Ghrelin is produced in the stomach and is a potent stimulator of appetite in the brain. In addition to increasing the uptake of nutrients by muscle, liver, and fat, insulin acts in the brain to suppress food intake. Gut-derived peptides such as GLP-1 augment insulin release from the pancreas. Leptin levels decline during weight loss and signal to the hypothalamus to stimulate feeding, reduce energy expenditure, and promote weight regain. As Rosenbaum et al. demonstrate in this issue of the JCI (4), low leptin levels during weight loss also increase the activity of brain areas involved in the decision-making and reward aspects of eating behavior. Thus, preventing the decline of leptin levels during weight loss by hormone replacement may be a means of overriding the homeostatic and behavioral tendencies toward energy conservation and weight regain during dieting. Image modified with permission from Gastroenterology (23). CCK, cholecystokinin; GLP-1, glucagon-like peptide–1; GRP, gastrin-releasing peptide; NMB, neuromedin B; OXY, oxyntomodulin; PAI-1, plasminogen activator inhibitor 1; PP, pancreatic polypeptide; PYY, peptide YY; RBP4, retinol-binding protein–4.