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Insulin and leptin intracellular signaling pathways converge and act synergistically on the hypothalamic phosphatidylinositol- 3-OH kinase/3-phosphoinositide-dependent protein kinase 1 (PDK1). However, little is known about whether PDK1 in agoutirelated peptide (AGRP) neurons contributes to energy homeostasis. We generated AGRP neuron-specific PDK1 knockout (AGRPPdk1-/-) mice and mice with selective expression of transactivation-defective Foxo1 (Δ256Foxo1AGRPPdk1-/-). The AGRPPdk12/2 mice showed reductions in food intake, body length, and body weight. The Δ256Foxo1AGRPPdk1-/- mice showed increased body weight, food intake, and reduced locomotor activity. After four weeks of calorie-restricted feeding, oxygen consumption and locomotor activity were elevated in AGRPPdk1-/- mice and reduced in Δ256Foxo1AGRPPdk1-/-2 mice. In vitro, ghrelin-induced changes in [Ca2+]i and inhibition of ghrelin by leptin were significantly attenuated in AGRPPdk12/2 neurons compared to control neurons. However, ghrelin-induced [Ca2+]i changes and leptin inhibition were restored in Δ256Foxo1AGRPPdk1-/- mice. These results suggested that PDK1 and Foxo1 signaling pathways play important roles in the control of energy homeostasis through AGRP-independent mechanisms. [ABSTRACT FROM AUTHOR]