Insulin- and leptin-stimulated phosphatidylinositol-3 kinase (PI3K) activation has been demonstrated to play a critical role in central control of energy homeostasis. To delineate the importance of pathways downstream of PI3K specifically in pro-opiomelanocortin (POMC) cell regulation, we have generated mice with selective inactivation of 3-phosphoinositide-dependent protein kinase 1 (PDK1) in POMC-expressing cells (PDK1(Delta POMC) mice). PDK1(Delta POMC) mice initially display hyperphagia, increased body weight, and impaired glucose metabolism caused by reduced hypothalamic POMC expression. On the other hand, PDK1(Delta POMC) mice exhibit progressive, severe hypocortisolism caused by loss of POW-expressing corti-cotrophs in the pituitary. Expression of a dominant-negative mutant of FOXO1 specifically in POW cells is sufficient to ameliorate positive energy balance in PDK1(Delta POMC) mice but cannot restore regular pituitary function. These results reveal important but differential roles for PDK1 signaling in hypothalamic and pituitary POMC cells in the control of energy homeostasis and stress response.