Endocrine Abstracts

There is clear evidence from epidemiological studies that adverse conditions during pregnancy can programme changes in offspring which lead to increased risk of developing type two diabetes and obesity, two diseases associated with metabolic syndrome. Whilst earlier investigations focused on undernutrition in relation to famine, it is also relevant in the developed world to consider how dieting may programme lasting changes in the offspring.

In models of maternal undernutrition, the offspring have increased glucose intolerance and obesity in later life. Therefore our aims were to determine how hypothalamic genes critically involved in energy balance are affected by maternal undernutrition, both in the fetus and in adult offspring. We have utilised a sheep model, where hypothalamic maturation occurs prior to birth, on a similar trajectory to humans. In this model, ewes were moderately undernourished around the time of conception.

We found that maternal undernutrition is associated with epigenetic changes in the glucocorticoid receptor (GR) and concomitant increases in GR mRNA and protein in the fetal hypothalamus. These changes persisted in adult offspring studied up to five years after the maternal insult. The increases in GR expression were associated with an increased NPY mRNA and would predict the obese phenotype seen in adult male sheep. In contrast to the hypothalamus, different epigenetic changes in the GR were identified in the hippocampus and pituitary, but only in the adult offspring.

Therefore, adverse nutritional environments during pregnancy can programme epigenetic changes in the glucocorticoid receptor, resulting in changes in expression in areas of the brain responsible for feeding behaviour, energy expenditure and glucose homeostasis. That these epigenetic changes are identified in the fetus but persist in adult offspring provides a mechanism for the increased propensity for metabolic disease.

Declaration of funding

The study was supported by the Barbara Mawer Endowment fund, UK National Institute of Health Research Manchester Biomedical Research Center, Health Research Council of New Zealand, New Zealand National Research Centre for Growth and Development (to Frank Bloomfield), the Canadian Institutes for Health Research (to John Challis).