Using physiological magnetic resonance imaging (physMRI), we previously characterised the spatiotemporal brain responses to intragastric lipid. Significant increases in the blood oxygen level dependent (BOLD) signal were observed in brain areas including the brain stem and hypothalamus (1,2). We recently showed that unlike lipid, intragastric glucose decreases BOLD signal in these brain areas (unpublished data); a finding that persists regardless of administration route, i.e. oral or intravenous. However, the doses of glucose used have been high (1M). The effect of lower, nutritionally relevant doses of intragastric glucose on brain activation remains to be explored. Furthermore it is unknown whether fructose, which is chemically similar to glucose but unlike glucose is not used by the brain as a primary energy source, affects brain activation similarly to glucose. To examine this, 8 healthy human volunteers completed 4 trial visits in randomised order. Participants attended after an overnight fast, had a naso-gastric tube inserted and underwent 30 minutes of physMRI acquisition (3.0T Philips scanner). After a 5 min baseline period, participants received 250 mL of test ‘drink’ (0.25M glucose, 0.5M glucose, 0.5M fructose or a saline control) into the stomach. Data were analysed using the p-block method with 2 min time-bins. Two one-way repeated measures ANOVAs were used to investigate regions within the brainstem and hypothalamus that showed significant differences at qFDR<0.05 for glucose 0.25M vs glucose 0.5M and for glucose 0.5M vs fructose 0.5M. There was a significant difference between 0.5M glucose and 0.5M fructose observed in the hypothalamus (P<0.05; Figure 1). The BOLD responses were similar until approximately 8 min. They diverged thereafter, with a decrease in BOLD evident with 0.5M glucose but a progressive increase following fructose. In the hypothalamus and pons, BOLD signal was decreased after 0.5M glucose but not after 0.25M glucose. The results demonstrate a dose-response effect to glucose. However, despite glucose and fructose being chemically similar, administration of a 0.5M dose of glucose or fructose elicits a divergent BOLD response in the hypothalamus. The precise mechanism is unknown but neurons within this region may display sugar selectivity and only respond to glucose in this way as the brain’s primary fuel. Furthermore, fructose does not elicit the same glycaemic and neuroendocrine responses as glucose, so differential changes in blood glucose and insulin could partly explain the different response seen. Similarly, a lower dose of glucose may be too low to exert any metabolic effect on glucose sensing neurons within the brain compared with 0.5M glucose, and thus explain the absence of a reduction in BOLD signal after a 0.25M glucose dose.