PDK1-Foxo1 in agouti-related peptide neurons regulates energy homeostasis by modulating food intake and energy expenditure.

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 agouti-related 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 AGRPPdk1−/− 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−/− mice. In vitro, ghrelin-induced changes in [Ca2+]i and inhibition of ghrelin by leptin were significantly attenuated in AGRPPdk1−/− 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.