ESPE2022 Poster Category 1 Fat, Metabolism and Obesity (73 abstracts)
Sex-specific POMC DNA methylation variability is associated with increased body weight
Lara Lechner 1 , Susanna Wiegand 1 , Elsa Leitão 2 , Christopher Schröder 2 , Karl-Heinz Jöckel 2 , Markus Nöthen 3 , Börge Schmidt 2 , Bernhardt Horsthemke 2 & Peter Kühnen 1
1Charité Universitätsmedizin Berlin, Berlin, Germany; 2University Hospital Essen, Essen, Germany; 3School of Medicine and University Hospital Bonn, Bonn, Germany
The increasing prevalence of obesity and associated comorbidities worldwide is a major problem for national health care systems. For this reason, it is of importance to gain knew knowledge about the central regulation of body weight and to identify factors which are leading to an increased individual risk to gain weight. Despite large genome weight associations studies and related genetic risk scores, the regulation of inter-individual body weight variability remains elusive. Therefore, it has been hypothesized that epigenetic modification might be relevant for the regulation of body weight. For this reason, we analyzed in a candidate approach DNA methylation of the POMC (Pro-opiomelanocortin) gene, whose protein product is embedded in the leptin-melanocortin pathway and is pivotal for body weight regulation. In a cohort of the HNR (Heinz Nixdorf Recall) study (n=1383), we identified increased POMC methylation levels in DNA extracted from peripheral blood cells (PBC) of obese female participants. This epigenetic variant led to a 1.44 increased risk of the variant carrier to develop obesity. Further analysis reveals that this POMC methylation variant is non-genetically determined. Additionally, POMC methylation analysis of PBC DNA of monozygotic- and dizygotic twin pairs provide evidence for an early setting in utero of this POMC methylation variant. Therefore, POMC methylation fulfill the criteria for a so-called metastable epiallele. This are epigenetic regions where methylation is set early in embryonic development, is non-tissue specific and stable over time. Methylation variability at metastable epialleles have been already described to be associated with body weight and fur color in the Avy mouse model. The presented data are pointing towards a relevant role of hypermethylation at this POMC metastable epiallele in body weight regulation.
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