Inverse agonism is emerging as a new endogenous principle for receptor regulation. Agouti-related protein (AgRP), following its release in the brain, stimulates food intake. AgRP binds to brain melanocortin receptors, which are involved in the regulation of body weight. In addition to antagonizing the effects of the melanocortin receptor agonist alpha-melanocyte-stimulating hormone (alpha-MSH), AgRP suppresses the constitutive activity of melanocortin MC(3) and MC(4) receptors, which characterizes AgRP as an inverse agonist rather than a neutral antagonist. The balance between the activity of AgRP-containing neurons and alpha-MSH-containing neurons determines the extent of activation of melanocortin receptors in neurons onto which they project. The identification of AgRP as an endogenous inverse agonist provides physiological relevance to inverse agonism in the control of body weight.