Both insulin and leptin signaling converge on phosphatidylinositol 3-OH kinase [PI(3)K]/3-phosphoinositide-dependent protein kinase-1 (PDK-1)/protein kinase B (PKB, also known as Akt) in proopiomelanocortin (POMC) neurons. Forkhead box-containing protein-O1 (FoxO1) is inactivated in a PI(3)K-dependent manner. However, the interrelationship between PI(3)K/PDK-1/Akt and FoxO1, and the chronic effects of the overexpression of FoxO1 in POMC neurons on energy homeostasis has not been elucidated. To determine the extent to which PDK-1 and FoxO1 signaling in POMC neurons was responsible for energy homeostasis, we generated POMC neuron-specific Pdk1 knockout mice (POMCPdk1^–/–) and mice selectively expressing a constitutively nuclear (CN)FoxO1 or transactivation-defective (256)FoxO1 in POMC neurons (CNFoxO1^POMC or 256FoxO1^POMC). POMCPdk1^–/– mice showed increased food intake and body weight accompanied by decreased expression of Pomc gene. The CNFoxO1^POMC mice exhibited mild obesity and hyperphagia compared with POMCPdk1^–/– mice. Although expression of the CNFoxO1 made POMCPdk1^–/– mice more obese due to excessive suppression of Pomc gene, overexpression of 256FoxO1 in POMC neurons had no effects on metabolic phenotypes and Pomc expression levels of POMCPdk1^–/– mice. These data suggest a requirement for PDK-1 and FoxO1 in transcriptional regulation of Pomc and food intake.