DNA methylation of genes involved in lipid metabolism drives adiponectin levels and metabolic disease

Lucy Sinke; Thomas Delerue; Rory Wilson; Xueling Lu; Yujing Xia; Ricardo Costeira; M Kamal Nasr; Marian Beekman; Lude Franke; Alexandra Zhernakova; Jingyuan Fu; Christian Gieger; Christian Herder; Wolfgang Koenig; Annette Peters; José M Ordovas; Marcus Dörr; Hans J Grabe; Matthias Nauck; Jordana T Bell; Alexander Teumer; Harold Snieder; Melanie Waldenberger; P Eline Slagboom; Bastiaan T Heijmans

doi:10.1007/s00125-025-06549-6

DNA methylation of genes involved in lipid metabolism drives adiponectin levels and metabolic disease

Lucy Sinke
, Thomas Delerue
, Rory Wilson
, Xueling Lu
, Yujing Xia
, Ricardo Costeira
, M Kamal Nasr
, Marian Beekman
, Lude Franke
, Alexandra Zhernakova
, Jingyuan Fu
, Christian Gieger
, Christian Herder
, Wolfgang Koenig
, Annette Peters
, José M Ordovas
, Marcus Dörr
, Hans J Grabe
, Matthias Nauck
, Jordana T Bell

Alexander Teumer, Harold Snieder, Melanie Waldenberger, P Eline Slagboom, Bastiaan T Heijmans^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

AIMS/HYPOTHESIS: Despite playing critical roles in the pathophysiology of type 2 diabetes and other metabolic disorders, the molecular mechanisms underlying circulating adipokine levels remain poorly understood. By identifying genomic regions involved in the regulation of adipokine levels and adipokine-mediated disease risk, we can improve our understanding of type 2 diabetes pathogenesis and inter-individual differences in metabolic risk.

METHODS: We conducted an epigenome-wide meta-analysis of associations between serum adiponectin (n=2791) and leptin (n=3661) and leukocyte DNA methylation at over 400,000 CpG sites across five European cohorts. The resulting methylation signatures were followed up using functional genomics, integrative analyses and causal inference methods.

RESULTS: Our findings revealed robust associations with adiponectin at 73 CpGs and leptin at 211 CpGs. Many of the identified sites were also associated with risk factors for the metabolic syndrome and located in enhancers close to relevant transcription factor binding sites. Integrative analyses additionally linked 35 of the adiponectin-associated CpGs to the expression of 46 genes, and 100 of the leptin-associated CpGs to the expression of 151 genes, with implicated genes enriched for lipid transport (e.g. ABCG1), metabolism (e.g. CPT1A) and biosynthesis (e.g. DHCR24). Bidirectional two-sample Mendelian randomisation further identified two specific CpG sites as plausible drivers of both adiponectin levels and metabolic health: one annotated to ADIPOQ, the gene encoding adiponectin; and another linked to the expression of SREBF1, an established modifier of type 2 diabetes risk known to exert its effects via adiponectin.

CONCLUSIONS/INTERPRETATION: Taken together, these large-scale and integrative analyses uncovered links between adipokines and widespread, yet functionally specific, differences in regulation of genes with a central role in type 2 diabetes and its risk factors.

Original language	English
Journal	Diabetologia
DOIs	https://doi.org/10.1007/s00125-025-06549-6
Publication status	E-pub ahead of print - 8-Oct-2025

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Sinke, L., Delerue, T., Wilson, R., Lu, X., Xia, Y., Costeira, R., Nasr, M. K., Beekman, M., Franke, L., Zhernakova, A., Fu, J., Gieger, C., Herder, C., Koenig, W., Peters, A., Ordovas, J. M., Dörr, M., Grabe, H. J., Nauck, M., ... Heijmans, B. T. (2025). DNA methylation of genes involved in lipid metabolism drives adiponectin levels and metabolic disease. Diabetologia. Advance online publication. https://doi.org/10.1007/s00125-025-06549-6

@article{48ccf83f47f84233947763878d95ea9d,

title = "DNA methylation of genes involved in lipid metabolism drives adiponectin levels and metabolic disease",

abstract = "AIMS/HYPOTHESIS: Despite playing critical roles in the pathophysiology of type 2 diabetes and other metabolic disorders, the molecular mechanisms underlying circulating adipokine levels remain poorly understood. By identifying genomic regions involved in the regulation of adipokine levels and adipokine-mediated disease risk, we can improve our understanding of type 2 diabetes pathogenesis and inter-individual differences in metabolic risk.METHODS: We conducted an epigenome-wide meta-analysis of associations between serum adiponectin (n=2791) and leptin (n=3661) and leukocyte DNA methylation at over 400,000 CpG sites across five European cohorts. The resulting methylation signatures were followed up using functional genomics, integrative analyses and causal inference methods.RESULTS: Our findings revealed robust associations with adiponectin at 73 CpGs and leptin at 211 CpGs. Many of the identified sites were also associated with risk factors for the metabolic syndrome and located in enhancers close to relevant transcription factor binding sites. Integrative analyses additionally linked 35 of the adiponectin-associated CpGs to the expression of 46 genes, and 100 of the leptin-associated CpGs to the expression of 151 genes, with implicated genes enriched for lipid transport (e.g. ABCG1), metabolism (e.g. CPT1A) and biosynthesis (e.g. DHCR24). Bidirectional two-sample Mendelian randomisation further identified two specific CpG sites as plausible drivers of both adiponectin levels and metabolic health: one annotated to ADIPOQ, the gene encoding adiponectin; and another linked to the expression of SREBF1, an established modifier of type 2 diabetes risk known to exert its effects via adiponectin.CONCLUSIONS/INTERPRETATION: Taken together, these large-scale and integrative analyses uncovered links between adipokines and widespread, yet functionally specific, differences in regulation of genes with a central role in type 2 diabetes and its risk factors.",

author = "Lucy Sinke and Thomas Delerue and Rory Wilson and Xueling Lu and Yujing Xia and Ricardo Costeira and Nasr, \{M Kamal\} and Marian Beekman and Lude Franke and Alexandra Zhernakova and Jingyuan Fu and Christian Gieger and Christian Herder and Wolfgang Koenig and Annette Peters and Ordovas, \{Jos{\'e} M\} and Marcus D{\"o}rr and Grabe, \{Hans J\} and Matthias Nauck and Bell, \{Jordana T\} and Alexander Teumer and Harold Snieder and Melanie Waldenberger and Slagboom, \{P Eline\} and Heijmans, \{Bastiaan T\}",

note = "{\textcopyright} 2025. The Author(s).",

year = "2025",

month = oct,

day = "8",

doi = "10.1007/s00125-025-06549-6",

language = "English",

journal = "Diabetologia",

issn = "0012-186X",

publisher = "Springer",

}

Sinke, L, Delerue, T, Wilson, R, Lu, X, Xia, Y, Costeira, R, Nasr, MK, Beekman, M, Franke, L , Zhernakova, A , Fu, J, Gieger, C, Herder, C, Koenig, W, Peters, A, Ordovas, JM, Dörr, M, Grabe, HJ, Nauck, M, Bell, JT, Teumer, A, Snieder, H, Waldenberger, M, Slagboom, PE & Heijmans, BT 2025, 'DNA methylation of genes involved in lipid metabolism drives adiponectin levels and metabolic disease', Diabetologia. https://doi.org/10.1007/s00125-025-06549-6

TY - JOUR

T1 - DNA methylation of genes involved in lipid metabolism drives adiponectin levels and metabolic disease

