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Endocrinology. Mar 2012; 153(3): 1031–1038.
Published online Jan 17, 2012. doi:  10.1210/en.2011-1805
PMCID: PMC3281534

Minireview: Epigenetic Programming of Diabetes and Obesity: Animal Models


A growing body of evidence suggests that the intrauterine (IU) environment has a significant and lasting effect on the long-term health of the growing fetus and the development of metabolic disease in later life as put forth in the fetal origins of disease hypothesis. Metabolic diseases have been associated with alterations in the epigenome that occur without changes in the DNA sequence, such as cytosine methylation of DNA, histone posttranslational modifications, and micro-RNA. Animal models of epigenetic modifications secondary to an altered IU milieu are an invaluable tool to study the mechanisms that determine the development of metabolic diseases, such as diabetes and obesity. Rodent and nonlitter bearing animals are good models for the study of disease, because they have similar embryology, anatomy, and physiology to humans. Thus, it is feasible to monitor and modify the IU environment of animal models in order to gain insight into the molecular basis of human metabolic disease pathogenesis. In this review, the database of PubMed was searched for articles published between 1999 and 2011. Key words included epigenetic modifications, IU growth retardation, small for gestational age, animal models, metabolic disease, and obesity. The inclusion criteria used to select studies included animal models of epigenetic modifications during fetal and neonatal development associated with adult metabolic syndrome. Experimental manipulations included: changes in the nutritional status of the pregnant female (calorie-restricted, high-fat, or low-protein diets during pregnancy), as well as the father; interference with placenta function, or uterine blood flow, environmental toxin exposure during pregnancy, as well as dietary modifications during the neonatal (lactation) as well as pubertal period. This review article is focused solely on studies in animal models that demonstrate epigenetic changes that are correlated with manifestation of metabolic disease, including diabetes and/or obesity.

The incidence of metabolic disease here and worldwide has reached epidemic proportions. A recent study, in which data for trends in glycemia and diabetes prevalence were obtained for adults, 25 yr of age and older, in 199 countries and territories, found that the number of people with diabetes had increased from approximately 153 million in 1980 to 347 million in 2008 (1). Of growing concern is the fact that the age of onset of these diseases has accelerated such that children and young adults are the fastest growing population with these conditions, which presents a significant human health problem. Genome-wide association studies, family linkages, and candidate gene analyses have all failed to account thus far for this rapid increase in incidence, early onset, and severity of these diseases. Epidemiological studies have suggested that modifications of the epigenome due to alterations in the intrauterine (IU) environment could play a significant role in the manifestation as well as the increased susceptibility to metabolic disease in later life. This concept, also known as the fetal origins of adult disease, has been extensively reviewed elsewhere (2, 3). There is evidence as well to suggest that postnatal alteration of the epigenome can also be associated with diabetes and obesity (4).

Molecular insight into some of the alterations in the epigenome has been gained from human population studies and animal models designed to mimic the human condition. These epigenomic modifications include posttranslational modifications (PTM) of specific amino acids on the tails of the histone subunits and the differentially methylated regions (DMR) of DNA (5, 6). These modifications alter chromatin packing, resulting in either “open” or “closed” states and thus affect gene expression. Some histone PTM, such as acetylation, are labile and associated with gene activation, others, such as methylation, are stable and are associated with gene inactivation (7). A number of studies has identified specific epigenetic changes associated with perturbations of the IU environment; thus, providing insight on some of the alterations of the epigenome in key organs of metabolism involved in glucose homeostasis, insulin sensitivity, and energy balance. They demonstrate how the IU environment may impact disease pathogenesis and suggest that these changes can be transmitted across multiple generations. Most of what we know about the epigenetic changes associated with metabolic disease has been gathered from animal models; thus, illustrating their utility. We will describe the benefits and limitations of each animal model as it relates to improving strategies to prevent diabetes and obesity in the future. A brief summary of all the known epigenetic changes that have been identified from animal models of diabetes and obesity are summarized in Table 1.

