JTP-426467 acts as a selective antagonist for peroxisome proliferator-activated receptor gamma in vitro and in vivo.

Abstract

AIM:

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.

• Authors: J Nishiu, M Ito, Y Ishida, M Kakutani, T Shibata, M Matsushita, M Shindo
• Journal: Diabetes, obesity & metabolism (Diabetes Obes Metab) Vol. 8 Issue 5 Pg. 508-16 (Sep 2006) ISSN: 1462-8902 [Print] England
• PMID: 16918585 (Publication Type: Journal Article)

Chemical References

• Anti-Obesity Agents
• Benzoxazoles
• Blood Glucose
• Hypoglycemic Agents
• JTP-426467
• Leptin
• PPAR gamma
• RNA, Messenger
• Thiazolidinediones
• Rosiglitazone

Topics

• Adipocytes (cytology, drug effects)
• Adipogenesis (drug effects)
• Animals
• Anti-Obesity Agents (pharmacology)
• Benzoxazoles (pharmacology)
• Blood Glucose (drug effects, metabolism)
• Cell Differentiation (drug effects)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Gene Expression Regulation (drug effects)
• Genes, Reporter
• HeLa Cells
• Humans
• Hypoglycemic Agents (pharmacology)
• Leptin (blood)
• Male
• Mice
• Obesity (blood, drug therapy)
• PPAR gamma (agonists, antagonists & inhibitors)
• RNA, Messenger (genetics)
• Rosiglitazone
• Thiazolidinediones (antagonists & inhibitors, pharmacology)
• Weight Gain (drug effects)