There is growing evidence that obesity represents a risk for enhanced gray matter (GM) density changes comparable to those demonstrated for mild cognitive impairment in the elderly. However, it is not clear what mechanisms underlie this apparent alteration in brain structure of overweight subjects and to what extent these changes can already occur in the adolescent human brain. In the present volumetric magnetic resonance imaging study, we investigated GM changes and serum levels of neuron-specific enolase (NSE), a marker for neuronal injury, in a set of overweight/obese subjects and controls. We report a negative correlation for overweight and obese subjects between serum NSE and GM density in hippocampal and cerebellar regions. To validate our neuroimaging findings, we complement these data with NSE gene expression information obtained from the Allen Brain atlas. GM density changes were localized in brain areas that mediate cognitive function-the hippocampus associated with memory performance, and the cognitive cerebellum (lateral posterior lobes) associated with executive, spatial and linguistic processing. The data of our present study highlight the importance of extending current research on cognitive function and brain plasticity in the elderly in the context of obesity to young adult subjects and include serum biomarkers to validate imaging findings generally.