Table 1.
Metabolic disease-related genes whose methylation status is changed by a maternal or paternal effect during prenatal, neonatal, or pubertal stage of development

Maternal Nutrition

Nutrient manipulation during pregnancy [high fat (HF), low protein (LP), or global caloric restriction] has been an established model of fetal growth restriction in humans (8) and animal models (9). These dietary alterations result in poor fetal growth followed by an early life catch up growth that increases the exposed offspring's susceptibility to insulin resistance, diabetes, and obesity later in life (9, 10). Studies using isolated mouse embryos have shown that culture conditions and the availability of nutrients can alter the expression of imprinted genes, such as the maternally expressed imprinted gene H19 (11) and the DMR upstream of H19. The latter was associated with a decreased expression of H19 and the IGF-II genes (12).

LP diets (8 vs. 20%) are associated with impaired fetal growth and the development of obesity, diabetes, and hypertension in the offspring (13, 14). Many epigenetic changes have been reported in diverse organs of offspring exposed to a maternal LP diet. In the liver of a LP Wistar rat model, decreased acetylation of histone H3 lysine K9 and K14 and increased histone H3K9me3 was shown to be associated with decreased fetal hepatic Jmjd2a (histone H3 K9 demethylase) expression, decreased cholesterol 7α-hydroxylase (Cyp7a1) expression and increased cholesterol levels (15). Also in Wistar rats, LP diet has been associated with hypomethylation of the promoter of the glucocorticoid receptor (GR) (16) in addition to a reduction in DNA methyltransferase (DNMT)1 expression and reduced expression and binding of methyl CpG binding protein 2 (MeCP2) in liver. This was correlated with altered histone modifications at the GR110 promoter (H3K9 and H4K9 hyperacetylation, increased H3K4 methylation and H3K9me3) that resulted in increased GR promoter activity (17). Another epigenetic change associated with a LP diet in this model is DNA hypomethylation of the peroxisomal proliferator-activated receptor α (PPARα) promoter that resulted in increased PPARα expression (16). In Sprague Dawley (SD) rats, LP diet resulted in DNA hypermethylation of H19/IGF-II locus, in addition to an increased expression of DNMT1, DNMT3a, and methyl-CpG binding domain protein 2 in liver of male offspring associated with increased expression of IGF-II and H19 (18). Additionally, LP diet in C57BL/6J mice is associated with DNA hypermethylation of the liver X-receptor (LXR)α promoter and reduced mRNA levels of LXRα and its target genes Abcg5/Abcg8 in fetal liver (19). In skeletal muscle (SM), a LP diet in SD rats is associated with hyperacetylation of lysines on histones H3 and H4 in the promoter region of (CCAAT/enhancer binding protein β, C/EBPβ) along with increased levels of C/EBPβ mRNA and protein levels in liver of female offspring (20, 21). Similarly, increased gene expression was measured for the amino acid response pathway and phosphoenol pyruvate carboxykinase (PEPCK), and the latter was associated with increased histone H3K9me3 and acetylated H4 (20, 21). In the SM of Meishan pigs exposed to a maternal LP diet, increased H3 acetylation and H3K27me (3) and decreased H3K9me on the myostatin promoter were observed (22). Lastly, IU exposure to a LP diet in Balb/c mice is associated with DNA hypomethylation of the leptin promoter in adipose tissue, changes in body composition (lower weight/adiposity), and increased food consumption in male offspring (23).

Nutrient restriction during gestation is also associated with metabolic dysfunction, including hypertension, hyperinsulinemia, hyperleptinemia, and obesity (24). Maternal caloric restriction (70% metabolizable energy) has been associated with several epigenetic changes. In a sheep model, it was associated with DNA hypomethylation of the proximal CTCF binding site in DMR of the IGF-II/H19 gene in the adrenal gland that is associated with decreased expression of IGF-II along with an increase in adrenal gland growth in both male and female offspring and an increase in the cortisol stress response in females (25). In SM of SD rats, calorie restriction resulted in increased histone H3K14 deacetylation, which is associated with increased recruitment of histone deacetylase (HDAC)1 and HDAC4 (26). Also reported was an increase in H3K9me2 that was associated with increased SUV39H1 methylase activity and reduced glucose transporter 4 mRNA and protein expression that correlated with insulin resistance, increased adiposity, hypertension, and alterations in immune response in male offspring (26). In fetal liver of sheep, maternal restriction of vitamin B12, folate, and methionine altered DNA methylation of 4% of the 1400 CpG islands examined, and more than half of these changes were specific to male offspring (27).