AU - Sinke, Lucy

AU - Delerue, Thomas

AU - Wilson, Rory

AU - Lu, Xueling

AU - Xia, Yujing

AU - Costeira, Ricardo

AU - Nasr, M Kamal

AU - Beekman, Marian

AU - Franke, Lude

AU - Zhernakova, Alexandra

AU - Fu, Jingyuan

AU - Gieger, Christian

AU - Herder, Christian

AU - Koenig, Wolfgang

AU - Peters, Annette

AU - Ordovas, José M

AU - Dörr, Marcus

AU - Grabe, Hans J

AU - Nauck, Matthias

AU - Bell, Jordana T

AU - Teumer, Alexander

AU - Snieder, Harold

AU - Waldenberger, Melanie

AU - Slagboom, P Eline

AU - Heijmans, Bastiaan T

PY - 2025/10/8

Y1 - 2025/10/8

N2 - AIMS/HYPOTHESIS: Despite playing critical roles in the pathophysiology of type 2 diabetes and other metabolic disorders, the molecular mechanisms underlying circulating adipokine levels remain poorly understood. By identifying genomic regions involved in the regulation of adipokine levels and adipokine-mediated disease risk, we can improve our understanding of type 2 diabetes pathogenesis and inter-individual differences in metabolic risk.METHODS: We conducted an epigenome-wide meta-analysis of associations between serum adiponectin (n=2791) and leptin (n=3661) and leukocyte DNA methylation at over 400,000 CpG sites across five European cohorts. The resulting methylation signatures were followed up using functional genomics, integrative analyses and causal inference methods.RESULTS: Our findings revealed robust associations with adiponectin at 73 CpGs and leptin at 211 CpGs. Many of the identified sites were also associated with risk factors for the metabolic syndrome and located in enhancers close to relevant transcription factor binding sites. Integrative analyses additionally linked 35 of the adiponectin-associated CpGs to the expression of 46 genes, and 100 of the leptin-associated CpGs to the expression of 151 genes, with implicated genes enriched for lipid transport (e.g. ABCG1), metabolism (e.g. CPT1A) and biosynthesis (e.g. DHCR24). Bidirectional two-sample Mendelian randomisation further identified two specific CpG sites as plausible drivers of both adiponectin levels and metabolic health: one annotated to ADIPOQ, the gene encoding adiponectin; and another linked to the expression of SREBF1, an established modifier of type 2 diabetes risk known to exert its effects via adiponectin.CONCLUSIONS/INTERPRETATION: Taken together, these large-scale and integrative analyses uncovered links between adipokines and widespread, yet functionally specific, differences in regulation of genes with a central role in type 2 diabetes and its risk factors.

AB - AIMS/HYPOTHESIS: Despite playing critical roles in the pathophysiology of type 2 diabetes and other metabolic disorders, the molecular mechanisms underlying circulating adipokine levels remain poorly understood. By identifying genomic regions involved in the regulation of adipokine levels and adipokine-mediated disease risk, we can improve our understanding of type 2 diabetes pathogenesis and inter-individual differences in metabolic risk.METHODS: We conducted an epigenome-wide meta-analysis of associations between serum adiponectin (n=2791) and leptin (n=3661) and leukocyte DNA methylation at over 400,000 CpG sites across five European cohorts. The resulting methylation signatures were followed up using functional genomics, integrative analyses and causal inference methods.RESULTS: Our findings revealed robust associations with adiponectin at 73 CpGs and leptin at 211 CpGs. Many of the identified sites were also associated with risk factors for the metabolic syndrome and located in enhancers close to relevant transcription factor binding sites. Integrative analyses additionally linked 35 of the adiponectin-associated CpGs to the expression of 46 genes, and 100 of the leptin-associated CpGs to the expression of 151 genes, with implicated genes enriched for lipid transport (e.g. ABCG1), metabolism (e.g. CPT1A) and biosynthesis (e.g. DHCR24). Bidirectional two-sample Mendelian randomisation further identified two specific CpG sites as plausible drivers of both adiponectin levels and metabolic health: one annotated to ADIPOQ, the gene encoding adiponectin; and another linked to the expression of SREBF1, an established modifier of type 2 diabetes risk known to exert its effects via adiponectin.CONCLUSIONS/INTERPRETATION: Taken together, these large-scale and integrative analyses uncovered links between adipokines and widespread, yet functionally specific, differences in regulation of genes with a central role in type 2 diabetes and its risk factors.

U2 - 10.1007/s00125-025-06549-6

DO - 10.1007/s00125-025-06549-6

M3 - Article

C2 - 41057690

SN - 0012-186X

JO - Diabetologia

JF - Diabetologia

ER -

DNA methylation of genes involved in lipid metabolism drives adiponectin levels and metabolic disease

Abstract

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