There is growing interest in the use of manganese-enhanced MRI (MEMRI) to detect neuronal activity and architecture in animal models. The MEMRI neuronal activity studies have been generally performed either by stereotactic brain injection or by systemic administration of Mn2+ in conjunction with the disruption of the blood–brain barrier (BBB). These approaches, however, have limited the use of MEMRI because of the procedure-related morbidity/mortality or because brain activity measured by these methods can diverge from genuine physiological responses. In this study, the hypothesis that MEMRI, performed with systemic administration of Mn2+ without compromising the BBB integrity, is able to detect hypothalamic function associated with feeding was tested. This procedure was tested on a simple physiological condition, fasting, and with this method temporal and regional differences in Mn2+ enhancement could be detected. It is concluded that MEMRI can be used to study hypothalamic function in the murine brain without compromising the BBB. It was also shown that region-specific Mn2+ enhancement in the mouse brain can be modulated by fasting. More importantly, this non-invasive in vivo imaging technique is able to demonstrate differences in brain activities, previously possible only by in vitro studies.