| Autor: |
Lechner, Lara, Opitz, Robert, Silver, Matt J., Krabusch, Philipp M., Prentice, Andrew M., Field, Martha S., Stachelscheid, Harald, Leitão, Elsa, Schröder, Christopher, Fernandez Vallone, Valeria, Horsthemke, Bernhard, Jöckel, Karl-Heinz, Schmidt, Börge, Nöthen, Markus M., Hoffmann, Per, Herms, Stefan, Kleyn, Patrick W., Megges, Matthias, Blume-Peytavi, Ulrike, Weiss, Katja |
| Předmět: |
|
| Zdroj: |
Science Translational Medicine; 7/19/2023, Vol. 15 Issue 705, p1-15, 15p |
| Abstrakt: |
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. Editor's summary: The protein proopiomelanocortin (POMC) helps regulate satiety and energy expenditure via leptin-melanocortin signaling. Lechner et al. show that epigenetic modification of the POMC gene carries increased risk of obesity, particularly in females. Augmenting melanocortin signaling via administration of the melanocortin 4 receptor agonist setmelanotide in five individuals with non-genetic obesity plus POMC hypermethylation resulted in an average weight loss of 4.6%. DNA methylation was increased in hypothalamic neurons differentiated from their less-methylated naïve human embryonic stem cell precursors, suggesting that nongenetic POMC hypermethylation may be established during development in humans. —Catherine Charneski [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
|
