Epigenetic Changes in the Hypothalamic Proopiomelanocortin and Glucocorticoid Receptor Genes in the Ovine Fetus after Periconceptional Undernutrition

Abstract

Maternal food restriction is associated with the development of obesity in offspring. This study examined how maternal undernutrition in sheep affects the fetal hypothalamic glucocorticoid receptor (GR) and the appetite-regulating neuropeptides, proopiomelanocortin (POMC) and neuropeptide Y, which it regulates. In fetuses from ewes undernourished from -60 to +30 d around conception, there was increased histone H3K9 acetylation (1.63-fold) and marked hypomethylation (62% decrease) of the POMC gene promoter but no change in POMC expression. In the same group, acetylation of histone H3K9 associated with the hypothalamic GR gene was increased 1.60-fold and the GR promoter region was hypomethylated (53% decrease). In addition, there was a 4.7-fold increase in hypothalamic GR expression but no change in methylation of GR gene expression in the anterior pituitary or hippocampus. Interestingly, hypomethylation of both POMC and GR promoter markers in fetal hypothalami was also identified after maternal undernutrition from -60 to 0 d and -2 to +30 d. In comparison, the Oct4 gene, was hypermethylated in both control and underfed groups. Periconceptional undernutrition is therefore associated with marked epigenetic changes in hypothalamic genes. Increase in GR expression in the undernourished group may contribute to fetal programming of a predisposition to obesity, via altered GR regulation of POMC and neuropeptide Y. These epigenetic changes in GR and POMC in the hypothalamus may also predispose the offspring to altered regulation of food intake, energy expenditure, and glucose homeostasis later in life.

Thyroid hormone activation of retinoic acid synthesis in hypothalamic tanycytes

“…For example, changes in HDAC expression and histone acetylation have been observed in the ventromedial and paraventricular hypothalamic nuclei of mice that were either fasted or fed a high‐fat diet (Funato et al, 2011). In addition, epigenetic changes in the foetal hypothalamus caused by maternal stress have been linked to long‐term alterations in energy balance, including susceptibility to diet‐induced obesity (Paternain et al, 2012; Stevens et al, 2010). …”

“…Control of corticotropin‐releasing hormone in the hypothalamus by the glucocorticoid receptor, another member of the nuclear receptor superfamily, is potentially mediated by HDACI (Miller et al, 2011). Epigenetic changes in the DNA methylation and histone acetylation states of the promoters of hypothalamic genes involved in energy balance, such as Pomc and Npy , have been found to result from maternal undernutrition or stress (Paternain et al, 2012; Stevens et al, 2010). This represents a mechanism by which hypothalamic plasticity may be moulded.…”

Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives

“…Some of these signals consist of orexigenic and anorexigenic neuropeptides, such as POMC, MC4R, NPY and CART, some of which have been reported to be regulated epigenetically. Thus, periconceptional undernutrition induces proopiomelanocortin (POMC) promoter hypomethylation in the hypothalamus of sheep (Stevens et al, 2010), and is also associated with reduced DNA methyltransferase activity and altered histone methylation and acetylation (Begum et al, 2012). On the other hand, when suffering early overfeeding, the hypothalamic POMC promoter becomes hypermethylated (Plagemann et al, 2009).…”

Forty research issues for the redesign of animal production systems in the 21st century

“…Farming practices in the fetal stage and early life affect behavior, response to stress, immunity and performance of adult animals, and there is some evidence of transmission to the next generation (Stevens et al, 2010). In this sense, epigenetic marks reversibly or heritably present in the genome can contribute to animal robustness.…”