Forkhead protein FoxO1 mediates Agrp-dependent effects of leptin on food intake.
Leptin controls food intake by regulating the transcription of key neuropeptides in the hypothalamus. The mechanism by which leptin regulates gene expression is unclear, however. Here we show that delivery of adenovirus encoding a constitutively nuclear mutant FoxO1, a transcription factor known to control liver metabolism and pancreatic beta-cell function, to the hypothalamic arcuate nucleus of rodents results in a loss of the ability of leptin to curtail food intake and suppress expression of Agrp. Conversely, a transactivation-deficient FoxO1 mutant prevents induction of Agrp by fasting. We also find that FoxO1 and the transcription factor Stat3 exert opposing actions on the expression of Agrp and Pomc through transcriptional squelching. FoxO1 promotes opposite patterns of coactivator-corepressor exchange at the Pomc and Agrp promoters, resulting in activation of Agrp and inhibition of Pomc. Thus, FoxO1 represents a shared component of pathways integrating food intake and peripheral metabolism.
Kitamura
Tadahiro
T
Department of Medicine, Columbia University Medical Center, 1150 St. Nicholas Avenue, New York, New York 10032, USA.
Feng
Yun
Y
Kitamura
Yukari Ido
YI
Chua
Streamson C
SC
Xu
Allison W
AW
Barsh
Gregory S
GS
Rossetti
Luciano
L
Accili
Domenico
D
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D054369:Agouti-Related Protein; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D004435:Eating; D005215:Fasting; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism
D054369:Agouti-Related Protein; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; D011506:Proteins; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D011333:Pro-Opiomelanocortin