title: Integrated control of hepatic lipogenesis versus glucose production requires FoxO transcription factors.
abstract: Insulin integrates hepatic glucose and lipid metabolism, directing nutrients to storage as glycogen and triglyceride. In type 2 diabetes, levels of the former are low and the latter are exaggerated, posing a pathophysiologic and therapeutic conundrum. A branching model of insulin signalling, with FoxO1 presiding over glucose production and Srebp-1c regulating lipogenesis, provides a potential explanation. Here we illustrate an alternative mechanism that integrates glucose production and lipogenesis under the unifying control of FoxO. Liver-specific ablation of three FoxOs (L-FoxO1,3,4) prevents the induction of glucose-6-phosphatase and the repression of glucokinase during fasting, thus increasing lipogenesis at the expense of glucose production. We document a similar pattern in the early phases of diet-induced insulin resistance, and propose that FoxOs are required to enable the liver to direct nutritionally derived carbons to glucose versus lipid metabolism. Our data underscore the heterogeneity of hepatic insulin resistance during progression from the metabolic syndrome to overt diabetes, and the conceptual challenge of designing therapies that curtail glucose production without promoting hepatic lipid accumulation.
authors.affiliation: 1] Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA [2] Department of Medicine, Columbia University, New York, New York 10032, USA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Haeusler
authors.affiliation: Department of Medicine, Albert Einstein University, Bronx, New York 10461, USA.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Hartil
authors.affiliation: Department of Medicine, Albert Einstein University, Bronx, New York 10461, USA.
authors.forename: Bhavapriya
authors.initials: B
authors.lastname: Vaitheesvaran
authors.affiliation: Department of Medicine, Albert Einstein University, Bronx, New York 10461, USA.
authors.forename: Isabel
authors.initials: I
authors.lastname: Arrieta-Cruz
authors.affiliation: Department of Medicine, Albert Einstein University, Bronx, New York 10461, USA.
authors.forename: Colette M
authors.initials: CM
authors.lastname: Knight
authors.affiliation: Department of Medicine, Columbia University, New York, New York 10032, USA.
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Cook
authors.affiliation: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
authors.forename: Helene L
authors.initials: HL
authors.lastname: Kammoun
authors.affiliation: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Febbraio
authors.affiliation: Department of Medicine, Albert Einstein University, Bronx, New York 10461, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Gutierrez-Juarez
authors.affiliation: Department of Medicine, Albert Einstein University, Bronx, New York 10461, USA.
authors.forename: Irwin J
authors.initials: IJ
authors.lastname: Kurland
authors.affiliation: Department of Medicine, Columbia University, New York, New York 10032, USA.
authors.forename: Domenico
authors.initials: D
authors.lastname: Accili
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D005215:Fasting / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005941:Glucokinase / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D050356:Lipid Metabolism; D050155:Lipogenesis; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D018797:Cell Cycle Proteins; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C525394:FoxO4 protein, mouse; C467200:Foxo1 protein, mouse; D007328:Insulin; D005941:Glucokinase; D005952:Glucose-6-Phosphatase; D005947:Glucose