title: Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1.
abstract: Considerable data support the idea that forkhead box O1 (Foxo1) drives the liver transcriptional program during fasting and is then inhibited by thymoma viral proto-oncogene 1 (Akt) after feeding. Here we show that mice with hepatic deletion of Akt1 and Akt2 were glucose intolerant, insulin resistant and defective in their transcriptional response to feeding in the liver. These defects were normalized with concomitant liver-specific deletion of Foxo1. Notably, in the absence of both Akt and Foxo1, mice adapted appropriately to both the fasted and fed state, and insulin suppressed hepatic glucose production normally. A gene expression analysis revealed that deletion of Akt in liver led to the constitutive activation of Foxo1-dependent gene expression, but again, concomitant ablation of Foxo1 restored postprandial regulation, preventing the inhibition of the metabolic response to nutrient intake caused by deletion of Akt. These results are inconsistent with the canonical model of hepatic metabolism in which Akt is an obligate intermediate for proper insulin signaling. Rather, they show that a major role of hepatic Akt is to restrain the activity of Foxo1 and that in the absence of Foxo1, Akt is largely dispensable for insulin- and nutrient-mediated hepatic metabolic regulation in vivo.
authors.affiliation: The Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Mingjian
authors.initials: M
authors.lastname: Lu
authors.forename: Min
authors.initials: M
authors.lastname: Wan
authors.forename: Karla F
authors.initials: KF
authors.lastname: Leavens
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Chu
authors.forename: Bobby R
authors.initials: BR
authors.lastname: Monks
authors.forename: Sully
authors.initials: S
authors.lastname: Fernandez
authors.forename: Rexford S
authors.initials: RS
authors.lastname: Ahima
authors.forename: Kohjiro
authors.initials: K
authors.lastname: Ueki
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Birnbaum
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004435:Eating; D005215:Fasting / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D018149:Glucose Intolerance / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; C514862:Akt1 protein, mouse; C494922:Akt2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt