Oxidative stress is implicated in cancer, neurodegeneration and aging. hMTH1 is a hydrolase able to remove oxidized precursors from nucleotide’s pool, thus avoiding oxidative nucleic acids damage. Overexpression of hMTH1 in mice is protective against oxidative damage, neurodegeneration and prolongs life span. Our study showed that the overexpression of hMTH1 in mice fed with high fat diet (HFD), a dietary regimen linked to inflammation, is associated with increased brown interscapular fat (linked to protection from obesity) and with reduced perivesical fat volume (indicator of poor cardiovascular outcomes) up to four weeks. These effects seem to be reversed by prolonging HFD.