JTP-426467 acts as a selective antagonist for peroxisome proliferator-activated receptor gamma in vitro and in vivo.
OBJECTIVE
JTP-426467 was identified as a result of screening in search of selective antagonist for peroxisome proliferator-activated receptor gamma (PPARgamma). We examined whether JTP-426467 functioned as a PPARgamma antagonist in vitro and in vivo and investigated physiological effects of JTP-426467.


METHODS
The effect of JTP-426467 as a PPARgamma antagonist was studied in a cell-based reporter assay and an adipocyte differentiation assay. Target mRNA expression levels were determined by branched DNA (bDNA) assay. To examine the effects as a PPARgamma antagonist in vivo, a competitive study between JTP-426467 and BRL49653 (rosiglitazone), a PPARgamma agonist, was performed using KK-Ay mice. The effects of JTP-426467 alone after administration to KK-Ay mice were also explored. JTP-426467 antagonized PPARgamma activity in a reporter assay system, but not PPARalpha.


RESULTS
JTP-426467 inhibited the expression of hormone-sensitive lipase (HSL) mRNA, an adipocyte-abundant gene, but not PPARgamma itself or cyclophilin mRNA (as constitutive mRNA), and also suppressed triglyceride accumulation in differentiated stromal vascular fraction cells (SVFs). JTP-426467 antagonized PPARgamma agonistic action by BRL49653 in KK-Ay mice on high-fat diet, in terms of plasma glucose, body weight gain and interscapular brown adipose tissue (IBAT) weight. JTP-426467 alone inhibited body weight gain and decreased plasma leptin level in KK-Ay mice.


CONCLUSIONS
JTP-426467 acted as a pure and potent PPARgamma antagonist in vitro. Interestingly, JTP-426467 completely antagonized the effects of PPARgamma agonist BRL49653 in an obese diabetic model. JTP-426467 may be a useful tool for the study of PPARgamma in biological and physiological function.
Nishiu
J
J
Japan Tobacco, Central Pharmaceutical Research Institute, Takatsuki, Osaka, Japan. jun.nishiu@ims.jti.co.jp
Ito
M
M
Ishida
Y
Y
Kakutani
M
M
Shibata
T
T
Matsushita
M
M
Shindo
M
M
D017667:Adipocytes / Q000166:cytology / Q000187:drug effects; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology; D001583:Benzoxazoles / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D009765:Obesity / Q000097:blood / Q000188:drug therapy; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000235:genetics; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015430:Weight Gain / Q000187:drug effects
D019440:Anti-Obesity Agents; D001583:Benzoxazoles; D001786:Blood Glucose; D007004:Hypoglycemic Agents; C520139:JTP-426467; D020738:Leptin; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D000077154:Rosiglitazone