PLoS ONE (Jan 2011)

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

  • Yongheng Cao,
  • Masanori Nakata,
  • Shiki Okamoto,
  • Eisuke Takano,
  • Toshihiko Yada,
  • Yasuhiko Minokoshi,
  • Yukio Hirata,
  • Kazunori Nakajima,
  • Kristy Iskandar,
  • Yoshitake Hayashi,
  • Wataru Ogawa,
  • Gregory S Barsh,
  • Hiroshi Hosoda,
  • Kenji Kangawa,
  • Hiroshi Itoh,
  • Tetsuo Noda,
  • Masato Kasuga,
  • Jun Nakae

DOI
https://doi.org/10.1371/journal.pone.0018324
Journal volume & issue
Vol. 6, no. 4
p. e18324

Abstract

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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 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 (Δ256Foxo1(AGRP)Pdk1(-/-)). The AGRPPdk1(-/-) mice showed reductions in food intake, body length, and body weight. The Δ256Foxo1(AGRP)Pdk1(-/-) 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 Δ256Foxo1(AGRP)Pdk1(-/-) mice. In vitro, ghrelin-induced changes in [Ca(2+)](i) and inhibition of ghrelin by leptin were significantly attenuated in AGRPPdk1(-/-) neurons compared to control neurons. However, ghrelin-induced [Ca(2+)](i) changes and leptin inhibition were restored in Δ256Foxo1(AGRP)Pdk1(-/-) mice. These results suggested that PDK1 and Foxo1 signaling pathways play important roles in the control of energy homeostasis through AGRP-independent mechanisms.