adipose tissue. Int. J. Obes. (Lond.) http://dx.doi.org/10.1038/ ijo.2012.196 32 Eriksson, J. et al. (2002) Size at birth, fat-free mass and resting metabolic rate in adult life. Horm. Metab. Res. 34, 72–76

Review 33 Rasmussen, E.L. et al. (2005) Altered fat tissue distribution in young adult men who had low birth weight. Diabetes Care 28, 151–153 34 Vahratian, A. (2009) Prevalence of overweight and obesity among women of childbearing age. Matern. Child Health J. 13, 268–273 35 Alfaradhi, M.Z. and Ozanne, S.E. (2011) Developmental programming in response to maternal overnutrition. Front. Genet. 2, 27 36 Lawlor, D.A. et al. (2011) Does maternal weight gain in pregnancy have long-term effects on offspring adiposity?. A sibling study in a prospective cohort of 146,894 men from 136,050 families. Am. J. Clin. Nutr. 94, 142–148 37 Yu, Z. et al. (2013) Pre-pregnancy body mass index in relation to infant birth weight and offspring overweight/obesity: a systematic review and meta-analysis. PLoS ONE 8, e61627 38 Doshani, A. and Konje, J. (2009) Diabetes in pregnancy. Insulin resistance, obesity, and placental dysfunction. Br. J. Diabetes Vasc. 9, 208–212 39 Bowers, K. et al. (2013) Gestational diabetes, pre-pregnancy obesity and pregnancy weight gain in relation to excess fetal growth: variations by race/ethnicity. Diabetologia 56, 1263–1271 40 Dabelea, D. and Crume, T. (2011) Maternal environment and the transgenerational cycle of obesity and diabetes. Diabetes 60, 1849–1855 41 Catalano, P.M. et al. (2009) Fetuses of obese mothers develop insulin resistance in utero. Diabetes Care 32, 1076–1080 42 Rising, R. and Lifshitz, F. (2008) Lower energy expenditures in infants from obese biological mothers. Nutr. J. 16, 7–15 43 Hedderson, M.M. et al. (2010) Gestational weight gain and risk of gestational diabetes mellitus. Obstet. Gynecol. 115, 597–604 44 Catalano, P.M. (2003) Obesity and pregnancy – the propagation of a viscous cycle? J. Clin. Endocrinol. Metab. 88, 3505–3506 45 Long, N.M. et al. (2010) Maternal obesity and increased nutrient intake before and during gestation in the ewe results in altered growth, adiposity, and glucose tolerance in adult offspring. J. Anim. Sci. 88, 3546–3553 46 Farley, D. et al. (2009) Feto-placental adaptations to maternal obesity in the baboon. Placenta 30, 752–760 47 Ainge, H. et al. (2011) A systematic review on animal models of maternal high fat feeding and offspring glycaemic control. Int. J. Obes. (Lond.) 35, 325–335 48 Samuelsson, A.M. et al. (2008) Diet-induced obesity in female mice leads to offspring hyperphagia, adiposity, hypertension, and insulin resistance: a novel murine model of developmental programming. Hypertension 51, 383–392 49 Howie, G.J. (2009) Maternal nutritional history predicts obesity in adult offspring independent of postnatal diet. J. Physiol. 587, 905–915 50 Carone, B.R. et al. (2010) Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 143, 1084–1096 51 Ng, S.F. et al. (2010) Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature 467, 963–966 52 Ferguson-Smith, A.C. and Patti, M.E. (2011) You are what your dad ate. Cell Metab. 13, 115–117 53 Sibley, C.P. et al. (2010) Review: adaptation in placental nutrient supply to meet fetal growth demand: implications for programming. Placenta 31, 70–74 54 De Castro, J. et al. (2011) Implication of low level inflammation in the insulin resistance of adipose tissue at late pregnancy. Endocrinology 152, 4094–4105 55 Belkacemi, L. et al. (2010) Maternal undernutrition influences placental-fetal development. Biol. Reprod. 83, 325–331 56 Challier, J.C. et al. (2008) Obesity in pregnancy stimulates macrophage accumulation and inflammation in the placenta. Placenta 29, 274–281 57 Zhu, M.J. et al. (2010) Maternal obesity up-regulates inflammatory signaling pathways and enhances cytokine expression in the midgestation sheep placenta. Placenta 31, 387–391 58 Mayeur, S. et al. (2013) Maternal calorie restriction modulates placental mitochondrial biogenesis and bioenergetic efficiency: putative involvement in fetoplacental growth defects in rats. Am. J. Physiol. Endocrinol. Metab. 304, E14–E22 59 Vogt, M.C. and Bruning, J.C. (2013) CNS insulin signaling in the control of energy homeostasis and glucose metabolism – from embryo to old age. Trends Endocrinol. Metab. 24, 76–84


