title: A mutant allele encoding DNA binding-deficient FoxO1 differentially regulates hepatic glucose and lipid metabolism.
abstract: Insulin signaling in the liver blunts glucose production and stimulates triglyceride biosynthesis. FoxO1 is required for cAMP induction of hepatic glucose production and is permissive for the effect of insulin to suppress this process. Moreover, FoxO1 ablation increases lipogenesis. In this study, we investigated the pleiotropic actions of FoxO1 on glucose and lipid metabolism. To this end, we reconstituted FoxO1 function in mice with a liver-specific deletion of Foxo1 using targeted knock-in of an allele encoding a DNA binding-deficient FoxO1 mutant (L-DBD). Chow-reared L-DBD mice showed defects in hepatic glucose production but normal liver triglyceride content despite increased rates of de novo lipogenesis and impaired fatty acid oxidation in isolated hepatocytes. Gene expression studies indicated that FoxO1 regulates the expression of glucokinase via a cell-nonautonomous coregulatory mechanism, while its regulation of glucose-6-phosphatase proceeds via a cell-autonomous action as a direct transcriptional activator. These conclusions support a differential regulation of hepatic glucose and lipid metabolism by FoxO1 based on the mechanism by which it alters the expression of key target genes involved in each process.
authors.affiliation: Department of Medicine, Columbia University, New York, NY.
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Cook
authors.affiliation: Department of Medicine, Columbia University, New York, NY Department of Molecular Metabolic Regulation, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Department of Medicine, Columbia University, New York, NY Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Banks
authors.affiliation: Department of Medicine, Columbia University, New York, NY Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Gunma, Japan.
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Kitamura
authors.affiliation: Department of Medicine, Columbia University, New York, NY Department of Clinical and Molecular Endocrinology, Tokyo Medical and Dental University Graduate School, Tokyo, Japan.
authors.forename: Kyoichiro
authors.initials: K
authors.lastname: Tsuchiya
authors.affiliation: Department of Medicine, Columbia University, New York, NY da230@columbia.edu.
authors.forename: Domenico
authors.initials: D
authors.lastname: Accili
mesh_terms: D000483:Alleles; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology; D050155:Lipogenesis / Q000235:genetics / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D011485:Protein Binding
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D004247:DNA; D005947:Glucose