PDK-1/FoxO1 pathway in POMC neurons regulates Pomc expression and food intake.
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 (Delta256)FoxO1 in POMC neurons (CNFoxO1(POMC) or Delta256FoxO1(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 Delta256FoxO1 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.
Iskandar
Kristy
K
International Center for Medical Research and Treatment, Kobe University Graduate school of Medicine, Japan.
Cao
Yongheng
Y
Hayashi
Yoshitake
Y
Nakata
Masanori
M
Takano
Eisuke
E
Yada
Toshihiko
T
Zhang
Changliang
C
Ogawa
Wataru
W
Oki
Miyo
M
Chua
Streamson
S
Itoh
Hiroshi
H
Noda
Tetsuo
T
Kasuga
Masato
M
Nakae
Jun
J
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D002843:Chromatin / Q000378:metabolism; D004435:Eating / Q000235:genetics* / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D005951:Glucose Tolerance Test; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D009765:Obesity / Q000235:genetics; D010101:Oxygen Consumption / Q000502:physiology; D010957:Plasmids / Q000235:genetics; D011333:Pro-Opiomelanocortin / Q000096:biosynthesis* / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000324:Adrenocorticotropic Hormone; D002843:Chromatin; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D011333:Pro-Opiomelanocortin; D017346:Protein Serine-Threonine Kinases; D012313:RNA; D050396:TRPP Cation Channels; C467200:Foxo1 protein, mouse; C578564:Pdpk1 protein, mouse