Background: There is a growing consensus that sugar consumption should be reduced and the naturally occurring, low-calorie sweeteners xylitol and erythritol are gaining popularity as substitutes, but their effect on brain circuitry regulating appetite is unknown. Aim: The study’s objective was to examine the effects of the two sweeteners on cerebral blood flow (rCBF) and resting functional connectivity in brain networks involved in appetite regulation, and test whether these effects are related to gut hormone release. Methods: The study was performed as a randomized, double-blind, placebo-controlled, cross-over trial. Twenty volunteers received intragastric (ig) loads of 50g xylitol, 75g erythritol, 75g glucose dissolved in 300mL tap water or 300mL tap water. Resting perfusion and blood oxygenation level-dependent data were acquired to assess rCBF and functional connectivity. Blood samples were collected for determination of CCK, PYY, insulin and glucose. Results: We found: (i) xylitol, but not erythritol, increased rCBF in the hypothalamus, whereas glucose had the opposite effect; (ii) graph analysis of resting functional connectivity revealed a complex pattern of similarities and differences in brain network properties following xylitol, erythritol, and glucose; (iii) erythritol and xylitol induced a rise in CCK and PYY, (iv) erythritol had no and xylitol only minimal effects on glucose and insulin. Conclusion: Xylitol and erythritol have a unique combination of properties: no calories, virtually no effect on glucose and insulin while promoting the release of gut hormones, and impacting appetite-regulating neurocircuitry consisting of both similarities and differences with glucose.