60 Hill, J.W. et al. (2010) Direct insulin and leptin action on proopiomelanocortin neurons is required for normal glucose homeostasis and fertility. Cell Metab. 11, 286–297 61 Bruning, J.C. et al. (2000) Role of brain insulin receptor in control of body weight and reproduction. Science 289, 2122–2125 62 Grove, K.L. et al. (2005) Development of metabolic systems. Physiol. Behav. 86, 646–660 63 Bouret, S.G. (2010) Role of early hormonal and nutritional experiences in shaping feeding behavior and hypothalamic. J. Nut. 140, 653–657 64 Morris, M.J. and Chen, H. (2009) Established maternal obesity in the rat reprograms hypothalamic appetite regulators and leptin signaling at birth. Int. J. Obes. (Lond.) 33, 115–122 65 Rother, E. et al. (2012) Hypothalamic JNK1 and IKKb activation and impaired early postnatal glucose metabolism after maternal perinatal high-fat feeding. Endocrinology 153, 770–781 66 Fukami, T. et al. (2012) Mechanism of programmed obesity in intrauterine fetal growth restricted offspring: paradoxically enhanced appetite stimulation in fed and fasting states. Reprod. Sci. 19, 423–430 67 Garcia, A.P. et al. (2010) Moderate caloric restriction during gestation results in lower arcuate nucleus NPY- and alphaMSH-neurons and impairs hypothalamic response to fed/fasting conditions in weaned rats. Diabetes Obes. Metab. 12, 403–413 68 Bouret, S.G. (2012) Nutritional programming of hypothalamic development: critical periods and windows of opportunity. Int. J. Obesity Suppl. 2, S19–S24 69 Isganaitis, E. and Lustig, R.H. (2005) Fast food, central nervous system, insulin resistance and obesity. Arterioscler. Thromb. Vasc. Biol. 25, 2451–2462 70 Jornayvaz, F.R. et al. (2010) The role of muscle insulin resistance in the pathogenesis of atherogenic dyslipidemia and nonalcoholic fatty liver disease associated with the metabolic syndrome. Annu. Rev. Nutr. 30, 273–290 71 Du, M. et al. (2010) Maternal obesity, inflammation and fetal skeletal muscle development. Biol. Reprod. 82, 4–12 72 Bayol, S.A. et al. (2005) A maternal cafeteria diet during gestation and lactation promotes adiposity and impairs skeletal muscle development and metabolism in rat offspring at weaning. J. Physiol. 567, 951–961 73 Yan, X. et al. (2010) Up-regulation of Toll-like receptor 4/nuclear factorkappaB signaling is associated with enhanced adipogenesis and insulin resistance in fetal skeletal muscle of obese sheep at late gestation. Endocrinology 151, 380–387 74 Shelley, P. et al. (2009) Altered skeletal muscle insulin signaling and mitochondrial complex II-III linked activity in adult offspring of obese mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 297, 675–681 75 Simar, D. et al. (2012) Interaction between maternal obesity and postnatal over-nutrition on skeletal muscle metabolism. Nutr. Metab. Cardiovasc. Dis. 22, 269–276 76 Tchernof, A. and Despres, J.P. (2013) Pathophysiology of human visceral obesity: an update. Physiol. Rev. 93, 359–404 77 Rosen, E.D. and Spiegelman, B.M. (2006) Adipocytes as regulators of energy balance and glucose homeostasis. Nature 444, 847–853 78 Symonds, M.E. et al. (2012) Adipose tissue and fetal programming. Diabetologia 55, 1597–1606 79 Sharkey, D. et al. (2009) Adipose tissue inflammation: developmental ontogeny and consequences of gestational nutrient restriction in offspring. Endocrinology 150, 3913–3920 80 Garcia, A.P. et al. (2011) Moderate caloric restriction during gestation in rats alters adipose tissue sympathetic innervation and later adiposity in offspring. PLoS ONE 6, e17313 81 Borengasser, S.J. et al. (2011) Maternal obesity during gestation impairs fatty acid oxidation and mitochondrial SIRT3 expression in rat offspring at weaning. PLoS ONE 6, e24068 82 Ashino, N.G. et al. (2012) Maternal high-fat feeding through pregnancy and lactation predisposes mouse offspring to molecular insulin resistance and fatty liver. J. Nutr. Biochem. 