The hypothesis that circulating ghrelin regulates body weight via a negative-feedback loop predicts that its levels should increase with weight loss, as part of the known adaptive response to energy deficit. Indeed, elevated ghrelin levels occur with weight loss resulting from caloric restriction (Figure 2),75,76 cancer anorexia,76 cardiac cachexia,77 anorexia nervosa,51,64,78 and bulimia nervosa.79 A trend toward decreased ghrelin levels was found in subjects who gained weight through overfeeding, a finding that suggests bidirectional regulation.80 Obese individuals who lose even 5% of body weight manifest significantly increased circulating ghrelin levels.81 Because reduced food intake accompanies all of the above conditions of weight loss, it is theoretically possible that ghrelin levels increase in these settings because of decreased inhibitory input from ingested nutrients rather than from weight loss per se. We have found, however, that weight loss achieved by chronic exercise without hypophagia in humans also increases plasma ghrelin levels (Karen E. Foster, MD, Anne McTiernan, MD, and D.E.C., unpublished data, 2002). Moreover, mice subjected to mild caloric restriction, insufficient to reduce body weight, show no alteration in plasma ghrelin levels (Eugene N. Bush, PhD, and D.E.C., unpublished data, 2002). Together, these findings suggest that circulating ghrelin levels fluctuate in response to changes in body weight. This phenomenon is consistent with a role for ghrelin in the adaptive response to body weight changes, and thus, in long-term energy homeostasis. The important implications are that an increase in ghrelin levels caused by weight loss may contribute to weight regain and, therefore, pharmacologic ghrelin blockade may help maintain voluntary weight loss.