title: Diminished production of nitric oxide synthase cofactor tetrahydrobiopterin by rosiglitazone in adipocytes.
abstract: Increased nitric oxide (NO) synthesis has been proposed to participate in the generation of insulin resistance in adipose and muscle tissues. Therefore, we examined the potential rate-limiting role of tetrahydrobiopterin (BH4) in cytokine-induced NO synthesis, and the effect of peroxisome proliferator activated receptor-gamma (PPARgamma) activation using the insulin-sensitizer rosiglitazone on cytokine-induced BH4 synthesis in 3T3-L1 adipocytes. Our data indicate that modulated availability of the mandatory nitric oxide synthase (NOS) cofactor BH4 affected cytokine-induced NO generation. Semiquantitative linear range reverse transcription polymerase chain reaction (RT-PCR) analysis demonstrated that rosiglitazone not only reduced inducible nitric oxide synthase (iNOS) mRNA transcription, but also guanosine triphosphate cyclohydrolase (GTPCH), the rate-limiting and controlling step of BH4 synthesis. Accordingly, intracellular BH4 concentration was reduced by 45% following rosiglitazone treatment. Furthermore, we observed a transient inhibitory effect of natural PPARgamma ligand 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PJ2) on cytokine-mediated iNOS and GTPCH induction. Thus, the inhibition of cytokine-induced NO synthesis by rosiglitazone is at least in part attributable to reduced availability of BH4, the synthesis of which might represent a potential new target in the treatment of type 2 diabetes and insulin resistance.
authors.affiliation: Department of Research and Division of Endocrinology, Diabetology and Clinical Nutrition, University Hospitals, 4031 Basel, Switzerland. philippe.linscheid@unibas.ch
authors.forename: Philippe
authors.initials: P
authors.lastname: Linscheid
authors.forename: Ulrich
authors.initials: U
authors.lastname: Keller
authors.forename: Nenad
authors.initials: N
authors.lastname: Blau
authors.forename: Dominik J
authors.initials: DJ
authors.lastname: Schaer
authors.forename: Beat
authors.initials: B
authors.lastname: Müller
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D001708:Biopterins; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; C003402:sapropterin