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Early life diet conditions the molecular response to post-weaning protein restriction in the mouse.

ABSTRACT: BACKGROUND:Environmental influences fluctuate throughout the life course of an organism. It is therefore important to understand how the timing of exposure impacts molecular responses. Herein, we examine the responses of two key molecular markers of dietary stress, namely variant-specific methylation at ribosomal DNA (rDNA) and small RNA distribution, including tRNA fragments, in a mouse model of protein restriction (PR) with exposure at pre- and/or post-weaning. RESULTS:We first confirm that pre-weaning PR exposure modulates the methylation state of rDNA in a genotype-dependent manner, whereas post-weaning PR exposure has no such effect. Conversely, post-weaning PR induces a shift in small RNA distribution, but there is no effect in the pre-weaning PR model. Intriguingly, mice exposed to PR throughout their lives show neither of these two dietary stress markers, similar to controls. CONCLUSIONS:The results show that the timing of the insult affects the nature of the molecular response but also, critically, that 'matching' diet exposure either side of weaning eliminates the stress response at the level of rDNA methylation and small RNA in sperm.

SUBMITTER: Danson AF

PROVIDER: S-EPMC5930764 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Early life diet conditions the molecular response to post-weaning protein restriction in the mouse.

Danson Amy F AF Marzi Sarah J SJ Lowe Robert R Holland Michelle L ML Rakyan Vardhman K VK

BMC biology 20180502 1

<h4>Background</h4>Environmental influences fluctuate throughout the life course of an organism. It is therefore important to understand how the timing of exposure impacts molecular responses. Herein, we examine the responses of two key molecular markers of dietary stress, namely variant-specific methylation at ribosomal DNA (rDNA) and small RNA distribution, including tRNA fragments, in a mouse model of protein restriction (PR) with exposure at pre- and/or post-weaning.<h4>Results</h4>We first ...[more]

PMID: 29720174

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Project description:AimsObesity during pregnancy increases risk of cardiovascular disease (CVD) in the offspring and individuals exposed to over-nutrition during fetal life are likely to be exposed to a calorie-rich environment postnatally. Here, we established the consequences of combined exposure to a maternal and post-weaning obesogenic diet on offspring cardiac structure and function using an established mouse model of maternal diet-induced obesity.Methods and resultsThe impact of the maternal and postnatal environment on the offspring metabolic profile, arterial blood pressure, cardiac structure, and function was assessed in 8-week-old C57BL/6 male mice. Measurement of cardiomyocyte cell area, the transcriptional re-activation of cardiac fetal genes as well as genes involved in the regulation of contractile function and matrix remodelling in the adult heart were determined as potential mediators of effects on cardiac function. In the adult offspring: a post-weaning obesogenic diet coupled with exposure to maternal obesity increased serum insulin (P < 0.0001) and leptin levels (P < 0.0001); maternal obesity (P = 0.001) and a post-weaning obesogenic diet (P = 0.002) increased absolute heart weight; maternal obesity (P = 0.01) and offspring obesity (P = 0.01) caused cardiac dysfunction but effects were not additive; cardiac dysfunction resulting from maternal obesity was associated with re-expression of cardiac fetal genes (Myh7: Myh6 ratio; P = 0.0004), however, these genes were not affected by offspring diet; maternal obesity (P = 0.02); and offspring obesity (P = 0.05) caused hypertension and effects were additive.ConclusionsMaternal diet-induced obesity and offspring obesity independently promote cardiac dysfunction and hypertension in adult male progeny. Exposure to maternal obesity alone programmed cardiac dysfunction, associated with hallmarks of pathological left ventricular hypertrophy, including increased cardiomyocyte area, upregulation of fetal genes, and remodelling of cardiac structure. These data highlight that the perinatal period is just as important as adult-onset obesity in predicting CVD risk. Therefore, early developmental periods are key intervention windows to reduce the prevalence of CVD.

Dataset Information

Early life diet conditions the molecular response to post-weaning protein restriction in the mouse.

Publications

Early life diet conditions the molecular response to post-weaning protein restriction in the mouse.

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