Consumption of a HF diet during gestation (35–60% of calories from fat) is associated with phenotypic changes in offspring such as obesity, hypertension, abnormal cholesterol metabolism, and cardiovascular disease (13). HF diet has been associated with epigenetic changes in several animal models. In Japanese macaques that consumed a HF diet during gestation (35% calories from fat), hyperacetylation of histone H3K14, H3K9, and H3K18, along with an increase in DNMT1 expression, a decrease in HDAC1 expression, and an increase in hepatic triglycerides, was observed in fetal offspring liver (embryonic d 130 of 167 d) (28). In the brain of mice (C57BL/6J x DBA/2J F1 hybrids), a HF diet was associated with global and gene-specific promoter DNA hypomethylation, including the dopamine reuptake transporter, the μ opioid receptor (MOR), and preproenkephalin that was associated with altered dopamine and opioid gene expression as well as a change in feeding behavior (29). During the postnatal period of these mice, HF diet exposure was associated with increased DNA methylation and MeCP2 binding in the MOR promoter region of reward-related brain regions as well as increased H3K9 methylation and decreased H3 acetylation. These epigenomic changes were accompanied by decreased MOR expression in the ventral tegmental area, nucleus accumbens, and prefrontal cortex but not the hypothalamus and a decreased preference for sucrose in offspring (30). At present, it is unclear whether the abundance of reported epigenetic alterations, secondary to altered fetal nutrient availability, is critical for metabolic well being or if this is the most studied IU perturbation.

Surgical Models

Bilateral and unilateral uterine artery ligation of the pregnant rat has been used to generate a model of fetal growth restriction (31). This procedure is performed at d 18 or 19 of gestational age and is a model of both nutrient restriction as well as one of hypoxic exposure. These maternal manipulations have been associated with insulin resistance, glucose intolerance, hyperglycemia, hyperinsulinemia, and the development of diabetes in adulthood (32, 33).

Bilateral uterine ligation is associated with epigenetic changes in several organs. In liver, it resulted in epigenetic changes in the histone code along the entire length of IGF-I gene, resulting in decreased IGF-I levels in male and female SD rat offspring (31). In pancreatic islets, bilateral uterine ligation caused reduced expression of pancreatic and duodenal homeobox 1 (PDX1), which was accompanied by a general deacetylation of histone H3 and H4 in the PDX1 proximal promoter of male SD rats (34). Similarly, after birth, there was a decrease in histone H3K4me (3) and an increase in H3K9me2 followed by methylation of the CpG island in the proximal promoter of PDX1, resulting in gene silencing after the onset of diabetes (34) Additionally, in pancreatic islets, a genome-wide survey of male SD rat offspring showed altered DNA methylation of approximately 1400 loci that occurred predominantly in intergenic regions (35). The uterine artery ligation model of programmed metabolic disease yields a robust metabolic phenotype in offspring, yet there is a paucity of alterations in the epigenome. One may have assumed that epigenetic changes seen in this model might be overlapping with the nutrient restriction models discussed above. However, no overlap has been reported among these models, suggesting the hypoxia component of the uterine artery ligation model may be a dominant factor.

Environmental Toxins

Environmental exposure to toxins, such as heavy metals like arsenic, has been associated with increased risk for development of type 2 diabetes (36, 37). These toxins cause mitochondrial damage and increases oxidative stress in SM, as well as causing altered glucose and cholesterol metabolism, insulin resistance, and obesity (38, 39). Arsenic exposure during development is associated with global DNA hypomethylation of GC-rich regions as well as altered expression of genes in the insulin-like growth factor signaling pathway such as IGF-1, IGF receptor 2, and IGF binding protein 1, as well as the stress response genes metallothionein 1 in liver of male C3H offspring (40). Despite the correlation between toxin exposure and programmed metabolic disease, little is known about the epigenomic alterations associated with this model.