23, 341–348 83 Choi, G.Y. et al. (2007) Gender-specific programmed hepatic lipid dysregulation in intrauterine growth-restricted offspring. Am. J. Obstet. Gynecol. 196, 477.e1–477.e7 84 Muoio, D.M. and Newgard, C.B. (2008) Mechanisms of disease: molecular and metabolic mechanisms of insulin resistance and betacell failure in type 2 diabetes. Nat. Rev. Mol. Cell Biol. 9, 193–205 533

Review 85 Ford, S.P. et al. (2009) Maternal obesity accelerates fetal pancreatic beta-cell but not alpha-cell development in sheep: prenatal consequences. Am. J. Physiol. Regul. Integr. Comp. Physiol. 297, R835–R843 86 Cerf, M.E. et al. (2012) High-fat programming of hyperglycemia, hyperinsulinemia, insulin resistance, hyperleptinemia, and altered islet architecture in 3-month-old wistar rats. ISRN Endocrinol. 2012, 627270 87 Choi, J. et al. (2011) Emergence of insulin resistance in juvenile baboon offspring of mothers exposed to moderate maternal nutrient reduction. Am. J. Physiol. Regul. Integr. Comp. Physiol. 301, R757–R762 88 Theys, N. et al. (2009) Maternal low-protein diet alters pancreatic islet mitochondrial function in a sex-specific manner in the adult rat. Am. J. Physiol. Regul. Integr. Comp. Physiol. 297, R1516–R1525 89 Matveyenko, A.V. et al. (2010) Differential effects of prenatal and postnatal nutritional environment on ß-cell mass development and turnover in male and female rats. Endocrinology 151, 5647–5656 90 Theys, N. et al. (2011) Maternal malnutrition programs pancreatic islet mitochondrial dysfunction in the adult offspring. J. Nutr. Biochem. 22, 985–994 91 Reusens, B. et al. (2011) Maternal malnutrition programs the endocrine pancreas in progeny. Am. J. Clin. Nutr. 94, 1824S–1829S 92 Tarry-Adkins, J.L. et al. (2009) Poor maternal nutrition followed by accelerated postnatal growth leads to telomere shortening and increased markers of cell senescence in rat islets. FASEB J. 23, 1521–1528 93 Tremaroli, V. and Backhed, F. (2012) Functional interactions between the gut microbiota and host metabolism. Nature 489, 242–249 94 Clemente, J.C. et al. (2012) The impact of the gut microbiota on human health: an integrative view. Cell 148, 1258–1270 95 Koren, O. et al. (2012) Host remodeling of the gut microbiome and metabolic changes during pregnancy. Cell 150, 470–480 96 Jimenez, E. et al. (2008) Is meconium from healthy newborns actually sterile? Res. Microbiol. 159, 187–193 97 Nicholson, J.K. et al. (2012) Host–gut microbiota metabolic interactions. Science 336, 1262–1267 98 Kim, K.A. et al. (2012) High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway. PLoS ONE 7, e47713 99 Collado, M.C. et al. (2010) Effect of mother’s weight on infant’s microbiota acquisition, composition, and activity during early infancy: a prospective follow-up study initiated in early pregnancy. Am. J. Clin. Nutr. 92, 1023–1030 100 Bird, A. (2007) Perceptions of epigenetics. Nature 447, 396–398 101 Margueron, R. and Reinberg, D. (2010) Chromatin structure and the inheritance of epigenetic information. Nat. Rev. Genet. 11, 285–296 102 Waterland, R.A. et al. (2008) Methyl donor supplementation prevents transgenerational amplification of obesity. Int. J. Obes. (Lond.) 32, 1373–1379 103 Ozanne, S.E. et al. (2007) Mechanisms of disease: the developmental origins of disease and the role of the epigenotype. Nat. Clin. Pract. Endocrinol. Metab. 