title: FoxO6 integrates insulin signaling with gluconeogenesis in the liver.
abstract: OBJECTIVE
  Excessive endogenous glucose production contributes to fasting hyperglycemia in diabetes. This effect stems from inept insulin suppression of hepatic gluconeogenesis. To understand the underlying mechanisms, we studied the ability of forkhead box O6 (FoxO6) to mediate insulin action on hepatic gluconeogenesis and its contribution to glucose metabolism.
  
  
  METHODS
  We characterized FoxO6 in glucose metabolism in cultured hepatocytes and in rodent models of dietary obesity, insulin resistance, or insulin-deficient diabetes. We determined the effect of FoxO6 on hepatic gluconeogenesis in genetically modified mice with FoxO6 gain- versus loss-of-function and in diabetic db/db mice with selective FoxO6 ablation in the liver.
  
  
  RESULTS
  FoxO6 integrates insulin signaling to hepatic gluconeogenesis. In mice, elevated FoxO6 activity in the liver augments gluconeogenesis, raising fasting blood glucose levels, and hepatic FoxO6 depletion suppresses gluconeogenesis, resulting in fasting hypoglycemia. FoxO6 stimulates gluconeogenesis, which is counteracted by insulin. Insulin inhibits FoxO6 activity via a distinct mechanism by inducing its phosphorylation and disabling its transcriptional activity, without altering its subcellular distribution in hepatocytes. FoxO6 becomes deregulated in the insulin-resistant liver, accounting for its unbridled activity in promoting gluconeogenesis and correlating with the pathogenesis of fasting hyperglycemia in diabetes. These metabolic abnormalities, along with fasting hyperglycemia, are reversible by selective inhibition of hepatic FoxO6 activity in diabetic mice.
  
  
  CONCLUSIONS
  Our data uncover a FoxO6-dependent pathway by which the liver orchestrates insulin regulation of gluconeogenesis, providing the proof-of-concept that selective FoxO6 inhibition is beneficial for curbing excessive hepatic glucose production and improving glycemic control in diabetes.
authors.affiliation: Division of Immunogenetics, Department of Pediatrics, Children’s Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA. dongh@pitt.edu
authors.forename: Dae Hyun
authors.initials: DH
authors.lastname: Kim
authors.forename: German
authors.initials: G
authors.lastname: Perdomo
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Sandra
authors.initials: S
authors.lastname: Slusher
authors.forename: Sojin
authors.initials: S
authors.lastname: Lee
authors.forename: Brett E
authors.initials: BE
authors.lastname: Phillips
authors.forename: Yong
authors.initials: Y
authors.lastname: Fan
authors.forename: Nick
authors.initials: N
authors.lastname: Giannoukakis
authors.forename: Roberto
authors.initials: R
authors.lastname: Gramignoli
authors.forename: Stephen
authors.initials: S
authors.lastname: Strom
authors.forename: Steven
authors.initials: S
authors.lastname: Ringquist
authors.forename: H Henry
authors.initials: HH
authors.lastname: Dong
mesh_terms: D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D020868:Gene Silencing; D005943:Gluconeogenesis; D056945:Hep G2 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000502:physiology; D009765:Obesity / Q000378:metabolism; D009928:Organ Specificity; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction
chemical_list: C478770:FOXO6 protein, human; D051858:Forkhead Transcription Factors; C525395:Foxo6 protein, mouse; D007328:Insulin; D050505:Mutant Proteins