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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: |
Lechner, L.  ORCID: https://orcid.org/0000-0002-9318-6857, Opitz, R. ORCID: https://orcid.org/0000-0003-3143-0997, Silver, M.J. ORCID: https://orcid.org/0000-0002-3852-9677, Krabusch, P.M., Prentice, A.M. ORCID: https://orcid.org/0000-0001-5389-451X, Field, M.S., Stachelscheid, H. ORCID: https://orcid.org/0000-0002-9283-4605, Leitão, E. ORCID: https://orcid.org/0000-0001-5051-9714, Schröder, C., Fernandez Vallone, V. ORCID: https://orcid.org/0000-0003-3875-9170, Horsthemke, B., Jöckel, K.H. ORCID: https://orcid.org/0000-0002-1987-0255, Schmidt, B., Nöthen, M.M. ORCID: https://orcid.org/0000-0002-8770-2464, Hoffmann, P. ORCID: https://orcid.org/0000-0002-6573-983X, Herms, S. ORCID: https://orcid.org/0000-0002-2786-8200, Kleyn, P.W. ORCID: https://orcid.org/0000-0002-6249-8196, Megges, M. ORCID: https://orcid.org/0000-0001-6537-0975, Blume-Peytavi, U. ORCID: https://orcid.org/0000-0003-3528-3752, Weiss, K. ORCID: https://orcid.org/0000-0002-0658-8074, Mai, K., Blankenstein, O. ORCID: https://orcid.org/0000-0003-1803-5589, Obermayer, B. ORCID: https://orcid.org/0000-0002-9116-630X, Wiegand, S. ORCID: https://orcid.org/0000-0001-8341-9533 and Kühnen, P. ORCID: https://orcid.org/0000-0003-0211-176X
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| 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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