title: Homozygous staggerer (sg/sg) mice display improved insulin sensitivity and enhanced glucose uptake in skeletal muscle.
abstract: OBJECTIVE
  Homozygous staggerer (sg/sg) mice, which have decreased and dysfunctional Rorα (also known as Rora) expression in all tissues, display a lean and dyslipidaemic phenotype. They are also resistant to (high fat) diet-induced obesity. We explored whether retinoic acid receptor-related orphan receptor (ROR) α action in skeletal muscle was involved in the regulation of glucose metabolism.
  
  
  METHODS
  We used a three-armed genomic approach, including expression profiling, ingenuity analysis and quantitative PCR validation to identify the signalling pathway(s) in skeletal muscle that are perturbed in sg/sg mice. Moreover, western analysis, functional insulin and glucose tolerance tests, and ex vivo glucose uptake assays were used to phenotypically characterise the impact of aberrant v-AKT murine thymoma viral oncogene homologue (AKT) signalling.
  
  
  RESULTS
  Homozygous and heterozygous (sg/sg and sg/+) animals exhibited decreased fasting blood glucose levels, mildly improved glucose tolerance and increased insulin sensitivity. Illumina expression profiling and bioinformatic analysis indicated the involvement of RORα in metabolic disease and phosphatidylinositol 3-kinase-AKT signalling. Quantitative PCR and western analysis validated increased AKT2 (mRNA and protein) and phosphorylation in sg/sg mice in the basal state. This was associated with increased expression of Tbc1d1 and Glut4 (also known as Slc2a4) mRNA and protein. Finally, in agreement with the phenotype, we observed increased (absolute) levels of AKT and phosphorylated AKT (in the basal and insulin stimulated states), and of (ex vivo) glucose uptake in skeletal muscle from sg/sg mice relative to wild-type littermates.
  
  
  CONCLUSIONS
  We propose that Rorα plays an important role in regulation of the AKT2 signalling cascade, which controls glucose uptake in skeletal muscle.
authors.affiliation: Obesity Research Centre, Institute for Molecular Bioscience, The University of Queensland, Services Rd, St Lucia, Queensland 4072, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Lau
authors.forename: R L
authors.initials: RL
authors.lastname: Fitzsimmons
authors.forename: M A
authors.initials: MA
authors.lastname: Pearen
authors.forename: M J
authors.initials: MJ
authors.lastname: Watt
authors.forename: G E O
authors.initials: GE
authors.lastname: Muscat
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002153:Calorimetry, Indirect; D020690:GTPase-Activating Proteins; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006579:Heterozygote; D006720:Homozygote; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008818:Mice, Neurologic Mutants; D018482:Muscle, Skeletal / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D016133:Polymerase Chain Reaction; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism
chemical_list: D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; D009687:Nuclear Proteins; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C539739:Rora protein, mouse; C495693:Slc2a4 protein, mouse; C095906:Tbc1d1 protein, mouse; C494922:Akt2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose