Impaired regulation of the hypothalamic-pituitary-adrenal (HPA) axis is substantially involved in several
psychiatric disorders. Smoking interferes with HPA axis by activating
proopiomelanocortin (
POMC) neurons and thus stimulating the expression of
POMC. The
POMC transcript is processed into several
peptide hormones, such as
adrenocorticotropic hormone (
ACTH) and
alpha-melanocyte-stimulating hormone (
alpha-MSH), that play a role in stress response and weight control. In
alcohol dependence,
POMC promoter methylation is associated with craving. Here, we describe evidence of altered
POMC promoter methylation in smoking. To determine how
tobacco dependence and its withdrawal affect
POMC promoter-specific DNA methylation, we assessed blood samples of 36 tobacco dependent individuals at day 1, 7 and 14 of withdrawal compared to 41 healthy controls using direct
bisulfite sequencing. We found that
POMC promoter methylation is significantly higher in smokers than in non-smokers. Moreover, this methylation difference does not readapt within 14 days of abstinence. We offer two explanatory models: Smokers could have a higher methylation state before the onset of smoking and this premorbid status might be acquired by environmental factors in early life. Alternatively, smoking may activate
POMC neurons and its
protein expression. Therefore, increasing methylation status of its promoter might be an adjustment to keep homeostasis. In either way, altered
POMC methylation in smokers seems to indicate an adaptation of stress signaling, thereby potentially serving as a marker for stress-related functions that support the addiction.