Multigenerational programming in the glucocorticoid programmed rat is associated with generation-specific and parent of origin effects

Drake, Amanda J.; Liu, Lincoln; Kerrigan, David; Meehan, Richard R.; Seckl, Jonathan R.

doi:10.4161/epi.6.11.17942

Cited by 71 publications

(82 citation statements)

References 60 publications

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“…Studies in F1 sperm have shown a role for altered IGF2 and H19 expression in the transmission of a phenotype to the F2 offspring [22]. However, not all studies reporting a paternal line transmission have reported epigenetic alterations in the F1 sperm [57]. Work by Radford et al [58 ]failed to find any evidence that the epigenetic reprogramming of imprinting control regions in the germline was susceptible to nutritional restriction, thus implying that mechanisms other than direct germline transmission are responsible.…”

Section: Discussionmentioning

confidence: 99%

Developmental Programming and Transgenerational Transmission of Obesity

Vickers¹

2014

Ann Nutr Metab

103

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The global obesity pandemic is often causally linked to marked changes in diet and lifestyle, namely marked increases in dietary intakes of high-energy diets and concomitant reductions in physical activity levels. However, far less attention has been paid to the role of developmental plasticity and alterations in phenotypic outcomes resulting from environmental perturbations during the early-life period. Human and animal studies have highlighted the link between alterations in the early-life environment and increased susceptibility to obesity and related metabolic disorders in later life. In particular, altered maternal nutrition, including both undernutrition and maternal obesity, has been shown to lead to transgenerational transmission of metabolic disorders. This association has been conceptualised as the developmental programming hypothesis whereby the impact of environmental influences during critical periods of developmental plasticity can elicit lifelong effects on the physiology of the offspring. Further, evidence to date suggests that this developmental programming is a transgenerational phenomenon, with a number of studies showing transmission of programming effects to subsequent generations, even in the absence of continued environmental stressors, thus perpetuating a cycle of obesity and metabolic disorders. The mechanisms responsible for these transgenerational effects remain poorly understood; evidence to date suggests a number of potential mechanisms underpinning the transgenerational transmission of the developmentally programmed phenotype through both the maternal and paternal lineage. Transgenerational phenotype transmission is often seen as a form of epigenetic inheritance with evidence showing both germline and somatic inheritance of epigenetic modifications leading to phenotype changes across generations. However, there is also evidence for non-genomic components as well as an interaction between the developing fetus with the in utero environment in the perpetuation of programmed phenotypes. A better understanding of how developmental programming effects are transmitted is essential for the implementation of initiatives aimed at curbing the current obesity crisis.

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Section: Discussionmentioning

confidence: 99%

Developmental Programming and Transgenerational Transmission of Obesity

Vickers¹

2014

Ann Nutr Metab

103

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“…These effects may be transmissible through both maternal and paternal lines (14,18,23,24,26). Although initial studies suggested that programmed effects occurring as a result of an insult in one generation may result in similar phenotypes in successive generations (14,23), emerging evidence suggests that the effects in subsequent generations may differ from those seen in the F1 who were exposed directly to an insult in utero (21,26). Indeed, we have demonstrated parent-of-origin-specific effects on fetal and placental growth and gene expression in a secondgeneration (F2) of animals after in utero glucocorticoid overexposure (14,21).…”

mentioning

confidence: 92%

“…Moreover, grandchild obesity is linked to grandparental obesity independent of parental weight (20). The transmission of programmed effects to subsequent generations has been reported in a number of animal models including prenatal glucocorticoid overexposure (14,21), maternal undernutrition (18,22,23), neonatal overnutrition (24), and maternal overnutrition (25). These effects may be transmissible through both maternal and paternal lines (14,18,23,24,26).…”

mentioning

confidence: 94%

“…Although initial studies suggested that programmed effects occurring as a result of an insult in one generation may result in similar phenotypes in successive generations (14,23), emerging evidence suggests that the effects in subsequent generations may differ from those seen in the F1 who were exposed directly to an insult in utero (21,26). Indeed, we have demonstrated parent-of-origin-specific effects on fetal and placental growth and gene expression in a secondgeneration (F2) of animals after in utero glucocorticoid overexposure (14,21). In this study, we used a model of moderate maternal diet-induced obesity (DIO) to explore effects on postnatal weight gain and glucose-insulin homeostasis in the first-and F2 offspring.…”

