title: Hepatic suppression of Foxo1 and Foxo3 causes hypoglycemia and hyperlipidemia in mice.
abstract: Dysregulation of blood glucose and triglycerides are the major characteristics of type 2 diabetes mellitus. We sought to identify the mechanisms regulating blood glucose and lipid homeostasis. Cell-based studies established that the Foxo forkhead transcription factors Forkhead box O (Foxo)-1, Foxo3, and Foxo4 are inactivated by insulin via a phosphatidylinositol 3-kinase/Akt-dependent pathway, but the role of Foxo transcription factors in the liver in regulating nutrient metabolism is incompletely understood. In this study, we used the Cre/LoxP genetic approach to delete the Foxo1, Foxo3, and Foxo4 genes individually or a combination of two or all in the liver of lean or db/db mice and assessed the role of Foxo inactivation in regulating glucose and lipid homeostasis in vivo. In the lean mice or db/db mice, hepatic deletion of Foxo1, rather than Foxo3 or Foxo4, caused a modest reduction in blood glucose concentrations and barely affected lipid homeostasis. Combined deletion of Foxo1 and Foxo3 decreased blood glucose levels, elevated serum triglyceride and cholesterol concentrations, and increased hepatic lipid secretion and caused hepatosteatosis. Analysis of the liver transcripts established a prominent role of Foxo1 in regulating gene expression of gluconeogenic enzymes and Foxo3 in the expression of lipogenic enzymes. Our findings indicate that Foxo1 and Foxo3 inactivation serves as a potential mechanism by which insulin reduces hepatic glucose production and increases hepatic lipid synthesis and secretion in healthy and diabetic states.
authors.affiliation: Division of Molecular Cardiology, Cardiovascular Research Institute, College of Medicine, Texas A&M Health Science Center, Central Texas Veterans Health Care System, Temple, Texas 76504, USA.
authors.forename: Kebin
authors.initials: K
authors.lastname: Zhang
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Qi
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhu
authors.forename: Boyi
authors.initials: B
authors.lastname: Gan
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
authors.forename: Travis
authors.initials: T
authors.lastname: Averitt
authors.forename: Shaodong
authors.initials: S
authors.lastname: Guo
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D018797:Cell Cycle Proteins; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D005943:Gluconeogenesis / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D006949:Hyperlipidemias / Q000378:metabolism*; D007003:Hypoglycemia / Q000378:metabolism*; D050356:Lipid Metabolism / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout
chemical_list: D001786:Blood Glucose; 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; D005947:Glucose