Hypothalamic insulin receptor expression and DNA promoter methylation are sex-specifically altered in adult offspring of high-fat diet (HFD)-overfed mother rats.

Maternal overnutrition around reproduction has been shown to increase the offspring's risk for "diabesity," mediated by altered hypothalamic neuropeptide expression. In this report, a possible contribution of altered hypothalamic sensing capacity for the peripheral satiety signals glucose, insulin and leptin will be addressed, taking into account potential sex differences. Specifically, we evaluated the effects a maternal high-fat diet (HFD) overfeeding has in rats pre- and during pregnancy and lactation on the hypothalamic gene expression patterns of insulin and leptin receptors (InsR, ObRb) and glucose transporter 3 (Glut3) as well as DNA methylation in the offspring at adult age (day 200 of life). Maternal HFD consumption resulted in a metabolic syndrome phenotype, i.e., obesity, hyperleptinemia, hyperinsulinemia, impaired glucose tolerance and increased homeostatic model assessment of insulin resistance. Interestingly, in turn, insulin resistance was more pronounced in male offspring, accompanied by decreased hypothalamic InsR-mRNA. This was linked with hypermethylation of an activating transcription factor binding site within the hypothalamic InsR promoter. The degree of methylation correlated inversely with respective InsR expression, while InsR expression itself was inversely related to phenotypic "diabesity." Expression of ObRb and Glut3 mRNA was not significantly changed. In conclusion, sex-specific alterations of hypothalamic InsR expression and DNA promoter methylation in adult offspring of HFD-overfed dams may lead to hypothalamic insulin resistance and "diabesity," with males predisposed to this epigenetic malprogramming.

Acquired alterations of hypothalamic gene expression of insulin and leptin receptors and glucose transporters in prenatally high-glucose exposed three-week old chickens do not coincide with aberrant promoter DNA methylation.

BACKGROUND: Prenatal exposures may have a distinct impact for long-term health, one example being exposure to maternal 'diabesity' during pregnancy increasing offspring 'diabesity' risk. Malprogramming of the central nervous regulation of body weight, food intake and metabolism has been identified as a critical mechanism. While concrete disrupting factors still remain unclear, growing focus on acquired epigenomic alterations have been proposed. Due to the independent development from the mother, the chicken embryo provides a valuable model to distinctively establish causal factors and mechanisms. AIM: The aim of this study was to determine the effects of prenatal hyperglycemia on postnatal hypothalamic gene expression and promoter DNA methylation in the chicken. METHODS AND FINDINGS: To temporarily induce high-glucose exposure in chicken embryos, 0.5 ml glucose solution (30 mmol/l) were administered daily via catheter into a vessel of the chorioallantoic egg membrane from days 14 to 17 of incubation. At three weeks of postnatal age, body weight, total body fat, blood glucose, mRNA expression (INSR, LEPR, GLUT1, GLUT3) as well as corresponding promoter DNA methylation were determined in mediobasal hypothalamic brain slices (Nucleus infundibuli hypothalami). Although no significant changes in morphometric and metabolic parameters were detected, strongly decreased mRNA expression occurred in all candidate genes. Surprisingly, however, no relevant alterations were observed in respective promoter methylation. CONCLUSION: Prenatal hyperglycemia induces strong changes in later hypothalamic expression of INSR, LEPR, GLUT1, and GLUT3 mRNA. While the chicken provides an interesting approach for developmental malprogramming, the classical expression regulation via promoter methylation was not observed here. This may be due to alternative/interacting brain mechanisms or the thus far under-explored bird epigenome.