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

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.

Forebrain neuronal SMC3 regulates body weight and metabolic health partially through regulation of hypothalamic Melanocortin 4 receptor

“…Setmelanotide was recently granted approval by the U.S. Food and Drug Administration (FDA) 19 Efficacy of Setmelanotide was determined in individuals with rare genetic mutations that disrupt the MC4r pathway such as POMC 36 . Of interest, a recent study found that Setmelanotide can also affect treat individuals with dysregulated methylation in the POMC gene, which further suggests that epigenetic dysregulation of this pathway may be treated with Setmelanotide 37 . A limitation of the current study is that we do not know which specific cell types in the hypothalamus are responsible for the phenotype.…”

IMPROVE 2022 International Meeting on Pathway‐Related Obesity: Vision of Excellence

“…What is the potential significance of epigenetics in obesity? Analysis of a large cohort ( n = 1383) found increased DNA methylation in a variably methylated region in the POMC gene, particularly in women 54 . POMC methylation is very stable over time and is present before the onset of obesity.…”

Genetische Ursachen der Adipositas und ihre therapeutischen Implikationen

“…Neben genetischen Varianten sind auch epigenetische Veränderungen am POMC-Gen beschrieben [43,44]. Personen mit einer veränderten DNA-Methylierung am POMC-Gen haben ein 1,4-fach erhöhtes Risiko für die Entwicklung einer Adipositas [44].…”

“…Neben genetischen Varianten sind auch epigenetische Veränderungen am POMC-Gen beschrieben [43,44]. Personen mit einer veränderten DNA-Methylierung am POMC-Gen haben ein 1,4-fach erhöhtes Risiko für die Entwicklung einer Adipositas [44]. Diese differenzielle Methylierung war zudem invers mit der POMC-Expression in den entsprechenden exprimierenden Neuronen assoziiert [44].…”

“…Personen mit einer veränderten DNA-Methylierung am POMC-Gen haben ein 1,4-fach erhöhtes Risiko für die Entwicklung einer Adipositas [44]. Diese differenzielle Methylierung war zudem invers mit der POMC-Expression in den entsprechenden exprimierenden Neuronen assoziiert [44]. Zudem korrelierte die Methylierung des Gens stark zwischen Eltern und Kindern [43].…”