3, 539–546 104 Masuyama, H. and Hiramatsu, Y. (2012) Effects of a high-fat diet exposure in utero on the metabolic syndrome-like phenomenon in mouse offspring through epigenetic changes in adipocytokine gene expression. Endocrinology 153, 2823–2830 105 Strakovsky, R.S. et al. (2011) Gestational high fat diet programs hepatic phosphoenolpyruvate carboxykinase gene expression and histone modification in neonatal offspring rats. J. Physiol. 589, 2707–2717 106 Gabory, A. et al. (2012) Maternal diets trigger sex-specific divergent trajectories of gene expression and epigenetic systems in mouse placenta. PLoS ONE 7, e47986 107 Slater-Jefferies, J.L. et al. (2011) Feeding a protein-restricted diet during pregnancy induces altered epigenetic regulation of peroxisomal proliferator-activated receptor-a in the heart of the offspring. J. Dev. Orig. Health Dis. 2, 250–255 108 Zheng, S. et al. (2011) Maternal protein restriction during pregnancy induces CCAAT/enhancer-binding protein (C/EBPb) expression through the regulation of histone modification at its promoter region in female offspring rat skeletal muscle. Epigenetics 6, 161–170

534


109 Sandovici, I. et al. (2011) Maternal diet and aging alter the epigenetic control of a promoter-enhancer interaction at the Hnf4a gene in rat pancreatic islets. Proc. Natl. Acad. Sci. U.S.A. 108, 5449–5454 110 Park, J.H. et al. (2008) Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1. J. Clin. Invest. 118, 2316–2324 111 Ferland-McCollough, D. et al. (2012) Programming of adipose tissue miR-483-3p and GDF-3 expression by maternal diet in type 2 diabetes. Cell Death Differ. 19, 1003–1012 112 Munch, E.M. et al. (2013) Transcriptome profiling of microRNA by next-gen deep sequencing reveals known and novel miRNA species in the lipid fraction of human breast milk. PLoS ONE 8, e50564 113 Heijmans, B.T. et al. (2008) Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc. Natl. Acad. Sci. U.S.A. 105, 17046–17049 114 Martin-Gronert, M.S. and Ozanne, S.E. (2012) Metabolic programming of insulin action and secretion. Diabetes Obes. Metab. 14 (Suppl. 3), 29–39 115 Ma, X. and Zhu, S. (2013) Metabolic syndrome in the prevention of cardiovascular diseases and diabetes – still a matter of debate? Eur. J. Clin. Nutr. 67, 518–521 116 Rajia, S. et al. (2012) Voluntary post weaning exercise restores metabolic homeostasis in offspring of obese rats. Nutr. Metab. Cardiovasc. Dis. http://dx.doi.org/10.1016/j.numecd.2011.12.009 117 Garg, M. et al. (2012) Early postnatal caloric restriction protects adult male intrauterine growth-restricted offspring from obesity. Diabetes 61, 1391–1398 118 Raab, E.L. et al. (2009) Neonatal exendin-4 treatment reduces oxidative stress and prevents hepatic insulin resistance in intrauterine growth-retarded rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 297, R1785–R1794 119 Garg, M. et al. (2010) Early exposure of the pregestational intrauterine and postnatal growth-restricted female offspring to a peroxisome proliferator-activated receptor-{gamma} agonist. Am. J. Physiol. Endocrinol. Metab. 298, E489–E498 120 Kalanderian, A. et al. (2013) Pioglitazone therapy in mouse offspring exposed to maternal obesity. Am. J. Obstet. Gynecol. 208, 308 e1–e7 121 Dolinsky, V.W. et al. (2011) Continued postnatal administration of resveratrol prevents diet-induced metabolic syndrome in rat offspring born growth restricted. Diabetes 60, 2274–2284 122 Mortensen, O.H. et al. (2010) Gestational protein restriction in mice has pronounced effects on gene expression in newborn offspring’s liver and skeletal muscle; protective effect of taurine. Pediatr. Res. 67, 47–53 123 Bringhenti, I. et al. (2011) An early fish oil-enriched diet reverses biochemical, liver and adipose tissue alterations in male offspring from maternal protein restriction in mice. J. Nutr. Biochem. 