FOXO1 in the ventromedial hypothalamus regulates energy balance.
The transcription factor FOXO1 plays a central role in metabolic homeostasis by regulating leptin and insulin activity in many cell types, including neurons. However, the neurons mediating these effects and the identity of the molecular targets through which FOXO1 regulates metabolism remain to be defined. Here, we show that the ventral medial nucleus of the hypothalamus (VMH) is a key site of FOXO1 action. We found that mice lacking FOXO1 in steroidogenic factor 1 (SF-1) neurons of the VMH are lean due to increased energy expenditure. The mice also failed to appropriately suppress energy expenditure in response to fasting. Furthermore, these mice displayed improved glucose tolerance due to increased insulin sensitivity in skeletal muscle and heart. Gene expression profiling and sequence analysis revealed several pathways regulated by FOXO1. In addition, we identified the nuclear receptor SF-1 as a direct FOXO1 transcriptional target in the VMH. Collectively, our data suggest that the transcriptional networks modulated by FOXO1 in VMH neurons are key components in the regulation of energy balance and glucose homeostasis.
Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center(UT Southwestern), Dallas, TX, USA.
Ki Woo
KW
Kim
Jose
J
Donato
Eric D
ED
Berglund
Yun-Hee
YH
Choi
Daisuke
D
Kohno
Carol F
CF
Elias
Ronald A
RA
Depinho
Joel K
JK
Elmquist
D000818:Animals; D001823:Body Composition / Q000235:genetics; D001835:Body Weight; D002395:Catecholamines / Q000097:blood; D002478:Cells, Cultured; D059305:Diet, High-Fat; D004734:Energy Metabolism; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance; D007473:Ion Channels / Q000097:blood; D020738:Leptin / Q000494:pharmacology / Q000502:physiology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000097:blood; D009928:Organ Specificity; D010101:Oxygen Consumption; D010641:Phenotype; D054339:Steroidogenic Factor 1 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D000071256:Uncoupling Protein 1; D014697:Ventromedial Hypothalamic Nucleus / Q000166:cytology / Q000378:metabolism*
D002395:Catecholamines; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007473:Ion Channels; D020738:Leptin; D024101:Mitochondrial Proteins; D054339:Steroidogenic Factor 1; D000071256:Uncoupling Protein 1; D005947:Glucose