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Scope Epigenetic aberrations caused by environmental factors and lifestyle choices have been associated with the development of a number of pathologies, including cardiovascular disorders. However, whether obesity-related heart dysfunction can occur via epigenetic mechanisms is largely undisclosed. The manifested role of DNA hydroxymethylation in heart pathophysiology prompts an investigation of its levels/machinery in heart of mice fed with high-fat diet (HFD) and its possible relation with genes linked to obesity-associated cardiac remodeling. Methods and results Alterations in levels of DNA methylation/hydroxymethylation modifications and in expression of Tet family of DNA hydroxylases are observed in hearts of mice treated with HFD for 8 and 16 weeks. Decreased levels of the Tet co-substrate alpha-ketoglutarate are also observed and associate with mitochondrial mass reduction and augmented oxidative stress. Finally, expression markers of cardiac remodeling are monitored by RT-qPCR analysis and associate with DNA hydroxymethylation signature by DNA immunoprecipitation and correlation analyses. Conclusion Global changes of DNA hydroxymethylation in hearts of HFD-fed mice are associated with upregulation of the dioxygenase Tet3 and decreased content of alpha-ketoglutarate. A relation between Tet genes and markers of cardiac hypertrophic response is observed and, if further validated, it will provide insights concerning epigenetics and obesity-related cardiac complications.