22, 1009–1014 124 von Hurst, P.R. et al. (2010) Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient – a randomised, placebocontrolled trial. Br. J. Nutr. 103, 549–555 125 Catov, J.M. et al. (2011) Periconceptional multivitamin use and risk of preterm or small-for-gestational-age births in the Danish National Birth Cohort. Am. J. Clin. Nutr. 94, 906–912 126 Laitinen, K. et al. (2009) Probiotics and dietary counselling contribute to glucose regulation during and after pregnancy: a randomised controlled trial. Br. J. Nutr. 101, 1679–1687 127 Luoto, R. et al. (2010) Impact of maternal probiotic-supplemented dietary counselling on pregnancy outcome and prenatal and postnatal growth: a double-blind, placebo-controlled study. Br. J. Nutr. 103, 1792–1799 128 Ilmonen, J. et al. (2011) Impact of dietary counselling and probiotic intervention on maternal anthropometric measurements during and after pregnancy: a randomized placebo-controlled trial. Clin. Nutr. 30, 156–164 129 Rowan, J.A. et al. (2011) Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition at 2 years of age. Diabetes Care 34, 2279–2284 130 Reynolds, L.P. and Caton, J.S. (2012) Role of the pre- and post-natal environment in developmental programming of health and productivity. Mol. Cell. Endocrinol. 354, 54–59 131 Gluckman, P.D. et al. (2008) Effect of in utero and early-life conditions on adult health and disease. N. Engl. J. Med. 359, 61–73

Review 132 Hales, C.N. and Barker, D.J. (2001) The thrifty phenotype hypothesis. Br. Med. Bull. 60, 5–20 133 Barker, D.J. et al. (1993) Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia 36, 62–67 134 Gluckman, P.D. et al. (2009) Towards a new developmental synthesis: adaptive developmental plasticity and human disease. Lancet 373, 1654–1657 135 Vaag, A.A. et al. (2012) The thrifty phenotype hypothesis revisited. Diabetologia 55, 2085–2088 136 Reinehr, T. et al. (2009) Small for gestational age status is associated with metabolic syndrome in overweight children. Eur. J. Endocrinol. 160, 579–584 137 Meas, T. et al. (2010) Independent effects of weight gain and fetal programming on metabolic complications in adults born small for gestational age. Diabetologia 53, 907–913 138 Chen, W. et al. (2012) Low birth weight is associated with higher blood pressure variability from childhood to young adulthood: the Bogalusa Heart Study. Am. J. Epidemiol. 176 (Suppl. 7), S99–S105 139 87 Poulsen, P. et al. (1997) Low birth weight is associated with NIDDM in discordant monozygotic and dizygotic twin pairs. Diabetologia 40, 439–446


140 Lima Nda, S. et al. (2011) Early weaning causes undernutrition for a short period and programmes some metabolic syndrome components and leptin resistance in adult rat offspring. Br. J. Nutr. 105, 1405–1413 141 Kappeler, L. et al. (2009) Early postnatal nutrition determines somatotropic function in mice. Endocrinology 150, 314–323 142 Wright, T.M. et al. (2011) Exposure to maternal consumption of cafeteria diet during the lactation period programmes feeding behaviour in the rat. Int. J. Dev. Neurosci. 29, 785–793 143 Todd, S.E. et al. (2009) Periconceptional undernutrition of ewes impairs glucose tolerance in their adult offspring. Pediatr. Res. 65, 409–413 144 de Oliveira, J.C. et al. (2013) Poor pubertal protein nutrition disturbs glucose-induced insulin secretion process in pancreatic islets and programs rats in adulthood to increase fat accumulation. J. Endocrinol. 216, 195–206 145 Skinner, M.K. et al. (2010) Epigenetic transgenerational actions of environmental factors in disease etiology. Trends Endocrinol. Metab. 21, 214–222 146 Hoile, S.P. et al. (2011) Dietary protein restriction during F0 pregnancy in rats induces transgenerational changes in the hepatic transcriptome in female offspring. PLoS ONE 6, e21668 147 Burdge, G.C. et al. (2011) Progressive, transgenerational changes in offspring phenotype and epigenotype following nutritional transition. PLoS ONE 6, e28282

535