Role of hypothalamic Foxo1 in the regulation of food intake and energy homeostasis.
Insulin signaling in the hypothalamus plays a role in maintaining body weight. Studies suggest that the forkhead transcription factor Foxo1 is an important mediator of insulin signaling in peripheral tissues. Here we demonstrate that in normal mice, hypothalamic Foxo1 expression is reduced by the anorexigenic hormones insulin and leptin. These hormones' effects on feeding are inhibited when hypothalamic Foxo1 is activated, establishing a new signaling pathway through which insulin and leptin regulate food intake in hypothalamic neurons. Moreover, activation of Foxo1 in the hypothalamus increases food intake and body weight, whereas inhibition of Foxo1 decreases both. Foxo1 stimulates the transcription of the orexigenic neuropeptide Y and Agouti-related protein through the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway, but suppresses the transcription of anorexigenic proopiomelanocortin by antagonizing the activity of signal transducer-activated transcript-3 (STAT3). Our data suggest that hypothalamic Foxo1 is an important regulator of food intake and energy balance.
Kim
Min-Seon
MS
Department of Internal Medicine, University of Ulsan College of Medicine, 138-736 Pungnap-dong, Songpa-ku, Seoul 138-736, Korea.
Pak
Youngmi K
YK
Jang
Pil-Geum
PG
Namkoong
Cherl
C
Choi
Yon-Sik
YS
Won
Jong-Chul
JC
Kim
Kyung-Sup
KS
Kim
Seung-Whan
SW
Kim
Hyo-Soo
HS
Park
Joong-Yeol
JY
Kim
Young-Bum
YB
Lee
Ki-Up
KU
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation / Q000379:methods; D004435:Eating / Q000187:drug effects / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D007150:Immunohistochemistry / Q000379:methods; D007328:Insulin / Q000494:pharmacology; D020738:Leptin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009447:Neuroblastoma; D034741:RNA, Small Interfering / Q000494:pharmacology
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D020738:Leptin; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins