title: Profound hyperglycemia in knockout mutant mice identifies novel function for POU4F2/Brn-3b in regulating metabolic processes.
abstract: The POU4F2/Brn-3b transcription factor has been identified as a potentially novel regulator of key metabolic processes. Loss of this protein in Brn-3b knockout (KO) mice causes profound hyperglycemia and insulin resistance (IR), normally associated with type 2 diabetes (T2D), whereas Brn-3b is reduced in tissues taken from obese mice fed on high-fat diets (HFD), which also develop hyperglycemia and IR. Furthermore, studies in C2C12 myocytes show that Brn-3b mRNA and proteins are induced by glucose but inhibited by insulin, suggesting that this protein is itself highly regulated in responsive cells. Analysis of differential gene expression in skeletal muscle from Brn-3b KO mice showed changes in genes that are implicated in T2D such as increased glycogen synthase kinase-3β and reduced GLUT4 glucose transporter. The GLUT4 gene promoter contains multiple Brn-3b binding sites and is directly transactivated by this transcription factor in cotransfection assays, whereas chromatin immunoprecipitation assays confirm that Brn-3b binds to this promoter in vivo. In addition, correlation between GLUT4 and Brn-3b in KO tissues or in C2C12 cells strongly supports a close association between Brn-3b levels and GLUT4 expression. Since Brn-3b is regulated by metabolites and insulin, this may provide a mechanism for controlling key genes that are required for normal metabolic processes in insulin-responsive tissues and its loss may contribute to abnormal glucose uptake.
authors.affiliation: Medical Molecular Biology Unit, University College London Institute of Child Health, London, United Kingdom;
authors.forename: Stavroula
authors.initials: S
authors.lastname: Bitsi
authors.affiliation: Medical Molecular Biology Unit, University College London Institute of Child Health, London, United Kingdom;
authors.forename: Houda
authors.initials: H
authors.lastname: Ali
authors.affiliation: Medical Molecular Biology Unit, University College London Institute of Child Health, London, United Kingdom;
authors.forename: Lauren
authors.initials: L
authors.lastname: Maskell
authors.affiliation: Medical Molecular Biology Unit, University College London Institute of Child Health, London, United Kingdom; Experimental Cardiology Unit, University of Lausanne Medical School, Lausanne, Switzerland.
authors.forename: Samir
authors.initials: S
authors.lastname: Ounzain
authors.affiliation: Adipokines and Metabolism Research Group, Division of Medicine, University College London, London, United Kingdom; and.
authors.forename: Vidya
authors.initials: V
authors.lastname: Mohamed-Ali
authors.affiliation: Medical Molecular Biology Unit, University College London Institute of Child Health, London, United Kingdom; v.budhram-mahadeo@ucl.ac.uk.
authors.forename: Vishwanie S
authors.initials: VS
authors.lastname: Budhram-Mahadeo
mesh_terms: D000818:Animals; D001835:Body Weight / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005937:Glucaric Acid / Q000494:pharmacology; D018149:Glucose Intolerance / Q000235:genetics; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D018398:Homeodomain Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D006943:Hyperglycemia / Q000235:genetics*; D015151:Immunoblotting; D007328:Insulin / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009154:Mutation; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050820:Transcription Factor Brn-3B / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism
chemical_list: D051275:Glucose Transporter Type 4; D018398:Homeodomain Proteins; D007328:Insulin; C085559:Pou4f2 protein, mouse; D012333:RNA, Messenger; C495693:Slc2a4 protein, mouse; D050820:Transcription Factor Brn-3B; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D005937:Glucaric Acid
keywords: GLUT4; POU4F2/Brn-3b; glucose intolerance; transcription factor