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Diet and temperature interactively impact brown adipose tissue gene regulation controlled by DNA methylation.
Mol. Metab. 104:102315 (2026)
Controlling brown adipose tissue (BAT) plasticity offers potential for novel obesity therapies. DNA methylation is closely linked to thermogenic and metabolic pathways and thereby influences BAT function. How metabolic state and cold exposure interact to shape methylation-dependent BAT gene regulation was investigated. Five-week-old mice were fed either chow for 11 weeks (lean) or high-fat diet for 22 weeks to induce obesity (DIO), after which cold exposure was applied for seven days. BAT transcriptomes (RNAseq) and methylomes (RRBS) were generated, and differentially methylated and expressed genes (DMEGs) showing metabolic state-dependent cold responses were identified. Pathway enrichment, epigenetic regulator screening, and transcription factor (TF) motif analyses were performed. DNA methylation was experimentally modulated in vitro to validate selected gene expression responses. A total of 1,364 differentially expressed genes (DEGs) were uniquely affected by the interaction of metabolic state and cold, with most downregulated in DIO mice. Sixty-five DMEGs (4% of DEGs) showed metabolic state-specific responses to cold. In DIO mice, DMEGs were enriched in pathways associated with mitochondrial dysfunction, altered lipid metabolism, neuroendocrine signaling, and stress responses. Several epigenetic regulators, including Tet2, Dnmt3a, and Apobec1, exhibited metabolic state- and cold-dependent expression, and TF-motif analyses highlighted roles for Ahr::Arnt and Foxn1. In vitro assays confirmed that DNA methylation influences expression of thermogenic genes. These findings provide the first evidence that the epigenetic cold response of BAT differs by metabolic condition. BAT remodeling is shaped by coordinated transcriptional and epigenetic mechanisms integrating environmental and metabolic cues.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Dna Methylation ; Brown Adipose Tissue ; Cold Exposure ; Epigenetics ; High Fat Diet ; Thermogenesis; Fat; Metabolism; Activation; Expression
ISSN (print) / ISBN
2212-8778
e-ISSN
2212-8778
Journal
Molecular Metabolism
Quellenangaben
Volume: 104,
Article Number: 102315
Publisher
Elsevier
Publishing Place
Amsterdam
Reviewing status
Peer reviewed
Institute(s)
Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
Grants
German Diabetes Association
European Association for the Study of Diabetes
Swedish Research Council
Studienstiftung des Deutschen Volkes
Formel1 Nachwuchsfoerderung of the Medical Faculty of the University Leipzig
Deutsche Forschungsgemeinschaft
European Association for the Study of Diabetes
Swedish Research Council
Studienstiftung des Deutschen Volkes
Formel1 Nachwuchsfoerderung of the Medical Faculty of the University Leipzig
Deutsche Forschungsgemeinschaft