Roles for ghrelin in the regulation of appetite and body weight

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Abstract
Ghrelin, the only known circulating appetite stimulant, has garnered widespread scientific interest and is currently featured in more than 2.3 new publications per day. Antagonists and agonists of its receptor are vigorously being developed by pharmaceutical companies to treat obesity and wasting conditions respectively. Here, the authors summarize the current state of knowledge regarding ghrelin's roles in energy homeostasis. Ghrelin is an acylated peptide produced primarily by the stomach and proximal small intestine. Circulating levels sharply increase before, and decrease after, meals. These and other findings implicate ghrelin in pre-meal hunger and meal initiation. Moreover, ghrelin satisfies established criteria for an adiposity-associated hormone involved in long-term body weight regulation. Blood levels correlate with energy stores and display compensatory changes in response to alterations of those stores. Ghrelin influences neuronal activity in brain areas critical to energy homeostasis. Excessive ghrelin signaling durably increases food intake and decreases energy expenditure, thereby promoting weight gain. Conversely, acute ghrelin blockade in adult animals reduces food intake and body weight, although the effects of lifelong genetic deletions are very subtle. Overproduction of ghrelin is etiologically implicated in Prader-Willi syndrome, whereas defective secretion may contribute to weight loss after gastric bypass surgery. Ghrelin appears to participate in mealtime hunger and meal initiation, as well as in long-term energy balance. Whether these roles are sufficiently important that ghrelin blockade will prove to be an effective antiobesity modality is a pivotal question that should soon be answered as ghrelin receptor antagonists are developed. Ghrelin agonists hold promise in the treatment of wasting conditions, for which few medications currently exist.