RECENTLY Zhanget al.¹ cloned a gene that is expressed only in adipose tissue of the mouse. The obese phenotype of the ob/ob mouse is linked to a mutation in theobese gene that results in expression of a truncated inactive protein. Human and rat homolo-gues for this gene are known^1,2. Previous experiments^3,4 predict such a hormone to have a hypothalamic target. Hypothalamic neuropeptide Y stimulates food intake, decreases thermogenesis, and increases plasma insulin and corticosterone levels making it a potential target⁵. Here we express theobese protein inEscherichia coli and find that it suppresses food intake and decreases body weight dramatically when administered to normal andob/ob mice but notdb/db (diabetic) mice, which are thought to lack the appropriate receptor. High-affinity binding was detected in the rat hypo-thalamus. One mechanism by which this protein regulated food intake and metabolism was inhibition of neuropeptide-Y synthesis and release.