Hypothalamic proopiomelanocortin promoter methylation becomes altered by early overfeeding: an epigenetic model of obesity and the metabolic syndrome

Abstract

Pre-and neonatal overfeeding programmes a permanent obesity disposition and accompanying diabetic and cardiovascular disorders, by unknown mechanisms. We proposed that early overfeeding may alter DNA methylation patterns of hypothalamic promoter regions of genes critically involved in the lifelong regulation of food intake and body weight. We induced neonatal overfeeding by rearing Wistar rats in small litters (SL) and thereafter mapped the DNA methylation status of CpG dinucleotides of gene promoters from hypothalamic tissue, using bisulfite sequencing. Neonatal overfeeding led to rapid early weight gain, resulting in a metabolic syndrome phenotype, i.e. obesity, hyperleptinaemia, hyperglycaemia, hyperinsulinaemia, and an increased insulin/glucose ratio. Accompanying, without group difference to controls, the promoter of the main orexigenic neurohormone, neuropeptide Y, was methylated at low levels (i.e. < 5%). In contrast, in SL rats the hypothalamic gene promoter of the main anorexigenic neurohormone, proopiomelanocortin (POMC), showed hypermethylation (P < 0.05) of CpG dinucleotides within the two Sp1-related binding sequences (Sp1, NF-κB) which are essential for the mediation of leptin and insulin effects on POMC expression. Consequently, POMC expression lacked upregulation, despite hyperleptinaemia and hyperinsulinaemia. Accordingly, the extent of DNA methylation within Sp1-related binding sequences was inversely correlated to the quotients of POMC expression/leptin (P = 0.02) and POMC expression/insulin (P < 0.001), indicating functionality of acquired epigenomic alterations. These data for the first time demonstrate a nutritionally acquired alteration of the methylation pattern and, consequently, the regulatory 'set point' of a gene promoter that is critical for body weight regulation. Our findings reveal overfeeding as an epigenetic risk factor of obesity programming and consecutive diabetic and cardiovascular disorders and diseases, in terms of the metabolic syndrome.

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

“…Thus, neonatal overfeeding alters DNA methylation patterns of the hypothalamic promoter region of the main anorexigenic neuropeptide, proopiomelanocortin (POMC) (Plagemann et al, 2009). …”

“…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). Neuropeptide Y (NPY), one of the main appetite-inducing factors, was one of the ten CpG sites that were hypermethylated in mucosa from colorectal cancer patients when compared to normal mucosa (Kim YH et al, 2011), and is also frequently hypermethylated in hepatocellular carcinoma tissue samples (Shin et al, 2010).…”

“…Genistein-induced epigenetic alterations seems to share important similarities with those found in intrauterine growth retardation neonates (Einstein et al, 2010), but the magnitude is markedly lower than the differences found between tissues or in cancer. As previously described, perinatal undernutrition (Jousse et al, 2011) or overnutrition (Plagemann et al, 2009), the intake of particular nutrients like methyl donors (Waterland et al, 2008) or PUFA (Kiec-Wilk et al, 2011), or the exposure to endocrine disruptors like bisphenol A (Rubin et al, 2011) are crucial in the in utero modulation of the epigenetic marks (DNA methylation or histone modifications), and more efforts must be made to unravel the epigenetic mechanisms involved in the pathogenesis of obesity and metabolic syndrome, including the doses of each compound, the interactions with the genotype and the period or length of the exposure. One interesting example of possible application of this research is the demonstration that leptin administration during the suckling period has protective effects against later obesity probably by inducing changes in promoter methylation of the hypothalamic POMC gene (Palou et al, 2011).…”

Nuclear factor κB (NF-κB) suppresses food intake and energy expenditure in mice by directly activating the Pomc promoter

“…Moreover, the methylation levels of the Pomc promoter are highly dynamic under physiological and pathological conditions. For example, Pomc promoter methylation is significantly higher in tissues that do not express Pomc [39], or is altered in human patients with anorexia nervosa [40], in SL rats with early overfeeding [41], and in ectopic expression in the Whole-cell, cytosolic and nuclear fractions were immunoprobed using antibodies against pSTAT3, STAT3, pRELA and RELA. β-actin was used as whole-cell lysis loading control, α-tubulin as cytosol loading control, and proliferating cell nuclear antigen as the nuclear loading control.…”

L’expérience sensorielle et nutritionnelle des parents et leur état métabolique orientent le comportement alimentaire de leur descendance

“…Cette régulation positive fait suite à la fixation des facteurs de transcription Sp1 et Stat3 sur son promoteur [33], laquelle dépend de son niveau de méthylation. En cas de suralimentation postnatale des petits, le niveau de méthylation du promoteur de Pomc est augmenté dans l'hypothalamus au moment du sevrage, ce qui se traduit par une baisse d'expression du gène malgré une hyperinsulinémie et une hyperleptinémie [34] ; il est au contraire diminué lors d'une restriction protéique maternelle [11]. Un régime maternel hyperlipidique induit également une hypométhylation des promoteurs de certains gènes du système de récompense chez la descendance à l'âge adulte et est corrélé à une préférence pour des aliments hyperénergétiques [35].…”