Obesity and smoking constitute two of the main causes of preventable deaths in the developed countries today. Many smokers motivate consumption as a means to control their body weight because smoking cessation increases the risk to gain weight. Although it is well established that nicotine reduces feeding in animals and that smoking is associated with reduced body weight in quasi-experimental studies of humans, acute nicotine effects are mixed and little is known about the brain networks supporting these effects. Thus, we investigated 26 normal-weighted never-smokers who received either nicotine (2 mg) or placebo gums following a double-blinded randomized cross-over design. We used functional magnetic resonance imaging (fMRI) to investigate reactivity to palatable food cues after both overnight fasting and following a standardized caloric intake (75 g oral glucose tolerance test (OGTT)). Participants viewed food or low-level control pictures in a block design and rated their current appetite after each block. Nicotine had a small- to medium-sized effect on subjective appetite and significantly altered food-cue reactivity in a region sensitive to caloric intake that extended from the right hypothalamus to the basal ganglia. During placebo sessions, the OGTT reduced functional coupling of this region with a 'salience network' (ie, amygdala, ventromedial prefrontal cortex) in processing of food pictures. Furthermore, nicotine reduced coupling with the nucleus accumbens and the OGTT reduced coupling with an 'interoceptive network' (ie, insula, operculum) instead. We conclude that locally restricted acute effects of nicotine in the hypothalamic area have profound effects on food-processing networks.Neuropsychopharmacology advance online publication, 19 June 2013; doi:10.1038/npp.2013.133.