Paternal Effect

Paternal diet can also affect the health of his offspring. As shown by Ng et al. (41), paternal HF diet exposure programs pancreatic β-cell dysfunction that leads to metabolic abnormality in F1 female offspring of SD rats, illustrating a sexually dimorphic response. The underlying mechanism for this could be dependent upon the hormonal differences between offspring or other mechanisms that have yet to be described. Paternal LP diet exposure programmed elevated hepatic mRNA expression of genes involved in lipid and cholesterol biosynthesis and decreased levels of cholesterol esters in C57BL/6J mice. These changes were associated with a modest increase in DNA methylation of the upstream region of the PPARα gene (42). Considering that the father's diet condition is inherited without changes to the DNA code itself, these findings suggest that sperm can undergo epigenetic alterations that are passed on to the offspring.

Effect of Neonatal Feeding

Epigenetic changes have also been shown to occur during the neonatal period (43). Leptin treatment in male Wistar rats during the suckling period is associated with DNA hypermethylation of proopiomelanocortin promoter in the hypothalamus that is involved in appetite and body weight control (44). Similarly, exendin 4 treatment during the neonatal period modified the hyperacetylation of histone H3 in the proximal promoter of PDX1 in pancreatic islets of SD rats (45). These results illustrate that the diversity of epigenetic modifications that have profound effects on energy balance and pancreatic development, contributing to obesity and diabetes pathogenesis, can be programmed during the neonatal period.

Transgenerational Effect

In general, epigenetic modifications are cleared and reestablished with each generation. However, in some cases, the epigenetic state at these alleles can be transmitted between generations. Burdge et al. (46) reported that the PPARα and GR promoters are hypomethylated in liver of male Wistar rat offspring exposed to a LP diet, although the expression of these genes was not different between the reference diet group and the LP diet. Interestingly, using this LP diet model, DNA hypomethylation of the hepatic PPARα and GR promoters seen in the F1 generation were transmitted to the F2 generation (46). Another study demonstrated that relatively few of these changes are consistently transmitted to the F3 generation (47). Of these, PEPCK promoter methylation and mRNA expression, as well as expression of genes in the adherens junctions pathway, were altered out to the F3 generation along with increased fasting glycemia. These findings imply that transmission of the altered epigenetic modification associated with altered maternal nutrient intake can be transmitted for at least one additional generation; however, changes in the interaction between the maternal phenotype and the environment can alter the signals received by the developing fetus, emphasizing again the correlation between altered fetal nutrient availability and epigenomic change.

Reversibility of Epigenetic Changes

The viable yellow agouti (Avy) mouse model, a sensor for nutritional and environmental alterations on the fetal epigenome (48), has been shown to cause variation in coat color, glucose tolerance, and tumor susceptibility according to the exposure to different nutrients during development (49). The Avy allele is a metastable epiallele that can be modified by epigenetic modifications that are established very early during development. Several dietary manipulations have been used to determine the effect of nutrients on the fetal epigenome. These studies include methyl supplementation of nonagouti a/a females with vitamin B12, choline, and betaine, which affects the phenotype of the Avy/a offspring by increasing CpG methylation at the Avy locus (50), leading to the coat color distribution of the offspring being shifted toward the pseudoagouti phenotype. Similarly, maternal dietary supplementation with genistein (phytoestrogen found in soy) results in hypermethylation of CpG sites, causing a decreased ectopic agouti expression protecting the offspring from obesity (51).

In other animal models, epigenetic modifications can be reversed by the addition of methyl donors, such as folic acid in the diet. Epigenetic modifications are not observed in Wistar rats that received a LP diet containing folic acid supplementation from conception to delivery, suggesting that the DNA hypomethylation was due to a deficiency in folic acid or its reduced availability (16). As discussed above, the mother's diet during pregnancy is the strong factor in deciding the epigenetic status of her offspring; however, it is known that the period of epigenetic plasticity may extend beyond the IU or lactation period. In Wistar rat offspring exposed to a maternal LP diet IU, folic acid supplementation during the pubertal period prevented DNA hypomethylation of following loci: hepatic and adipose PPARα promoter and insulin receptor promoter (52) and hepatic GR promoter (53). The stability of the epigenome is decreased during the juvenile-pubertal period; therefore, dietary supplementation with folic acid or methionine during this critical period may have the effect of modifying the methylation status of the PPARα and GR promoters.


