TY  - JOUR
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
TI  - DNA methylation of genes involved in lipid metabolism drives adiponectin levels and metabolic disease.
JO  - Diabetologia
VL  - 69
IS  - 1
SN  - 0012-186X
CY  - Heidelberg
PB  - Springer
M1  - DZNE-2025-01356
SP  - 127 - 145
PY  - 2026
AB  - 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.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.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.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.
KW  - Humans
KW  - Adiponectin: blood
KW  - Adiponectin: genetics
KW  - Adiponectin: metabolism
KW  - DNA Methylation: genetics
KW  - Lipid Metabolism: genetics
KW  - Diabetes Mellitus, Type 2: genetics
KW  - Diabetes Mellitus, Type 2: metabolism
KW  - Leptin: blood
KW  - Leptin: genetics
KW  - CpG Islands: genetics
KW  - Metabolic Diseases: genetics
KW  - Metabolic Diseases: metabolism
KW  - Genome-Wide Association Study
KW  - Female
KW  - Male
KW  - Adiponectin (Other)
KW  - Causal inference (Other)
KW  - Epigenomics (Other)
KW  - Leptin (Other)
KW  - Lipid metabolism (Other)
KW  - Meta-analysis (Other)
KW  - Metabolic health (Other)
KW  - Type 2 diabetes (Other)
KW  - Adiponectin (NLM Chemicals)
KW  - Leptin (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41057690
DO  - DOI:10.1007/s00125-025-06549-6
UR  - https://pub.dzne.de/record/282598
ER  -