title: Insulin-sensitizing effect of LXR agonist T0901317 in high-fat fed rats is associated with restored muscle GLUT4 expression and insulin-stimulated AS160 phosphorylation.
abstract: OBJECTIVE
  Liver X receptors (LXRs) are ligand-activated transcription factors that were shown to stimulate hepatic lipogenesis leading to liver steatosis and hypertriglyceridemia. Despite their pro-lipogenic action, LXR activators normalize glycemia and improve insulin sensitivity in rodent models of type 2 diabetes. Antidiabetic action of LXR agonists is thought to result from suppression of hepatic gluconeogenesis. However, it remains unclear whether LXR activation affects muscle insulin sensitivity. In the present study we attempted to answer this question.
  
  
  METHODS
  The experiments were performed on male Wistar rats fed for 5 weeks on either standard chow or high fat diet. The latter group was further divided into two subgroups receiving either selective LXR agonist - T0901317 (10mg/kg/d) or vehicle during the last week of the experiment. All animals were then anaesthetized and samples of the soleus as well as red and white sections of the gastrocnemius muscle were excised.
  
  
  RESULTS
  As expected, administration of T0901317 to high-fat fed rats augmented diet-induced hyperlipidemia. Nevertheless, it also normalized glucose tolerance and improved insulin-stimulated glucose uptake in isolated soleus muscle. In addition, LXR agonist completely restored glucose transporter 4 expression and insulin-stimulated Akt substrate of 160 kDa phosphorylation in all investigated muscles. Insulin-sensitizing effect of T0901317 was not related to changes in intramuscular level of lipid mediators of insulin resistance, since neither diacylglycerols nor ceramide content was affected by the treatment.
  
  
  CONCLUSIONS
  We conclude that improvement in muscle insulin sensitivity is one of the mechanisms underlying the antidiabetic action of LXR activators.
authors.affiliation: Department of Physiology, Medical University of Białystok, Białystok, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Baranowski
authors.forename: Piotr
authors.initials: P
authors.lastname: Zabielski
authors.forename: Agnieszka U
authors.initials: AU
authors.lastname: Błachnio-Zabielska
authors.forename: Ewa
authors.initials: E
authors.lastname: Harasim
authors.forename: Adrian
authors.initials: A
authors.lastname: Chabowski
authors.forename: Jan
authors.initials: J
authors.lastname: Górski
mesh_terms: D000818:Animals; D002518:Ceramides / Q000032:analysis; D059305:Diet, High-Fat; D004075:Diglycerides / Q000032:analysis; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D005951:Glucose Tolerance Test; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology*; D006949:Hyperlipidemias / Q000209:etiology; D007328:Insulin / Q000494:pharmacology*; D000071518:Liver X Receptors; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000819:agonists* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013230:Stearoyl-CoA Desaturase / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D002518:Ceramides; D004075:Diglycerides; D020690:GTPase-Activating Proteins; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D006845:Hydrocarbons, Fluorinated; D007328:Insulin; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D051057:Proto-Oncogene Proteins c-akt; D013230:Stearoyl-CoA Desaturase; D051780:Sterol Regulatory Element Binding Protein 1; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C533101:TBC1D4 protein, rat