Early-set POMC methylation variability is accompanied by increased risk for obesity and is addressable by MC4R agonist treatment

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Item Type:	Article
Title:	Early-set POMC methylation variability is accompanied by increased risk for obesity and is addressable by MC4R agonist treatment
Creators Name:	Lechner, L., Opitz, R., Silver, M.J., Krabusch, P.M., Prentice, A.M., Field, M.S., Stachelscheid, H., Leitão, E., Schröder, C., Fernandez Vallone, V., Horsthemke, B., Jöckel, K.H., Schmidt, B., Nöthen, M.M., Hoffmann, P., Herms, S., Kleyn, P.W., Megges, M., Blume-Peytavi, U., Weiss, K., Mai, K., Blankenstein, O., Obermayer, B., Wiegand, S. and Kühnen, P.
Abstract:	Increasing evidence points toward epigenetic variants as a risk factor for developing obesity. We analyzed DNA methylation of the POMC (pro-opiomelanocortin) gene, which is pivotal for satiety regulation. We identified sex-specific and nongenetically determined POMC hypermethylation associated with a 1.4-fold (confidence interval, 1.03 to 2.04) increased individual risk of developing obesity. To investigate the early embryonic establishment of POMC methylation states, we established a human embryonic stem cell (hESC) model. Here, hESCs (WA01) were transferred into a naïve state, which was associated with a reduction of DNA methylation. Naïve hESCs were differentiated via a formative state into POMC-expressing hypothalamic neurons, which was accompanied by re-establishment of DNA methylation patterning. We observed that reduced POMC gene expression was associated with increased POMC methylation in POMC-expressing neurons. On the basis of these findings, we treated POMC-hypermethylated obese individuals (n = 5) with an MC4R agonist and observed a body weight reduction of 4.66 ± 2.16% (means ± SD) over a mean treatment duration of 38.4 ± 26.0 weeks. In summary, we identified an epigenetic obesity risk variant at the POMC gene fulfilling the criteria for a metastable epiallele established in early embryonic development that may be addressable by MC4R agonist treatment to reduce body weight.
Keywords:	Body Weight, DNA Methylation, Obesity, Pregnancy, Pro-Opiomelanocortin, Type 4 Melanocortin Receptor, Risk Factors
Source:	Science Translational Medicine
ISSN:	1946-6234
Publisher:	American Association for the Advancement of Science
Volume:	15
Number:	705
Page Range:	eadg1659
Date:	July 2023
Official Publication:	https://doi.org/10.1126/scitranslmed.adg1659
PubMed:	View item in PubMed

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