Transcriptomic and Epigenetic Changes in the Hypothalamus Are Involved in an Increased Susceptibility to a High-Fat-Sucrose Diet in Prenatally Stressed Female Rats

Abstract

Disturbances in the prenatal period are linked to metabolic disorders in adulthood, implying the hypothalamic systems of appetite and energy balance regulation. In order to analyze the central effects of a high-fat-sucrose (HFS) diet in prenatally stressed (PNS) female adult rats, Wistar dams were exposed to chronic-mild-stress during the third week of gestation and were then compared with unstressed controls. Adult female offspring were fed a chow or HFS diet for 10 weeks. Changes in body weight, adiposity as well as expression and methylation levels of selected hypothalamic genes were analyzed. PNS induced lower birthweight and body length with no changes in body fat mass. After the HFS diet, the expected overweight model was observed accompanied by higher adiposity and insulin resistance, which was worsened by PNS. The stress model induced higher energy intake in adulthood. Hypothalamic gene expression analysis revealed that the HFS diet decreased Slc6a3 (dopamine active transporter), NPY (neuropeptide Y) and IR (insulin receptor) and increased POMC (pro-opiomelanocortin). Hypothalamic DNA methylation levels in the promoter region of Slc6a3 revealed that Slc6a3 was hypermethylated by the HFS diet in CpG site –53 bp to the transcription start site. HFS diet also hypermethylated CpG site –167 bp of the POMC promoter only in nonstressed animals. No correlations were found between gene expression and DNA methylation levels. These results imply that early-life stress in females increased predisposition to diet-induced obesity in adulthood.

Dopamine gene methylation patterns are associated with obesity markers and carbohydrate intake

“…In this study, two CpG sites at SLC6A3 gene correlated with BMI and carbohydrate intake with a positive trend. Consistently, it was reported that hypothalamic SLC6A3 was hypermethylated in the promoter region in response to high‐fat‐sucrose diet in prenatally stressed female adult rats (Paternain et al., 2012). Similarly, a significant increase in DNA methylation within the promoter region of SLC6A3 was found in the ventral tegmental area of mice fed a high‐fat diet, which associated with repressed expression (Vucetic et al., 2012).…”

“…Moreover, differential DNA methylation patterns at DAT and tyrosine hydroxylase ( TH ) were linked to altered DA‐related gene expression in response to chronic intake of high‐fat diet in mice (Vucetic, Carlin, Totoki, & Reyes, 2012). Furthermore, a set of transcriptional and epigenetic changes in the hypothalamus of prenatally stressed female rats were implicated in an increased susceptibility to a high‐fat‐sucrose diet (Paternain et al., 2012). This study hypothesized associations of DNA methylation signatures at genes modulating DA signaling with obesity features and accompanying metabolic profiles as well as an epigenetic influence on macronutrient intake.…”

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.…”

Methyl donor supplementation in rats reverses the deleterious effect of maternal separation on depression-like behaviour

“…Acute stress has been demonstrated to affect both the global DNA methylation profile of the brain [14] and the methylation levels of genes implicated in the regulation of the hippocampal function, such as the glucocorticoid receptor [15]. Moreover, it has been described that early-life stress in rodents induces adult behavioural impairments [16] and leads to epigenetic alterations in different regions of the brain [17,18], affecting for example the methylation of the promoters of reelin [15] and corticotropin-releasing factor [19] in the adult rat brain. It has been also described that these marks could be modified, even in terminally differentiated tissues, not only by pharmacological agents but also by stable variations in environmental conditions, such as the diet [20].…”