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ENDOCRINE AND DIABETES

Blood Glucose-Lowering Nuclear Receptor Agonists Only Partially Normalize Hepatic Gene Expression in db/db Mice

Clinical Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University Vienna, Vienna, Austria (M.L., W.W., T.M.S.); Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria (M.L., W.W., T.M.S.); Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Vienna and Ludwig Boltzmann Institute for Clinical and Experimental Oncology, Vienna, Austria (M.B.); and Laboratory of Molecular Pharmacology, National Cancer Institute, Bethesda, Maryland (M.R.)

Agonists of the nuclear receptors peroxisome proliferator-activated receptor (PPAR) , PPAR, 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 PPAR [rosiglitazone (Rosi); 10 mg/kg/day], PPAR [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.

Address correspondence to: Thomas M. Stulnig, Clinical Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria. E-mail: thomas.stulnig{at}meduniwien.ac.at

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