Reversal of dopamine system dysfunction in response to high fat diet

OBJECTIVE: To test whether high fat diet (HFD) decreases dopaminergic tone in reward regions of the brain and evaluate whether these changes reverse after removal of the HFD. DESIGN AND METHODS: Male and female mice were fed a 60% HFD for 12 weeks. An additional group was evaluated 4 weeks after removal of the HFD. These groups were compared to control fed, age-matched controls. Sucrose and saccharin preference was measured along with mRNA expression of dopamine related genes by RT-qPCR. Dopamine and DOPAC were measured using high performance liquid chromatography. DNA methylation of the DAT promoter was measured by methylated DNA immmunoprecipitation and RT-qPCR. RESULTS: After chronic HFD, sucrose preference was reduced, and then normalized after removal of the HFD. Decreased expression of dopamine genes, decreased dopamine content and alterations in DAT promoter methylation was observed. Importantly, response to HFD and the persistence of changes depended on sex and brain region. CONCLUSIONS: These data identify diminished dopamine tone after early-life chronic HFD with a complex pattern of reversal and persistence that varies by both sex and brain region. CNS changes that did not reverse after HFD withdrawal may contribute to the difficulty in maintaining weight-loss after diet intervention.