These studies demonstrate that the early life environment is very critical in determining disease susceptibility and that perturbations of the developmental milieu can have a profound impact on the age of onset and incidence of diabetes and obesity contributing to the current world-wide metabolic disease health crisis. Animal models of epigenetic changes during development are an effective and valuable tool in understanding the relationship between the fetal/neonatal environment and adult disease. We have to consider that the epigenetic transmission can occur in a sex or genetic background-dependent manner (54, 55), and although the complexities of the human condition cannot be thoroughly reproduced, animal models provide a useful tool that allow us the utilization of humane techniques that would be unethical to perform in humans. Although an array of animal models, as well as animal strains, has been used to induce fetal/neonatal/pubertal programming of adult metabolic disease, the epigenetic changes observed differ among the models (gene and tissue specific), yet each leads to similar metabolic phenotypic consequences (including obesity and/or diabetes), demonstrating that multiple factors contribute to the development of metabolic disease. Thus, it will be important to determine the most effective animal model for the study of the various aspects of epigenetic programming based on the recognition of the complex nature (background, sex, critical stage of development) of obesity and diabetes, which seems to be the common end stage of a number of interventions. In summary, the molecular results of these epigenomic studies characterized by alterations in DNA methylation and histone PTM suggest novel therapeutic interventions that may be used in managing the metabolic disturbances observed in diabetes and obesity. These findings also suggest that more care should be given to consumption of a healthy maternal diet and improved fetal nutrient availability that may lead to a more normal birth weight and early life growth, thereby reducing the risk for programmed metabolic disease.


We thank current and past members of the Charron laboratory for fruitful discussions on the subject of this review.

This work was supported by National Institutes of Health [Grants R21 DK081194 (to M.J.C.) and KO8 HD042172 (to P.M.V.), Diabetes Research and Training Center Grant P60 DK020541, Epigenomics, Liver, O'Brien Kidney, and Comprehensive Cancer Centers of Albert Einstein College of Medicine], Diabetes Action Foundation, and American Diabetes Association (to M.J.C.).

Disclosure Summary: The authors have nothing to disclose.



Viable yellow agouti
CCAAT/enhancer binding protein β
differentially methylated region
DNA methyltransferase
glucocorticoid receptor
histone deacetylase
high fat
low protein
liver X-receptor
methyl CpG binding protein 2
μ opioid receptor
pancreatic and duodenal homeobox 1
phosphoenol pyruvate carboxykinase
peroxisomal proliferator-activated receptor α
posttranslational modification
Sprague Dawley
skeletal muscle.


