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

被引：60

作者：

Iskandar, Kristy ^{[5
]}

Cao, Yongheng ^{[2
,4
,5
]}

Hayashi, Yoshitake ^{[5
]}

Nakata, Masanori

Takano, Eisuke

Yada, Toshihiko

Zhang, Changliang ^{[6
]}

Ogawa, Wataru ^{[7
]}

Oki, Miyo ^{[4
]}

Chua, Streamson, Jr. ^{[8
,9
]}

Itoh, Hiroshi ^{[1
]}

Noda, Tetsuo ^{[3
]}

Kasuga, Masato ^{[2
,7
]}

Nakae, Jun ^{[1
,4
]}

机构：

[1] Keio Univ, Div Endocrinol Metab & Nephrol, Dept Internal Med, Sch Med, Tokyo 1608582, Japan

[2] Int Med Ctr Japan, Res Inst, Tokyo, Japan

[3] Japanese Fdn Canc Res, Inst Canc, Dept Cell Biol, Tokyo 170, Japan

[4] Kobe Univ, 21st Century Ctr Excellence Program Signal Transd, Div Diabet Metab & Endocrinol, Dept Internal Med,Grad Sch Med, Kobe, Hyogo 657, Japan

[5] Kobe Univ, Grad Sch Med, Int Ctr Med Res & Treatment, Div Mol Med & Med Genet, Kobe, Hyogo 657, Japan

[6] Kobe Univ, Grad Sch Med, Div Cellular & Mol Med, Kobe, Hyogo 657, Japan

[7] Kobe Univ, Grad Sch Med, Dept Internal Med, Div Diabet Metab & Endocrinol, Kobe, Hyogo 657, Japan

[8] Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA

[9] Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10467 USA

来源：

AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM | 2010年 / 298卷 / 04期

关键词：

phosphoinositide-dependent protein kinase-1; forkhead box-containing protein O1; proopiomelanocortin neurons; Pomc; food intake; INSULIN-RECEPTOR SUBSTRATE-2; TRANSCRIPTION FACTOR FOXO1; NERVOUS-SYSTEM CONTROL; BODY-WEIGHT; BETA-CELLS; ARCUATE NUCLEUS; LEPTIN; BRAIN; ACTIVATION; PHOSPHORYLATION;

D O I：

10.1152/ajpendo.00512.2009

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Iskandar K, Cao Y, Hayashi Y, Nakata M, Takano E, Yada T, Zhang C, Ogawa W, Oki M, Chua S Jr, Itoh H, Noda T, Kasuga M, Nakae J. PDK-1/FoxO1 pathway in POMC neurons regulates Pomc expression and food intake. Am J Physiol Endocrinol Metab 298: E787-E798, 2010. First published January 26, 2010; doi:10.1152/ajpendo.00512.2009.-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 (Delta 256) FoxO1 in POMC neurons (CNFoxO1(POMC) or Delta 256FoxO1(POMC)). POMCPdk1(-/-) mice showed increased food intake and body weight accompanied by decreased expression of Pomc gene. The CNFoxO1(POMC) 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 Delta 256FoxO1 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.

引用

页码：E787 / E798

页数：12

共 42 条

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