Maternal overnutrition programs epigenetic changes in the regulatory regions of hypothalamic Pomc in the offspring of rats

Abstract

Background and objectiveMaternal overnutrition has been implicated in affecting the offspring by programming metabolic disorders such as obesity and diabetes, by mechanisms that are not clearly understood. This study aimed to determine the long-term impact of maternal high-fat (HF) diet feeding on epigenetic changes in the offspring’s hypothalamic Pomc gene, coding a key factor in the control of energy balance. Further, it aimed to study the additional effects of postnatal overnutrition on epigenetic programming by maternal nutrition.MethodsEight-week-old female Sprague–Dawley rats were fed HF diet or low-fat (LF) diet for 6 weeks before mating, and throughout gestation and lactation. At postnatal day 21, samples were collected from a third offspring and the remainder were weaned onto LF diet for 5 weeks, after which they were either fed LF or HF diet for 12 weeks, resulting in four groups of offspring differing by their maternal and postweaning diet.ResultsWith maternal HF diet, offspring at weaning had rapid early weight gain, increased adiposity, and hyperleptinemia. The programmed adult offspring, subsequently fed LF diet, retained the increased body weight. Maternal HF diet combined with offspring HF diet caused more pronounced hyperphagia, fat mass, and insulin resistance. The ARC Pomc gene from programmed offspring at weaning showed hypermethylation in the enhancer (nPE1 and nPE2) regions and in the promoter sequence mediating leptin effects. Interestingly, hypermethylation at the Pomc promoter but not at the enhancer region persisted long term into adulthood in the programmed offspring. However, there were no additive effects on methylation levels in the regulatory regions of Pomc in programmed offspring fed a HF diet.ConclusionMaternal overnutrition programs long-term epigenetic alterations in the offspring’s hypothalamic Pomc promoter. This predisposes the offspring to metabolic disorders later in life.

Chronic stress, epigenetics, and adipose tissue metabolism in the obese state

“…Similarly, maternal overnutrition induces epigenetic changes in the offspring. Offspring from rats fed a HFD throughout gestation and lactation had higher body weights, increased sWAT and vWAT masses, and hyperleptinemia at weaning compared to those from low fat diet (LFD) fed dams [139]. Moreover, the greater body weight, epididymal fat mass as well as the higher calorie intake persisted into adulthood, even when they were switched to a LFD, compared to their LFD counterparts whose dams also consumed the LFD [139].…”

Diet‐induced DNA methylation within the hypothalamic arcuate nucleus and dysregulated leptin and insulin signaling in the pathophysiology of obesity

“…In the studies evaluated herein, no methylation changes were observed for NPY, MC4R, or PPAR-γ when investigated (Cifani et al, 2015;Zheng et al, 2015), while the methylation status of POMC was consistently found to be altered and positively associated with increased levels of leptin and insulin and the development of the obesity phenotype and symptoms of MeS (Cifani et al, 2015;Gali Ramamoorthy et al, 2018;Marco et al, 2013;Andreas Plagemann et al, 2009;Wang et al, 2014;Zhang et al, 2014;Zheng et al, 2015).…”

“…In the studies evaluated herein, no methylation changes were observed for NPY , MC4R, or PPAR‐ γ when investigated (Cifani et al, ; Zheng et al, ), while the methylation status of POMC was consistently found to be altered and positively associated with increased levels of leptin and insulin and the development of the obesity phenotype and symptoms of MeS (Cifani et al, ; Gali Ramamoorthy et al, ; Marco et al, ; Andreas Plagemann et al, ; Wang et al, ; Zhang et al, ; Zheng et al, ). With POMC‐mediated leptin and insulin function playing a major role in the pathological development of obesity and MeS, the methylation status of POMC thus represents a pivotal therapeutic target.…”

“…In a recent study investigating the long‐term impact of maternal HFD on offspring susceptibility to developing obesity, POMC methylation was investigated at weaning and after 20 weeks of exposure to either a low‐fat diet (LFD) or HFD (Gali Ramamoorthy et al, ). The offspring of dams fed HFD had increased BW and adiposity as well as elevated leptin levels at weaning.…”

MicroRNAs are involved in the hypothalamic leptin sensitivity

“…Several studies have shown that Pomc gene expression is tightly controlled by different mechanisms. Particularly, epigenetic mechanisms such as histone modifications or DNA methylation were shown to modulate Pomc gene activity under different nutritional status [16][17][18][19]. For instance, hypomethylation of Pomc promoter markers in fetal hypothalami was identified after maternal undernutrition in the ovine [16].…”