We examined the effect of six doses of dexamethasone (dex) administered daily (2d to 7d) to postnatal rats on body weight gain, food and water intake, peripheral hormonal/metabolic milieu and hypothalamic neuropeptides that regulate food intake. We observed a dex induced acute (3d) suppression of endogenous corticosterone, and an increase in circulating leptin concentrations that were associated with a decrease in body weight in males and females. Follow-up during the suckling, post-suckling, and adult stages (7d to 120d) revealed hypoleptinemia in males and females, and hypoinsulinemia, a relative increase in the glucose to insulin ratio, and a larger increase in skeletal muscle glucose transporter (GLUT 4) concentrations predominantly in the males, reflective of a catabolic state associated with a persistent decrease in body weight gain. The increase in the glucose to insulin ratio and hyperglycemia was associated with an increase in water intake. In addition, the changes in the hormonal/metabolic milieu were associated with an increase in hypothalamic neuropeptide Y content in males and females during the suckling phase which persisted only in the 120d female with a transient postnatal decline in -MSH and CRF. This increase in NPY during the suckling phase in males and females was associated with a subsequent increase in adult food intake that outweighed the demands of body weight gain. In contrast to the adult hypothalamic findings, cerebral ventricular dilatation was more prominent in adult males. We conclude that postnatal dex treatment causes permanent sex-specific changes in the adult phenotype setting the stage for future development of diabetes (increased glucose:insulin ratio), obesity (increased NPY and food intake) and neurological impairment (loss of cerebral volume).