Prior studies suggest that fructose compared with glucose may be a weaker suppressor of appetite, and neuroimaging research shows that food cues trigger greater brain reward responses in a fasted relative to a fed state. We sought to determine the effects of ingesting fructose versus glucose on brain, hormone, and appetitive responses to food cues and food-approach behavior. Twenty-four healthy volunteers underwent two functional magnetic resonance imaging (fMRI) sessions with ingestion of either fructose or glucose in a double-blinded, random-order cross-over design. fMRI was performed while participants viewed images of high-calorie foods and nonfood items using a block design. After each block, participants rated hunger and desire for food. Participants also performed a decision task in which they chose between immediate food rewards and delayed monetary bonuses. Hormones were measured at baseline and 30 and 60 min after drink ingestion. Ingestion of fructose relative to glucose resulted in smaller increases in plasma insulin levels and greater brain reactivity to food cues in the visual cortex (in whole-brain analysis) and left orbital frontal cortex (in region-of-interest analysis). Parallel to the neuroimaging findings, fructose versus glucose led to greater hunger and desire for food and a greater willingness to give up long-term monetary rewards to obtain immediate highcalorie foods. These findings suggest that ingestion of fructose relative to glucose results in greater activation of brain regions involved in attention and reward processing and may promote feeding behavior.fructose | glucose | fMRI | food cue | decision making O besity is a major public health problem, and increases in the consumption of fructose as a sweetener may be an important contributor to the current obesity epidemic (1). Fructose and glucose are both monosaccharides with the same number of calories, but they are metabolized differently. In the glycolytic pathway, glucose metabolism is regulated through feedback inhibition by the end products ATP and citrate, but fructose bypasses the main regulatory step, catalyzed by phosphofructokinase (2). Whereas glucose is the main circulating sugar in the blood, the majority of fructose is extracted from the bloodstream into the liver, where unregulated fructose metabolism can lead to increased lipogenesis (3). Similarly, unregulated fructose metabolism in the hypothalamus may lead to rapid depletion of hypothalamic ATP and consequently to increased food intake (4). Moreover, unlike glucose, fructose does not stimulate the secretion of insulin (5), a hormone that signals the brain to increase satiety and to blunt the reward value of food (6, 7). These unique properties of fructose versus glucose may help explain their differential effects on brain appetite pathways (4,8). The central administration of fructose was shown to decrease hypothalamic satiety signaling and increase feeding in animals, whereas glucose increased satiety signaling and reduced food intake (4). Likewise, the hypothala...