PDK-1/FoxO1 pathway in POMC neurons regulates Pomc expression and food intake

Kristy Iskandar, Yongheng Cao, Yoshitake Hayashi, Masanori Nakata, Eisuke Takano, Toshihiko Yada, Changliang Zhang, Wataru Ogawa, Miyo Oki, Streamson C. Chua, Jr., Hiroshi Itoh, Tetsuo Noda, Masato Kasuga, Jun Nakae

Research output: Contribution to journalArticle

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Abstract

Both insulin and leptin signaling converge on phosphatidylinositol 3-OH kinase [PI(3)K]/3-phosphoinositide-dependent protein kinase-1 (PDK-1)/protein kinase B (PKB, also known as Akt) in proopiomelanocortin (POMC) neurons. Forkhead box-containing protein-O1 (FoxO1) is inactivated in a PI(3)K-dependent manner. However, the interrelationship between PI(3)K/PDK-1/Akt and FoxO1, and the chronic effects of the overexpression of FoxO1 in POMC neurons on energy homeostasis has not been elucidated. To determine the extent to which PDK-1 and FoxO1 signaling in POMC neurons was responsible for energy homeostasis, we generated POMC neuron-specific Pdk1 knockout mice (POMCPdk1-/-) and mice selectively expressing a constitutively nuclear (CN)FoxO1 or transactivation-defective (Δ256)FoxO1 in POMC neurons (CNFoxO1 POMC or Δ256FoxO1POMC). POMCPdk1-/- mice showed increased food intake and body weight accompanied by decreased expression of Pomc gene. The CNFoxO1POMC mice exhibited mild obesity and hyperphagia compared with POMCPdk1-/- mice. Although expression of the CNFoxO1 made POMCPdk1-/- mice more obese due to excessive suppression of Pomc gene, overexpression of Δ256FoxO1 in POMC neurons had no effects on metabolic phenotypes and Pomc expression levels of POMCPdk1 -/- mice. These data suggest a requirement for PDK-1 and FoxO1 in transcriptional regulation of Pomc and food intake.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume298
Issue number4
DOIs
StatePublished - Apr 2010

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Pro-Opiomelanocortin
Phosphatidylinositols
Protein Kinases
Eating
Neurons
Phosphatidylinositol 3-Kinases
3-Phosphoinositide-Dependent Protein Kinases
Homeostasis
Appetite Regulation
Obese Mice
Hyperphagia
Proto-Oncogene Proteins c-akt
Leptin
Knockout Mice
Transcriptional Activation
Obesity
Body Weight
Insulin
Phenotype
Gene Expression

Keywords

  • Food intake
  • Forkhead box-containing protein O1
  • Phosphoinositide-dependent protein kinase-1
  • Pomc
  • Proopiomelanocortin neurons

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Endocrinology, Diabetes and Metabolism

Cite this

PDK-1/FoxO1 pathway in POMC neurons regulates Pomc expression and food intake. / Iskandar, Kristy; Cao, Yongheng; Hayashi, Yoshitake; Nakata, Masanori; Takano, Eisuke; Yada, Toshihiko; Zhang, Changliang; Ogawa, Wataru; Oki, Miyo; Chua, Jr., Streamson C.; Itoh, Hiroshi; Noda, Tetsuo; Kasuga, Masato; Nakae, Jun.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 298, No. 4, 04.2010.

Research output: Contribution to journalArticle

Iskandar, K, Cao, Y, Hayashi, Y, Nakata, M, Takano, E, Yada, T, Zhang, C, Ogawa, W, Oki, M, Chua, Jr., SC, Itoh, H, Noda, T, Kasuga, M & Nakae, J 2010, 'PDK-1/FoxO1 pathway in POMC neurons regulates Pomc expression and food intake', American Journal of Physiology - Endocrinology and Metabolism, vol. 298, no. 4. https://doi.org/10.1152/ajpendo.00512.2009
Iskandar, Kristy ; Cao, Yongheng ; Hayashi, Yoshitake ; Nakata, Masanori ; Takano, Eisuke ; Yada, Toshihiko ; Zhang, Changliang ; Ogawa, Wataru ; Oki, Miyo ; Chua, Jr., Streamson C. ; Itoh, Hiroshi ; Noda, Tetsuo ; Kasuga, Masato ; Nakae, Jun. / PDK-1/FoxO1 pathway in POMC neurons regulates Pomc expression and food intake. In: American Journal of Physiology - Endocrinology and Metabolism. 2010 ; Vol. 298, No. 4.
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abstract = "Both insulin and leptin signaling converge on phosphatidylinositol 3-OH kinase [PI(3)K]/3-phosphoinositide-dependent protein kinase-1 (PDK-1)/protein kinase B (PKB, also known as Akt) in proopiomelanocortin (POMC) neurons. Forkhead box-containing protein-O1 (FoxO1) is inactivated in a PI(3)K-dependent manner. However, the interrelationship between PI(3)K/PDK-1/Akt and FoxO1, and the chronic effects of the overexpression of FoxO1 in POMC neurons on energy homeostasis has not been elucidated. To determine the extent to which PDK-1 and FoxO1 signaling in POMC neurons was responsible for energy homeostasis, we generated POMC neuron-specific Pdk1 knockout mice (POMCPdk1-/-) and mice selectively expressing a constitutively nuclear (CN)FoxO1 or transactivation-defective (Δ256)FoxO1 in POMC neurons (CNFoxO1 POMC or Δ256FoxO1POMC). POMCPdk1-/- mice showed increased food intake and body weight accompanied by decreased expression of Pomc gene. The CNFoxO1POMC mice exhibited mild obesity and hyperphagia compared with POMCPdk1-/- mice. Although expression of the CNFoxO1 made POMCPdk1-/- mice more obese due to excessive suppression of Pomc gene, overexpression of Δ256FoxO1 in POMC neurons had no effects on metabolic phenotypes and Pomc expression levels of POMCPdk1 -/- mice. These data suggest a requirement for PDK-1 and FoxO1 in transcriptional regulation of Pomc and food intake.",
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