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confidence: 95%

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Maternal Obesity Has Little Effect on the Immediate Offspring but Impacts on the Next Generation

et al. 2013

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Maternal obesity during pregnancy has been linked to an increased risk of obesity and cardiometabolic disease in the offspring, a phenomenon attributed to developmental programming. Programming effects may be transmissible across generations through both maternal and paternal inheritance, although the mechanisms remain unclear. Using a mouse model, we explored the effects of moderate maternal diet-induced obesity (DIO) on weight gain and glucose-insulin homeostasis in first-generation (F1) and second-generation offspring. DIO was associated with insulin resistance, hyperglycemia and dyslipidemia before pregnancy. Birth weight was reduced in female offspring of DIO mothers (by 6%, P = .039), and DIO offspring were heavier than controls at weaning (males by 47%, females by 27%), however there were no differences in glucose tolerance, plasma lipids, or hepatic gene expression at 6 months. Despite the relative lack of effects in the F1, we found clear fetal growth restriction and persistent metabolic changes in otherwise unmanipulated second-generation offspring with effects on birth weight, insulin levels, and hepatic gene expression that were transmitted through both maternal and paternal lines. This suggests that the consequences of the current dietary obesity epidemic may also have an impact on the descendants of obese individuals, even when the phenotype of the F1 appears largely unaffected.

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“…In fact, increased total cholesterol, plasma, and liver triacylglycerol were found in the HF-F1 offspring, but the HF-F2 offspring seems to have been spared these alterations. Of course, the effects on subsequent generations may differ from those seen in the F1, who were exposed directly to the insult in utero (Drake et al, 2011;Dunn & Bale). The maternal insulin resistance and HF diet combined showed additional effects on adiposity in the offspring early life (Carmody et al; Barbosa-da-Silva et al).…”

Section: Discussionmentioning

confidence: 99%

Both Hepatic Lipogenesis and Beta-Oxidation are Altered in Offspring of Mothers Fed a High-Fat Diet in the First Two Generations (F1 and F2)

et al. 2015

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SUMMARY:The high fat (HF) fed mothers may program susceptibility in offspring to chronic diseases and affect subsequent generations. The present study evaluated the liver structure in adulthood, focusing on the F1 and F2 generations. Females C57BL/6 (F0) were fed standard chow (SC) or HF diet (8 weeks) prior to mating and during the gestation and lactation to provide the F1 generation (SC-F1 and HF-F1). All other mothers and offspring fed SC. At 3 months old, F1 females were mated to produce the F2 generation (SC-F2 and HF-F2). The liver was kept in several fragments and prepared for histological analysis or frozen for biochemical and molecular analyzes. The F1 and F2 offspring were studied at 3 months old. HF-F1 had higher body mass (BM) compared to SC-F1 (P= 0.001), but not HF-F2 compared to SC-F2. HF-F1 had glucose intolerance when compared to SC-F1, but not HF-F2 compared to SC-F2. HF-F1 (P= 0.009) and HF-F2 (P= 0.03) showed hyperinsulinemia compared to their counterparts. Both groups HF-F1 and HF-F2 showed more steatosis than the SC counterparts (F1 and F2, P<0.0001). HF-F1 showed increased expression of PPAR-gamma and SREBP1-c compared to SC-F1 (P= 0.01). HF-F2 showed increased PPAR-gamma expression compared to SC-F2 (P= 0.04). In conclusion, HF-fed mother impairs both lipogenesis and beta-oxidation pathways in F1 through upregulation of PPAR-gamma and downregulation of PPAR-alpha. In F2, the only lipogenesis is enhanced, but it causes a disrupted PPAR balance, favoring the hepatic lipid accumulation and impaired metabolism in these animals that were not directly exposed to the maternal HF intake.

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Multigenerational programming in the glucocorticoid programmed rat is associated with generation-specific and parent of origin effects

Cited by 71 publications

References 60 publications

Developmental Programming and Transgenerational Transmission of Obesity

Developmental Programming and Transgenerational Transmission of Obesity

Maternal Obesity Has Little Effect on the Immediate Offspring but Impacts on the Next Generation

Both Hepatic Lipogenesis and Beta-Oxidation are Altered in Offspring of Mothers Fed a High-Fat Diet in the First Two Generations (F1 and F2)

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