Endocrine Abstracts

Glucocorticoids are known to have a role in the programming of appetite regulation but the mechanisms have not been fully delineated. This study examined the effect of maternal undernutrition on glucocorticoid receptor (GR) as a key regulator of the appetite regulating neuropeptides, proopiomelanocortin (POMC) and neuropeptide Y (NPY) in the hypothalamus.

Ewes were undernourished (UN, n=4) for 30 days pre- and 60 days post-mating or given normal feed (N, n=4). Hypothalami were dissected at post mortem (day 135). GR mRNA was quantitated in whole hypothalamic extracts (Quantigene, Panomics). There was a 1.8 fold increase in GR mRNA in the UN group compared to the N group (P=0.015). This correlated with hypomethylation of the GR gene (40% decrease; P=0.039) measured by methylation PCR. There was no change in plasma cortisol levels between UN and N foetal groups.

To explore GR expression in the arcuate nucleus, data were collected from a new cohort of periconceptional undernutrition. Ventral hypothalamus samples (enriched for arcuate nucleus) were taken from UN, (n=11) and N, (n=9) foetal groups. A 4.7 fold increase in GR expression was demonstrated (P=0.041) which correlated with hypomethylation (53% decrease, P=0.028). The transcriptional activation of the GR gene was investigated in these samples using chromatin immunoprecipitation (ChIP) for acetylated histone H3K9. This experiment revealed increased H3K9 acetylation of the GR promoter in the UN group (1.6 fold increase, P=0.00025).

Periconceptional undernutrition is therefore associated with marked changes in hypothalamic glucocorticoid receptor. Hypomethylation and increased histone H3K9 acetylation are associated with ‘opening’ of chromatin structure suggesting increased transcriptional activation. This correlated with the observed increase in hypothalamic GR gene transcription in the UN group. The GR epigenetic changes in the undernourished group may affect foetal programming of adult hypothalamic appetite regulation, predisposing to obesity, via altered regulation of components such as POMC.