1. Finucane MM, Stevens GA, Cowan MJ, Danaei G, Lin JK, Paciorek CJ, Singh GM, Gutierrez HR, Lu Y, Bahalim AN, Farzadfar F, Riley LM, Ezzati M. 2011. National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants. Lancet 377:557–567 [PubMed]
2. Warner MJ, Ozanne SE. 2010. Mechanisms involved in the developmental programming of adulthood disease. Biochem J 427:333–347 [PubMed]
3. Burdge GC, Lillycrop KA. 2010. Nutrition, epigenetics, and developmental plasticity: implications for understanding human disease. Annu Rev Nutr 30:315–339 [PubMed]
4. Barres R, Zierath JR. 2011. DNA methylation in metabolic disorders. Am J Clin Nutr 93:897S–S900 [PubMed]
5. Cheng X, Blumenthal RM. 2010. Coordinated chromatin control: structural and functional linkage of DNA and histone methylation. Biochemistry 49:2999–3008 [PMC free article] [PubMed]
6. Delcuve GP, Rastegar M, Davie JR. 2009. Epigenetic control. J Cell Physiol 219:243–250 [PubMed]
7. Lee JS, Smith E, Shilatifard A. 2010. The language of histone crosstalk. Cell 142:682–685 [PMC free article] [PubMed]
8. Lillycrop KA. 2011. Effect of maternal diet on the epigenome: implications for human metabolic disease. Proc Nutr Soc 70:64–72 [PubMed]
9. Vuguin PM. 2007. Animal models for small for gestational age and fetal programming of adult disease. Horm Res 68:113–123 [PMC free article] [PubMed]
10. Hartil K, Vuguin PM, Kruse M, Schmuel E, Fiallo A, Vargas C, Warner MJ, Durand JL, Jelicks LA, Charron MJ. 2009. Maternal substrate utilization programs the development of the metabolic syndrome in male mice exposed to high fat in utero. Pediatr Res 66:368–373 [PMC free article] [PubMed]
11. Doherty AS, Mann MR, Tremblay KD, Bartolomei MS, Schultz RM. 2000. Differential effects of culture on imprinted H19 expression in the preimplantation mouse embryo. Biol Reprod 62:1526–1535 [PubMed]
12. Khosla S, Dean W, Brown D, Reik W, Feil R. 2001. Culture of preimplantation mouse embryos affects fetal development and the expression of imprinted genes. Biol Reprod 64:918–926 [PubMed]
13. Bertram CE, Hanson MA. 2001. Animal models and programming of the metabolic syndrome. Br Med Bull 60:103–121 [PubMed]
14. Bocock PN, Aagaard-Tillery KM. 2009. Animal models of epigenetic inheritance. Semin Reprod Med 27:369–379 [PubMed]
15. Sohi G, Marchand K, Revesz A, Arany E, Hardy DB. 2011. Maternal protein restriction elevates cholesterol in adult rat offspring due to repressive changes in histone modifications at the cholesterol 7α-hydroxylase promoter. Mol Endocrinol 25:785–798 [PubMed]
16. Lillycrop KA, Phillips ES, Jackson AA, Hanson MA, Burdge GC. 2005. Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr 135:1382–1386 [PubMed]
17. Lillycrop KA, Slater-Jefferies JL, Hanson MA, Godfrey KM, Jackson AA, Burdge GC. 2007. Induction of altered epigenetic regulation of the hepatic glucocorticoid receptor in the offspring of rats fed a protein-restricted diet during pregnancy suggests that reduced DNA methyltransferase-1 expression is involved in impaired DNA methylation and changes in histone modifications. Br J Nutr 97:1064–1073 [PMC free article] [PubMed]
18. Gong L, Pan YX, Chen H. 2010. Gestational low protein diet in the rat mediates Igf2 gene expression in male offspring via altered hepatic DNA methylation. Epigenetics 5:619–626 [PubMed]
19. van Straten EM, Bloks VW, Huijkman NC, Baller JF, van Meer H, Lütjohann D, Kuipers F, Plösch T. 2010. The liver X-receptor gene promoter is hypermethylated in a mouse model of prenatal protein restriction. Am J Physiol Regul Integr Comp Physiol 298:R275–R282 [PubMed]
20. Zheng S, Rollet M, Pan YX. 2011. Maternal protein restriction during pregnancy induces CCAAT/enhancer-binding protein (C/EBPβ) expression through the regulation of histone modification at its promoter region in female offspring rat skeletal muscle. Epigenetics 6:161–170 [PubMed]
