We found that (1) exercise increased levels of TTR specifically in the DMH, (2) icv administration of TTR reduced food intake and body weight and decreased hypothalamic NPY levels, (3) preventing TTR-induced reduction of NPY prevented its anorectic effect, and (4) mimicking the effect of exercise in OLETF rats, chronic icv infusion of TTR in OLETF rats reduced DMH NPY levels and reversed their hyperphagia and obesity. The gene discussed is NPY; the disease is Obesity.