TY - JOUR
T1 - PDK1-Foxo1 in agouti-related peptide neurons regulates energy homeostasis by modulating food intake and energy expenditure
AU - Cao, Yongheng
AU - Nakata, Masanori
AU - Okamoto, Shiki
AU - Takano, Eisuke
AU - Yada, Toshihiko
AU - Minokoshi, Yasuhiko
AU - Hirata, Yukio
AU - Nakajima, Kazunori
AU - Iskandar, Kristy
AU - Hayashi, Yoshitake
AU - Ogawa, Wataru
AU - Barsh, Gregory S.
AU - Hosoda, Hiroshi
AU - Kangawa, Kenji
AU - Itoh, Hiroshi
AU - Noda, Tetsuo
AU - Kasuga, Masato
AU - Nakae, Jun
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0018324
DO - 10.1371/journal.pone.0018324
M3 - Article
C2 - 21694754
AN - SCOPUS:79954455756
SN - 1932-6203
VL - 6
JO - PloS one
JF - PloS one
IS - 4
M1 - e18324
ER -