21. Zhou D, Pan YX. 2011. Gestational low protein diet selectively induces the amino acid response pathway target genes in the liver of offspring rats through transcription factor binding and histone modifications. Biochim Biophys Acta 1809:549–556 [PubMed]
22. Liu X, Wang J, Li R, Yang X, Sun Q, Albrecht E, Zhao R. 2011. Maternal dietary protein affects transcriptional regulation of myostatin gene distinctively at weaning and finishing stages in skeletal muscle of Meishan pigs. Epigenetics 6:899–907 [PubMed]
23. Jousse C, Parry L, Lambert-Langlais S, Maurin AC, Averous J, Bruhat A, Carraro V, Tost J, Letteron P, Chen P, Jockers R, Launay JM, Mallet J, Fafournoux P. 2011. Perinatal undernutrition affects the methylation and expression of the leptin gene in adults: implication for the understanding of metabolic syndrome. FASEB J 25:3271–3278 [PubMed]
24. Vickers MH, Reddy S, Ikenasio BA, Breier BH. 2001. Dysregulation of the adipoinsular axis—a mechanism for the pathogenesis of hyperleptinemia and adipogenic diabetes induced by fetal programming. J Endocrinol 170:323–332 [PubMed]
25. Zhang S, Rattanatray L, MacLaughlin SM, Cropley JE, Suter CM, Molloy L, Kleemann D, Walker SK, Muhlhausler BS, Morrison JL, McMillen IC. 2010. Periconceptional undernutrition in normal and overweight ewes leads to increased adrenal growth and epigenetic changes in adrenal IGF2/H19 gene in offspring. FASEB J 24:2772–2782 [PubMed]
26. Raychaudhuri N, Raychaudhuri S, Thamotharan M, Devaskar SU. 2008. Histone code modifications repress glucose transporter 4 expression in the intrauterine growth-restricted offspring. J Biol Chem 283:13611–13626 [PMC free article] [PubMed]
27. Sinclair KD, Allegrucci C, Singh R, Gardner DS, Sebastian S, Bispham J, Thurston A, Huntley JF, Rees WD, Maloney CA, Lea RG, Craigon J, McEvoy TG, Young LE. 2007. DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status. Proc Natl Acad Sci USA 104:19351–19356 [PMC free article] [PubMed]
28. Aagaard-Tillery KM, Grove K, Bishop J, Ke X, Fu Q, McKnight R, Lane RH. 2008. Developmental origins of disease and determinants of chromatin structure: maternal diet modifies the primate fetal epigenome. J Mol Endocrinol 41:91–102 [PMC free article] [PubMed]
29. Vucetic Z, Kimmel J, Totoki K, Hollenbeck E, Reyes TM. 2010. Maternal high-fat diet alters methylation and gene expression of dopamine and opioid-related genes. Endocrinology 151:4756–4764 [PMC free article] [PubMed]
30. Vucetic Z, Kimmel J, Reyes TM. 2011. Chronic high-fat diet drives postnatal epigenetic regulation of mu-opioid receptor in the brain. Neuropsychopharmacology 36:1199–1206 [PMC free article] [PubMed]
31. Fu Q, Yu X, Callaway CW, Lane RH, McKnight RA. 2009. Epigenetics: intrauterine growth retardation (IUGR) modifies the histone code along the rat hepatic IGF-1 gene. FASEB J 23:2438–2449 [PMC free article] [PubMed]
32. Martin-Gronert MS, Ozanne SE. 2007. Experimental IUGR and later diabetes. J Intern Med 261:437–452 [PubMed]
33. Vuguin P, Raab E, Liu B, Barzilai N, Simmons R. 2004. Hepatic insulin resistance precedes the development of diabetes in a model of intrauterine growth retardation. Diabetes 53:2617–2622 [PubMed]
34. Park JH, Stoffers DA, Nicholls RD, Simmons RA. 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 [PMC free article] [PubMed]
35. Thompson RF, Fazzari MJ, Niu H, Barzilai N, Simmons RA, Greally JM. 2010. Experimental intrauterine growth restriction induces alterations in DNA methylation and gene expression in pancreatic islets of rats. J Biol Chem 285:15111–15118 [PMC free article] [PubMed]
36. Navas-Acien A, Silbergeld EK, Pastor-Barriuso R, Guallar E. 2008. Arsenic exposure and prevalence of type 2 diabetes in US adults. JAMA 300:814–822 [PubMed]
37. Lang IA, Galloway TS, Scarlett A, Henley WE, Depledge M, Wallace RB, Melzer D. 2008. Association of urinary bisphenol A concentration with medical disorders and laboratory abnormalities in adults. JAMA 300:1303–1310 [PubMed]
