THE ROLE OF NEUROPEPTIDE-Y IN THE ANTIOBESITY ACTION OF THE OBESE GENE-PRODUCT

RECENTLY Zhang et al.(1) cloned a gene that is expressed only in adipo se tissue of tbe mouse. The obese phenotype of the ob/ob mouse is link ed to a mutation in the obese gene that results in expression of a tru ncated inactive protein. Human and rat homologues for this gene are kn own(1,2). Previous experiments(3,4) predict such a hormone to have a h ypothalamic target. Hypothalamic neuropeptide Y stimulates food intake , decreases thermogenesis, and increases plasma insulin and corticoste rone levels making it a potential target(5). Here we express the obese protein in Escherichia coli and find that it suppresses food intake a nd decreases body weight dramatically when administered to normal and ob/ob mice but not db/db (diabetic) mice, which are thought to lack th e appropriate receptor. High-affinity binding was detected in the rat hypothalamus. One mechanism by which this protein regulated food intak e and metabolism was inhibition of neuropeptide-Y synthesis and releas e.