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	Eiji Kurosaki, Ryosuke Nakano, Akiyoshi Shimaya, Shigeru Yoshida, Motoko Ida, Takayuki Suzuki, Masayuki Shibasaki, Hisataka Shikama
Journal	Biochemical pharmacology (Biochem Pharmacol) Vol. 65 Issue 5 Pg. 795-805 (Mar 01 2003) ISSN: 0006-2952 [Print] England
PMID	12628477 (Publication Type: Journal Article)
Chemical References	Carrier Proteins FABP-1 protein, Lateolabrax japonicus Fatty Acid-Binding Proteins Fish Proteins Hypoglycemic Agents Ion Channels Membrane Proteins Mitochondrial Proteins Oxadiazoles RNA, Messenger Receptors, Cytoplasmic and Nuclear Thiazoles Thiazolidinediones Transcription Factors UCP1 protein, human Ucp1 protein, mouse Uncoupling Protein 1 YM 440 Rosiglitazone Glucokinase Trypsin
Topics	3T3 Cells Adipose Tissue (drug effects, metabolism) Animals Binding Sites Biological Transport Carrier Proteins (biosynthesis, genetics) Diabetes Mellitus (enzymology) Disease Models, Animal Fatty Acid-Binding Proteins Fish Proteins Glucokinase (metabolism) Humans Hypoglycemic Agents (pharmacology) Ion Channels Liver (drug effects, enzymology) Male Membrane Proteins (biosynthesis, genetics) Mice Mice, Inbred C57BL Mitochondrial Proteins Oxadiazoles (pharmacology) RNA, Messenger (biosynthesis, drug effects) Receptors, Cytoplasmic and Nuclear (drug effects, metabolism) Rosiglitazone Thiazoles (pharmacology) Thiazolidinediones Transcription Factors (drug effects, metabolism) Transcriptional Activation (drug effects) Trypsin (metabolism) Tumor Cells, Cultured Uncoupling Protein 1

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