38. Hyman M. 2007. Systems biology, toxins, obesity, and functional medicine. Altern Ther Health Med 13:S134–S139 [PubMed]
39. Hyman MA. 2010. Environmental toxins, obesity, and diabetes: an emerging risk factor. Altern Ther Health Med 16:56–58 [PubMed]
40. Xie Y, Liu J, Benbrahim-Tallaa L, Ward JM, Logsdon D, Diwan BA, Waalkes MP. 2007. Aberrant DNA methylation and gene expression in livers of newborn mice transplacentally exposed to a hepatocarcinogenic dose of inorganic arsenic. Toxicology 236:7–15 [PMC free article] [PubMed]
41. Ng SF, Lin RC, Laybutt DR, Barres R, Owens JA, Morris MJ. 2010. Chronic high-fat diet in fathers programs β-cell dysfunction in female rat offspring. Nature 467:963–966 [PubMed]
42. Carone BR, Fauquier L, Habib N, Shea JM, Hart CE, Li R, Bock C, Li C, Gu H, Zamore PD, Meissner A, Weng Z, Hofmann HA, Friedman N, Rando OJ. 2010. Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 143:1084–1096 [PMC free article] [PubMed]
43. Wiedmeier JE, Joss-Moore LA, Lane RH, Neu J. 2011. Early postnatal nutrition and programming of the preterm neonate. Nutr Rev 69:76–82 [PubMed]
44. Palou M, Pico C, McKay JA, Sanchez J, Priego T, Mathers JC, Palou A. 2011. Protective effects of leptin during the suckling period against later obesity may be associated with changes in promoter methylation of the hypothalamic pro-opiomelanocortin gene. Br J Nutr:1–10 [PubMed]
45. Pinney SE, Jaeckle Santos LJ, Han Y, Stoffers DA, Simmons RA. 2011. Exendin-4 increases histone acetylase activity and reverses epigenetic modifications that silence Pdx1 in the intrauterine growth retarded rat. Diabetologia 54:2606–2614 [PubMed]
46. Burdge GC, Slater-Jefferies J, Torrens C, Phillips ES, Hanson MA, Lillycrop KA. 2007. Dietary protein restriction of pregnant rats in the F0 generation induces altered methylation of hepatic gene promoters in the adult male offspring in the F1 and F2 generations. Br J Nutr 97:435–439 [PMC free article] [PubMed]
47. Hoile SP, Lillycrop KA, Thomas NA, Hanson MA, Burdge GC. 2011. Dietary protein restriction during F(0) pregnancy in rats induces transgenerational changes in the hepatic transcriptome in female offspring. PLoS One 6:e21668. [PMC free article] [PubMed]
48. Dolinoy DC. 2008. The agouti mouse model: an epigenetic biosensor for nutritional and environmental alterations on the fetal epigenome. Nutr Rev 66(Suppl 1):S7–S11 [PMC free article] [PubMed]
49. Morgan HD, Sutherland HG, Martin DI, Whitelaw E. 1999. Epigenetic inheritance at the agouti locus in the mouse. Nat Genet 23:314–318 [PubMed]
50. Waterland RA, Jirtle RL. 2003. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 23:5293–5300 [PMC free article] [PubMed]
51. Dolinoy DC, Weidman JR, Waterland RA, Jirtle RL. 2006. Maternal genistein alters coat color and protects Avy mouse offspring from obesity by modifying the fetal epigenome. Environ Health Perspect 114:567–572 [PMC free article] [PubMed]
52. Burdge GC, Lillycrop KA, Phillips ES, Slater-Jefferies JL, Jackson AA, Hanson MA. 2009. Folic acid supplementation during the juvenile-pubertal period in rats modifies the phenotype and epigenotype induced by prenatal nutrition. J Nutr 139:1054–1060 [PubMed]
53. Lillycrop KA, Phillips ES, Torrens C, Hanson MA, Jackson AA, Burdge GC. 2008. Feeding pregnant rats a protein-restricted diet persistently alters the methylation of specific cytosines in the hepatic PPARα promoter of the offspring. Br J Nutr 100:278–282 [PMC free article] [PubMed]
54. Waterland RA, Travisano M, Tahiliani KG, Rached MT, Mirza S. 2008. Methyl donor supplementation prevents transgenerational amplification of obesity. Int J Obes 32:1373–1379 [PMC free article] [PubMed]
55. Dunn GA, Morgan CP, Bale TL. 2011. Sex-specificity in transgenerational epigenetic programming. Horm Behav 59:290–295 [PubMed]

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