Differential activation of peroxisome proliferator-activated receptor-gamma by troglitazone and rosiglitazone.
The antidiabetic thiazolidinediones, which include troglitazone and rosiglitazone, are ligands for the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-gamma and exert their antihyperglycemic effects by regulation of PPAR-gamma-responsive genes. We report here that PPAR-gamma activation by troglitazone depends on the experimental setting. Troglitazone acts as a partial agonist for PPAR-gamma in transfected muscle (C2C12) and kidney (HEK 293T) cells, producing a submaximal transcriptional response (1.8- to 2.5-fold activation) compared with rosiglitazone (7.4- to 13-fold activation). Additionally, troglitazone antagonizes rosiglitazone-stimulated PPAR-gamma transcriptional activity. Limited protease digestion of PPAR-gamma suggests conformational differences in the receptor bound to troglitazone versus rosiglitazone. Consistent with this finding, an in vitro coactivator association assay demonstrated that troglitazone-bound PPAR-gamma recruited the transcriptional coactivators p300 and steroid receptor coactivator 1 less efficiently than rosiglitazone-bound receptor. In contrast to these observations, troglitazone behaves as a full agonist of PPAR-gamma in 3T3L1 adipocytes. Two-dimensional protein gel electrophoresis demonstrated that troglitazone and rosiglitazone regulated distinct but overlapping sets of genes in several cell types. Thus, troglitazone may behave as a partial agonist under certain physiological circumstances and as a full agonist in others. These differences could be caused by variations in the amount of specific cofactors, differences in PPAR response elements, or the presence of different isoforms of PPAR-gamma.
Camp
H S
HS
Department of Cell Biology, Warner-Lambert Company, Ann Arbor, Michigan, USA.
Li
O
O
Wise
S C
SC
Hong
Y H
YH
Frankowski
C L
CL
Shen
X
X
Vanbogelen
R
R
Leff
T
T
D016475:3T3 Cells; D000818:Animals; D002460:Cell Line; D002839:Chromans / Q000494:pharmacology*; D015180:Electrophoresis, Gel, Two-Dimensional; D004847:Epithelial Cells; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007668:Kidney; D051379:Mice; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D000077288:Troglitazone; D014357:Trypsin / Q000378:metabolism
D002839:Chromans; D007004:Hypoglycemic Agents; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D014357:Trypsin; D000077288:Troglitazone