title: Blood glucose-lowering nuclear receptor agonists only partially normalize hepatic gene expression in db/db mice.
abstract: Agonists of the nuclear receptors peroxisome proliferator-activated receptor (PPAR) gamma, PPARalpha, and liver X receptors (LXRs) reduce blood glucose in type 2 diabetic patients and comparable mouse models. Since the capacity of these drugs to normalize hepatic gene expression is not known, we compared groups of obese diabetic db/db mice treated with agonists for PPARgamma [rosiglitazone (Rosi); 10 mg/kg/day], PPARalpha [Wy 14643 (Wy; 4-chloro-6-(2,3-xylidino)-2-pyrimidinyl)thioacetic acid); 30 mg/kg/day], and LXR [T0901317 (T09; N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1(trifluoromethyl)-ethyl]phenyl]-benzenesulfonamide); 40 mg/kg/day] and from untreated nondiabetic litter mates (db/+) by oligonucleotide microarrays and quantitative reverse transcriptase-polymerase chain reaction. The 10-day treatment period of db/db mice with Rosi, Wy, and T09 altered expression of 300, 620, and 735 genes including agonist-specific target genes, respectively. However, from the 337 genes differentially regulated in untreated db/+ versus db/db animals, only 34 (10%), 51 (15%), and 82 (24%) were regulated in the direction of the db/+ group by Rosi, Wy, and T09, respectively. Gene expression normalization by drug treatment involved glucose homeostasis, lipid homeostasis, and local glucocorticoid activation. In addition, our data pointed to hitherto unknown interference of these nuclear receptors with growth hormone receptor gene expression and endoplasmic reticulum stress. However, many diabetes-associated gene alterations remained unaffected or were even aggravated by nuclear receptor agonist treatment. These results suggest that diabetes-induced gene expression is minimally reversed by potent blood glucose-lowering nuclear receptor agonists.
authors.affiliation: Clinical Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Loffler
authors.forename: Martin
authors.initials: M
authors.lastname: Bilban
authors.forename: Mark
authors.initials: M
authors.lastname: Reimers
authors.forename: Werner
authors.initials: W
authors.lastname: Waldhäusl
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Stulnig
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D007004:Hypoglycemic Agents / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D005810:Multigene Family; D020411:Oligonucleotide Array Sequence Analysis; D047495:PPAR gamma / Q000819:agonists*; D012313:RNA / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D012313:RNA