title: Differential effects of YM440 a hypoglycemic agent on binding to a peroxisome proliferator-activated receptor gamma and its transactivation.
abstract: Peroxisome proliferator-activated receptor (PPAR) gamma is a ligand-inducible transcription factor mediating glucose and lipid metabolism. Prior studies showed that YM440 ameliorated hyperglycemia in diabetic mice without affecting body fat weight or PPARgamma transactivation. In this study we have examined further the effects of YM440 on PPARgamma binding, transactivation and conformational change. YM440, pioglitazone and rosiglitazone displaced [3H]rosiglitazone from PPARgamma with K(i) values of 4.0, 3.1, and 0.20 microM, indicating that YM440 was comparable to pioglitazone and 20-fold less potent than rosiglitazone. Although pioglitazone and rosiglitazone increased both PPARgamma transactivation in cells expressing human full-length PPARgamma2 or GAL4-PPARgamma and mRNA expression of PPARgamma responsive genes in 3T3-L1 cells, YM440 had weak effects on PPARgamma transactivation and mRNA expression being 550- to 790-fold and 36- to 110-fold less active than rosiglitazone, respectively. YM440 and rosiglitazone induced interaction between PPARgamma and the transcriptional cofactor, p300 or SRC-1, but YM440 was 151- and 1091-fold less potent than rosiglitazone, respectively. The weak transcriptional activity of YM440 was not due to poor cell permeability. Limited trypsin digestion of the full-length human PPARgamma2 with YM440 or rosiglitazone showed distinct patterns of digestion, suggesting a difference in the conformational change of PPARgamma. When db/db mice were treated with YM440 (100mg/kg) for 28 days, YM440 increased hepatic glucokinase expression but not adipose tissue FABP and UCP1 expression, indicating a tissue selective expression of PPARgamma-related genes. Unique properties regarding the binding-transactivation of PPARgamma by YM440 may lead to the hypoglycemic activity without affecting body fat weight in diabetic mice.
authors.affiliation: Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kurosaki
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Nakano
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Shimaya
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yoshida
authors.forename: Motoko
authors.initials: M
authors.lastname: Ida
authors.forename: Takayuki
authors.initials: T
authors.lastname: Suzuki
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shibasaki
authors.forename: Hisataka
authors.initials: H
authors.lastname: Shikama
mesh_terms: D016475:3T3 Cells; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D001692:Biological Transport; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D003920:Diabetes Mellitus / Q000201:enzymology; D004195:Disease Models, Animal; D050556:Fatty Acid-Binding Proteins; D029941:Fish Proteins; D005941:Glucokinase / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007473:Ion Channels; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins; D010069:Oxadiazoles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism*; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014357:Trypsin / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000071256:Uncoupling Protein 1
chemical_list: D002352:Carrier Proteins; C425124:FABP-1 protein, Lateolabrax japonicus; D050556:Fatty Acid-Binding Proteins; D029941:Fish Proteins; D007004:Hypoglycemic Agents; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D010069:Oxadiazoles; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; C406084:YM 440; D000077154:Rosiglitazone; D005941:Glucokinase; D014357:Trypsin