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. 2025 Jul 31;25(1):749.
doi: 10.1186/s12888-025-07162-y.

Overweight and POMC methylation: epigenetic associations with adolescent depression

Ye Ye  1   2 , Jia-Hui Hu  1   3 , Xing-Yu Xiao  4 , Ting Ji  5 , Fei Wang  1   2 , Fu-Jun Jia  6   7 , Cai-Lan Hou  8   9
Affiliations

Overweight and POMC methylation: epigenetic associations with adolescent depression

Ye Ye et al. BMC Psychiatry. .

Abstract

Introduction: To evaluate whether BMI status influences POMC methylation levels and subsequently affects the course of adolescent depression. This study examined the relationship between the methylation levels of different CpG sites in the POMC gene and clinical symptoms across various BMI categories in adolescent depression.

Methods: A total of 108 adolescent patients with depressive disorders including 68 with unipolar depression and 40 with bipolar depression participated in the study. They were divided into three groups: 11 underweight individuals (BMI below the age-specific threshold), 75 normal-weight individuals (BMI within the defined normal range), and 22 overweight individuals (BMI between the overweight threshold and obesity threshold). Pyrosequencing methylation analysis was used to assess POMC gene promoter methylation levels

Results: Adolescents in the overweight group exhibited significantly lower methylation levels at CpG6 and CpG8 of the POMC gene compared to their normal-weight and underweight peers. Furthermore, methylation at these sites was associated with clinical and psychological indicators such as Childhood Trauma Questionnaire (CTQ) and Montgomery–Asberg Depression Rating Scale (MADRS) scores. After adjusted for medication use, multivariate linear regression analysis revealed a negative correlation between CpG6 methylation levels and CTQ scores in overweight group.

Conclusion: This study shows the association between POMC methylation levels and depressive symptoms in adolescents across different BMI categories. The findings suggest a potential interaction between epigenetic mechanisms, depression and overweight providing a foundation for further mechanistic investigations.

Trial registration: Not applicable.

Supplementary Information: The online version contains supplementary material available at 10.1186/s12888-025-07162-y.

Keywords: BMI; Depression; Methylation; Overweight; POMC.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The study was approved by the Ethics Review Committee of Guangdong Provincial People’s Hospital (Approval No. KY-Z-2021-108-02) and conducted under its supervision. All human participant procedures complied with institutional/national ethics committee requirements and the 1964 Helsinki Declaration (including subsequent amendments or equivalent standards).All participants and guardians provided written informed consent. Consent for publication: All participants and guardians provided written informed consent. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Multifunctional regulation by POMC-derived peptides: Integrating HPA axis activity, metabolic balance, and affective states The POMC gene encodes a precursor polypeptide cleaved into bioactive peptides with distinct functions. Chronic stress activates hypothalamic POMC neurons, triggering release of ACTH from the pituitary.ACTH stimulates adrenal cortisol secretion, leading to sustained hypercortisolemia, which is linked to both depressive symptoms and visceral obesity.And α-MSH binds to melanocortin-4 receptors (MC4R) in the hypothalamus, suppressing appetite and promoting energy expenditure.Dysfunctional α-MSH/MC4R signaling contributes to hyperphagia and weight gain.Another POMC derivative, β-Endorphin, modulates mood and reward processing via opioid receptors.Reduced β-endorphin activity is associated with anhedonia and emotional dysregulation in depression. (By Figdraw.)
Fig. 2
Fig. 2
Comparison of POMC gene promoter region methylation level among depression with weight loss group, depression with weight normal BMI group, and depression with overweight group. Bold values: P < 0.05. Abbreviations: CpG Cytosine-phosphate-Guanine, CpG1-8 CpG island methylation site 1–8
Fig. 3
Fig. 3
Spearman correlation analysis between POMC gene promoter methylation levels and psychometric scores. (A) Depression with weight normal BMI group; (B) Depression with overweight group; (C) Depression with weight loss group
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