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

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25 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere18324
JournalPloS one
Volume6
Issue number4
DOIs
Publication statusPublished - 2011 Apr 21

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Cao, Y., Nakata, M., Okamoto, S., Takano, E., Yada, T., Minokoshi, Y., Hirata, Y., Nakajima, K., Iskandar, K., Hayashi, Y., Ogawa, W., Barsh, G. S., Hosoda, H., Kangawa, K., Itoh, H., Noda, T., Kasuga, M., & Nakae, J. (2011). PDK1-Foxo1 in agouti-related peptide neurons regulates energy homeostasis by modulating food intake and energy expenditure. PloS one, 6(4), [e18324]. https://doi.org/10.1371/journal.pone.0018324