Epigenetic malprogramming of the insulin receptor promoter due to developmental overfeeding

Plagemann, Andreas; Roepke, Katharina; Harder, Thomas; Brunn, Matthias; Harder, Anja; Wittrock-Staar, Manon; Ziska, Thomas; Schellong, Karen; Rodekamp, Elke; Melchior, Kerstin; Dudenhausen, Joachim W.

doi:10.1515/jpm.2010.051

Cited by 120 publications

(77 citation statements)

References 38 publications

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“…The fact that MD supplementation tended to reverse immobility time in the Porsolt test (although not the NORT results) suggests that this beneficial effect could be related to the trend towards significance in the interaction between MS and MD in the hippocampal expression of IR. Previous studies have reported that neonatal overnutrition could regulate IR in the brain (hypothalamus) via DNA methylation of its promoter [54]. However, in our study, no differences in IR methylation in the hypothalamus were observed as a result of MS and MD.…”

Section: Discussioncontrasting

confidence: 88%

Methyl donor supplementation in rats reverses the deleterious effect of maternal separation on depression-like behaviour

Paternain

Martišová

Campión

et al. 2016

Behavioural Brain Research

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Adverse early life events are associated with altered stress responsiveness and metabolic disturbances in the adult life. Dietary methyl donor supplementation could be able to reverse the negative effects of maternal separation by affecting DNA methylation in the brain. In this study, maternal separation during lactation reduced body weight gain in the female adult offspring without affecting food intake, and altered total and HDLcholesterol levels. Also, maternal separation induced a cognitive deficit as measured by NORT and an increase in the immobility time in the Porsolt forced swimming test, consistent with increased depression-like behaviour. An 18-week dietary supplementation with methyl donors (choline, betaine, folate and vitamin B12) from postnatal day 60 also reduced body weight without affecting food intake. Some of the deleterious effects induced by maternal separation, such as the abnormal levels of total and HDL-cholesterol, but especially the depression-like behaviour as measured by the Porsolt test, were reversed by methyl donor supplementation. Also, the administration of methyl donors increased total DNA methylation (measured by immunohistochemistry) and affected the expression of insulin receptor in the hippocampus of the adult offspring. However, no changes were observed in the DNA methylation status of insulin receptor and corticotropin-releasing hormone (CRH) promoter regions in the hypothalamus. In summary, methyl donor supplementation reversed some of the deleterious effects of an early life-induced model of depression in rats and altered the DNA methylation profile in the brain.

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Section: Discussioncontrasting

confidence: 88%

Methyl donor supplementation in rats reverses the deleterious effect of maternal separation on depression-like behaviour

Paternain

Martišová

Campión

et al. 2016

Behavioural Brain Research

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“…The mechanisms that lead to increased adiposity in infants of mothers with GDM in early infancy merit consideration. One possible explanation is that intrauterine or neonatal exposure to an excess of nutrients may alter hypothalamic sensing, leading to alterations in satiety and appetite (33,34). Another potential mechanism for the differences described concerns differences in breast milk composition.…”

Section: Discussionmentioning

confidence: 99%

Development of Early Adiposity in Infants of Mothers With Gestational Diabetes Mellitus

