Ghrelin is directly involved with short-term regulation of energy balance. Although circulating levels of ghrelin are elevated in anorexia nervosa and reduced in obesity, the role of ghrelin in regulating long-term energy balance in healthy women has not been investigated. We examined the effects of a 3-month energy deficit-imposing diet and exercise intervention on circulating ghrelin in normal-weight, healthy women. Body composition, resting metabolic rate, and serum ghrelin were measured at pre-, mid-, and postintervention in controls (n = 7), who performed no exercise, and exercising women who remained weight stable (n = 5) or lost weight (n = 10). Exercise training occurred five times per week, and subjects were fed a specific diet. Ghrelin significantly increased over time (770 +/- 296 to 1322 +/- 664 pmol/liter) in the weight-loss group compared with the controls and the weight-stable group (P < 0.05). Changes in ghrelin were negatively correlated with changes in body weight (r = -0.61; P < 0.05). Body fat, body weight, and resting metabolic rate significantly decreased in the weight-loss group before the increase in ghrelin. These findings suggest that ghrelin responds in a compensatory manner to changes in energy homeostasis in healthy young women, and that ghrelin exhibits particular sensitivity to changes in body weight.