title: Peroxisome proliferator-activated receptor (PPAR) gamma and retinoid X receptor (RXR) agonists have complementary effects on glucose and lipid metabolism in human skeletal muscle.
abstract: OBJECTIVE
  To determine the independent and potentially synergistic effects of agonists for PPAR gamma and RXR on glucose and lipid metabolism, as well as gene expression, in human skeletal muscle cell cultures.
  
  
  METHODS
  Fully differentiated myotubes from non-diabetic subjects and subjects with Type II (non-insulin-dependent) diabetes mellitus were chronically (2 days) treated with LG100268 (4 mumol/l), an RXR agonist, or troglitazone (4.6 mumol/l), a PPAR gamma agonist or both, to determine the effects on glucose uptake, activity of glycogen synthase and palmitate oxidation.
  
  
  RESULTS
  The combination of both agents increased glucose uptake (60 +/- 9% compared to control subjects) but not either agent alone (16 +/- 9 and 26 +/- 6% for LG100268 and troglitazone, p < 0.01, respectively). The agent LG100268 alone had little effect on the activity of glycogen synthase but the effect of troglitazone increased with LG100268 (p < 0.05). With chronic exposure, LG100268 upregulated palmitate oxidation (53 +/- 12% increase, p < 0.005), in a way similar to troglitazone (68 +/- 23%, p < 0.005). Synergism was observed when both agonists were combined (146 +/- 38%, p < 0.005 vs either agent alone). Treatment with either agent led to about a twofold increase in the expression of fatty acid transporter (FAT/CD36). Troglitazone upregulated PPAR gamma protein expression, whereas LG100268 had no effect. Furthermore, neither LG100268 nor troglitazone had any effect on the protein expression of RXR isoforms or PPAR alpha.
  
  
  CONCLUSIONS
  Co-activation of PPAR gamma and RXR results in additive or synergistic effects on glucose and lipid metabolism in skeletal muscle, but unlike troglitazone, LG100268 does not alter expression of its own receptor.
authors.affiliation: Veterans Affairs San Diego Healthcare System, San Diego and Department of Medicine, University of California, San Diego, California, USA.
authors.forename: B S
authors.initials: BS
authors.lastname: Cha
authors.forename: T P
authors.initials: TP
authors.lastname: Ciaraldi
authors.forename: L
authors.initials: L
authors.lastname: Carter
authors.forename: S E
authors.initials: SE
authors.lastname: Nikoulina
authors.forename: S
authors.initials: S
authors.lastname: Mudaliar
authors.forename: R
authors.initials: R
authors.lastname: Mukherjee
authors.forename: J R
authors.initials: JR
authors.lastname: Paterniti
authors.forename: R R
authors.initials: RR
authors.lastname: Henry
mesh_terms: D018955:CD36 Antigens / Q000378:metabolism; D002839:Chromans / Q000008:administration & dosage / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006006:Glycogen Synthase / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D009539:Nicotinic Acids / Q000008:administration & dosage / Q000494:pharmacology; D010084:Oxidation-Reduction; D019308:Palmitic Acid / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000187:drug effects / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000819:agonists* / Q000187:drug effects / Q000378:metabolism; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000494:pharmacology; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists* / Q000187:drug effects / Q000378:metabolism; D000077288:Troglitazone
chemical_list: D018955:CD36 Antigens; D002839:Chromans; D009539:Nicotinic Acids; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D019308:Palmitic Acid; D006006:Glycogen Synthase; D000077288:Troglitazone; D005947:Glucose; C095104:LG 100268