Our research: Maternal trans-fats and programming of cardiovascular disease.

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Trans-fatty acids are unsaturated fatty acids in which double bonds exist in the trans-isomer configuration. This is rare in nature as most fatty acids produced through biological processes have cis-double bonds. Trans-fatty acids in the food chain are therefore mostly generated through industrial processing in which hydrogenation of oils to produce solid fats changes the chemical structure of the fatty acids. Industrially generated trans-fatty acids are known to be associated with cardiovascular disease as they increase concentrations of low density lipoprotein cholesterol. In the US levels of trans-fatty acids in food are considered unsafe and a ban is likely to emerge in the near future. Other countries have legal limits on industrial trans-fatty acids in food. Trans fatty acids are also present in produce from ruminants as these animals produce vaccenic acid and conjugated linoleic acid in milk and meat. There is some evidence that ruminant-derived fatty acids may be beneficial to cardiovascular health.

Our group is interested in the early life origins of disease and it was therefore of interest to evaluate whether early life exposure to trans-fatty acids might impact upon risk of atherosclerosis in adult life. Our project, funded by the US Department of Agriculture (PI Adam Lock, CoIs Andy Salter, Simon Langley-Evans) utilised the ApoE*3 Leiden mouse to evaluate the effects of feeding different sources of trans-fatty acids during pregnancy alone, or during pregnancy and lactation upon the development of atherosclerosis in the offspring. The ApoE*3 Leiden mouse is a transgenic mouse which carries a mutated human ApoE3 gene. This mutation means that the mice will develop atherosclerosis when fed a high cholesterol, atherogenic diet. There is generally a relationship between the intake of cholesterol and the extent of atherosclerosis, but we have previously shown that variation in the maternal diet can impact upon the extent of atherosclerosis developed in response to atherogenic diet.

In the USDA funded study, offspring carrying the ApoE*3 Leiden gene were generated by mating wild type female mice with transgenic males. The pregnant mice were then fed diets either containing industrial trans-fats or ruminant-derived trans-fats during pregnancy. Offspring with the ApoE*3 Leiden gene were then selected for feeding either standard mouse diet or atherogenic diet. Atherosclerotic plaque formation was measured in these adult offspring. We hope to publish the findings from this work shortly.

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Our projects: Fetal programming of the insulin signalling pathway

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Undernutrition during fetal life is associated with programming of metabolic function, type-2 diabetes and cardiovascular disease. Evidence is mounting that maternal obesity is also a risk for adverse programming. However, exploration of the mechanistic basis of programming is challenging, as animal models of obesity generally use hypercaloric diets based upon a narrow range of pure fats or sugars. These may have effects independently of maternal body composition. A cafeteria diet (a varying panel of highly palatable foods) is known to have a programming effect on glucose homeostasis in rodents, through epigenetic modification and altered expression of the insulin-signalling pathway. Our British Heart Foundation project, funding a studentship for Grace Robinson, will utilize an established rat model of cafeteria feeding to investigate tissue sensitivity of such effects and the role of epigenetics in programming the insulin-signalling pathway. The relative contributions of maternal obesity and over-feeding to establishing metabolic and cardiovascular phenotypes will be dissected through cross-fostering and staged feeding experiments. We will evaluate vessel function using wire myography, blood pressure, glucose homeostasis and consider expression of insulin-signalling targets at the mRNA and protein level.

Our projects: Optimal weaning

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The World Health Organization recommends that babies are exclusively breastfed until the age of 6 months, at which point the introduction of complementary foods should occur (weaning). An extensive literature suggests that infant feeding practices may determine long-term metabolic health in children, with effects running through to adulthood. In particular, breastfeeding has been identified as being protective against childhood obesity. Although this literature has been subject to robust criticism on the basis of confounding factors, the balance of opinion is that breastfeeding is beneficial for long-term health.

With respect to weaning, the literature is less robust and there are limited studies that consider the impact of weaning upon long-term health. Using funding from the Feeding for Life Foundation, we performed two systematic reviews of the literature to address separate questions related to the timing of weaning and the types of food used in weaning and subsequent obesity during childhood.

Our first study, including 10 reports, considered the impact of different types of weaning foods. Some association was found between high protein intakes at 2–12 months of age and higher body mass index (BMI) or body fatness in childhood, but this was not the case in all studies. Higher energy intake during complementary feeding was associated with higher BMI in childhood. Adherence to dietary guidelines during weaning was associated with a higher lean mass, but consuming specific foods or food groups made no difference to children’s BMI. We concluded that high intakes of energy and protein, particularly dairy protein, in infancy could be associated with an increase in BMI and body fatness, but further research is needed to establish the nature of the relationship.

The second review evaluated whether weaning earlier than 6 months was detrimental in terms of the later adiposity of infants. From 23 included studies we noted that there was no clear association between the timing of the introduction of complementary foods and childhood overweight or obesity. There was some evidence to suggest that very early introduction (at or before 4 months), rather than at 4–6 months or >6 months, may increase the risk of childhood overweight.

Our projects: Magnesium and vascular endothelial cell function

Intakes of magnesium are often low in the population and successive National Diet and Nutrition Surveys in the UK have indicated that the majority of adults fail to consume at the RNI. Our project, funded by the Saudi Arabian Ministry of Higher Education as a studentship for Lujain Almousa, is investigating the effects of magnesium deficiency upon the proliferation and gene expression of human umbilical vascular endothelial cells in culture.

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Our projects: Intergenerational programming of reno-vascular function

We have long been interested in the impact of maternal undernutrition upon cardiovascular function across several generations. Just a few years after our first demonstration that protein restriction in rat pregnancy resulted in higher blood pressure in the exposed offspring, we showed that the effect could also be transmitted to a second generation (published as an abstract only Dunn et al. Proc Nutr Soc 1996). Funding from the British Heart Foundation (PI Simon Langley-Evans) enabled us to investigate this in more detail and across three generations.

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Working with then PhD student, Matt Harrison, we carried out a study in which protein restricted rat dams (F0) were used to generate male and female F1 offspring. These were then used to generate F2 without further dietary insult and the F2 produced an F3 generation. In the F1 generation exposure to protein restriction was associated with higher blood pressure and a reduced nephron number, which is out well-characterised programmed phenotype. We generated 4 groups of F2 offspring by crossing male controls with female controls, low protein males with control females, control males with low protein females and low protein male and females. The phenotype observed in the F1 generation was also present in all F2 groups, showing that not only did programming have an intergenerational effect, that effect could be passed down both the male and female lineage. By F3 the effect was no longer observable.

Initial analysis of the tissues collected from this experiment suggested that there were some genes associated with hypertension that may be differentially expressed across F1, F2 and F3. We are now working in collaboration with Dr Elia Stupka and colleagues at the San Raffaele Institute in Milan to investigate this further. We have considered maternal diet related effects on the epigenome in F1, F2 and F3 generations and have observed clear evidence of differential DNA methylation related to the original dietary insult, across all three generations. We are now using RNASeq to evaluate the relationship between DMRs in known gene promoter regions and gene expression.

Our projects: Fetal programming of the cell cycle

In 2008 we received funding from the BBSRC (PI Simon Langley-Evans, CoI Sarah McMullen, Harry McArdle, Lorraine Gambling) to carry out what we called the Gatekeeper Study. This aimed to examine the effects of maternal protein restriction and iron deficiency in rat pregnancy upon the whole embryonic transcriptome and proteome in order to identify common genes, pathways and proteins that were differentially regulated in common with the two insults. The hypothesis was that these common (gatekeeper) targets must play a critical role in linking maternal undernutrition to the renal and cardiovascular phenotypes associated with the two insults. The principal of this is set out in our review in Medical Hypotheses.

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Our findings, as described in two PlosOne articles, showed that regulation of the cell cycle was disturbed by both protein restriction and iron deficiency and this finding was subsequently verified in a study of the neonatal hepatic transcriptome (in collaboration with Adrian Clark and Elia Stupka). Maternal undernutrition impacts upon expression of several of the cyclins (A2, B, H and E), genes which regulate DNA replication and genes that are involved in the G1/S and G2/M checkpoints. Our working hypothesis is that disruption of cell cycle regulation during embryonic and fetal life impacts upon the development of organs and tissues, resulting in tissue remodelling and irreversible loss of functional capacity.

This work is currently proceeding as an MRes studentship (Alice Cordon) which will examine expression of key gene and protein targets in a range of tissues from offspring of protein restricted pregnancies at different ages. It is likely that transient changes in expression is sufficient to perturb tissue development and that the transcriptome will not show permanent consequences of maternal dietary exposure.

Visiting Fellows Scheme

The University of Nottingham has announced a call for the 2015 Visiting Fellowships Scheme. The scheme will  allow 30 early career researchers from outside the European Union (EU) the opportunity to complete a three month period of research in Nottingham and is a good springboard to submit an application for a prestigious Nottingham Research Fellowship or Anne McLaren Fellowship in 2016.

If you are interested in the early life origins of disease and would like to spend a period of time with my group through this scheme, please get in touch.