Logan

Jeffries

et al. 2016

Diabetes Care

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OBJECTIVEInfants born to mothers with gestational diabetes mellitus (GDM) are at greater risk of later adverse metabolic health. We examined plausible candidate mediators, adipose tissue (AT) quantity and distribution and intrahepatocellular lipid (IHCL) content, comparing infants of mothers with GDM and without GDM (control group) over the first 3 postnatal months. RESEARCH DESIGN AND METHODSWe conducted a prospective longitudinal study using MRI and spectroscopy to quantify whole-body and regional AT volumes, and IHCL content, within 2 weeks and 8-12 weeks after birth. We adjusted for infant size and sex and maternal prepregnancy BMI. Values are reported as the mean difference (95% CI). RESULTSWe recruited 86 infants (GDM group 42 infants; control group 44 infants). Mothers with GDM had good pregnancy glycemic control. Infants were predominantly breast-fed up to the time of the second assessment (GDM group 71%; control group 74%). Total AT volumes were similar in the GDM group compared with the control group at a median age of 11 days (228 cm 3 [95% CI 2121, 65], P = 0.55), but were greater in the GDM group at a median age of 10 weeks (247 cm 3 [56, 439], P = 0.01). After adjustment for size, the GDM group had significantly greater total AT volume at 10 weeks than control group infants (16.0% [6.0, 27.1], P = 0.002). AT distribution and IHCL content were not significantly different at either time point. CONCLUSIONSAdiposity in GDM infants is amplified in early infancy, despite good maternal glycemic control and predominant breast-feeding, suggesting a potential causal pathway to later adverse metabolic health. Reduction in postnatal adiposity may be a therapeutic target to reduce later health risks.Diabetes in pregnancy is increasing and currently affects up to 5% of women in the U.K.(1) and up to 9.2% in the U.S. (2). Approximately 87.5% of cases are gestational diabetes mellitus (GDM), 7.5% are type 1 diabetes, and 5% are type 2 diabetes (1). The offspring of mothers with diabetes have greater risks of adverse metabolic sequelae in childhood and later life that appear to be additional to genetic predisposition (3-5).The underlying mechanisms are unclear, but increased infant adiposity is a plausible mediator because adiposity in childhood and adult life are associated with type 2 diabetes and cardiovascular disease (6). The Hyperglycemia and Adverse

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“…Early nutritional insults may program long-term disease susceptibilities through epigenetic modification (14,15). Recently, the DNA methylation level of PGC-1α promoter in umbilical cord has been found to positively correlate with maternal pregestational BMI (24); moreover, the PGC-1α methylation level is increased in the muscle of low-birth-weight adults (19,25), and 5-d overfeeding may influence the DNA methylation of PGC-1α in a birth-weight-dependent manner (19); besides, maternal methyl donor-deficient diet leads to PGC-1α protein hypomethylation in the liver of the pups with subsequent impairment of fatty acid oxidation (26), suggesting that both Articles prenatal and postnatal nutritional status may play a crucial role in metabolic programing through the epigenetic modification of PGC-1α.…”

Section: Discussionmentioning

confidence: 99%

IUGR with infantile overnutrition programs an insulin-resistant phenotype through DNA methylation of peroxisome proliferator–activated receptor-γ coactivator-1α in rats

et al. 2015

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Background: Intrauterine growth restriction (IUGR) followed by postnatal accelerated growth (CG-IUGR) is associated with long-term adverse metabolic consequences, and an involvement of epigenetic dysregulation has been implicated. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a key orchestrator in energy homeostasis. We hypothesized that CG-IUGR programed an insulin-resistant phenotype through the alteration in DNA methylation and transcriptional activity of PGC-1α. Methods: A CG-IUGR rat model was adopted using maternal gestational nutritional restriction followed by infantile overnutrition achieved by reducing the litter size. The DNA methylation was determined by pyrosequencing. The mRNA expression and mitochondrial content were assessed by realtime PCR. The insulin-signaling protein expression was evaluated by western blotting. results: Compared with controls, the CG-IUGR rats showed an increase in the DNA methylation of specific CpG sites in PGC-1α, and a decrease in the transcriptional activity of PGC-1α, mitochondrial content, protein level of PI3K and phosphorylated-Akt2 in liver and muscle tissues. The methylation of specific CpG sites in PGC-1α was positively correlated with fasting insulin concentration. conclusion: IUGR followed by infantile overnutrition programs an insulin-resistant phenotype, possibly through the alteration in DNA methylation and transcriptional activity of PGC-1α. The genetic and epigenetic modifications of PGC-1α provide a potential mechanism linking early-life nutrition insult to long-term metabolic disease susceptibilities.

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Epigenetic malprogramming of the insulin receptor promoter due to developmental overfeeding

Cited by 120 publications

References 38 publications

Methyl donor supplementation in rats reverses the deleterious effect of maternal separation on depression-like behaviour

Methyl donor supplementation in rats reverses the deleterious effect of maternal separation on depression-like behaviour

Development of Early Adiposity in Infants of Mothers With Gestational Diabetes Mellitus

IUGR with infantile overnutrition programs an insulin-resistant phenotype through DNA methylation of peroxisome proliferator–activated receptor-γ coactivator-1α in rats

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