Insufficient responses to hypocaloric diets have been attributed to hormonal adaptations that override self- control of food intake. We tested this hypothesis by measuring circulating energy-balance hormones and brain functional magnetic resonance imaging reactivity to food cues in 24 overweight/obese participants before, and 1 and 3 months after starting a calorie restriction diet. Increased activity and functional connectivity in prefrontal regions at month 1 correlated with weight loss at months 1 and 3. Weight loss was also correlated with increased plasma ghrelin and decreased leptin, and these changes were associated with food cue reactivity in reward-related brain regions. However, the reduction in leptin did not counteract weight loss; indeed, it was correlated with further weight loss at month 3. Activation in prefrontal regions associated with self-control could contribute to successful weight loss and maintenance. This work supports the role of higher-level cognitive brain function in body-weight regulation in humans.