MBX-102/JNJ39659100, a Novel Non-TZD Selective Partial PPAR-𝛾 Agonist Lowers Triglyceride Independently of PPAR-𝛼 Activation

Abstract

MBX-102/JNJ-39659100 (MBX-102) is a selective, partial PPAR-𝛾 agonist that lowers glucose in the absence of some of the side effects, such as weight gain and edema, that are observed with the TZDs. Interestingly MBX-102 also displays pronounced triglyceride lowering in preclinical rodent models and in humans. Although in vitro reporter gene studies indicated that MBX-102 acid is a highly selective PPAR-𝛾 agonist that lacks PPAR-𝛼 activity, we sought to determine if PPAR-𝛼 activation in vivo could possibly contribute to the triglyceride lowering abilities of MBX-102. In vivo studies using ZDF and ZF rats demonstrated that MBX-102 lowered plasma triglycerides. However in ZF rats, MBX-102 had no effect on liver weight or on hepatic expression levels of PPAR-𝛼 target genes. Further in vitro studies in primary human hepatocytes supported these findings. Finally, the ability of MBX-102 to lower triglycerides was maintained in PPAR-𝛼 knockout mice, unambiguously establishing that the triglyceride lowering effect of MBX-102 is PPAR-𝛼 independent. The in vivo lipid lowering abilities of MBX-102 are therefore mediated by an alternate mechanism which is yet to be determined.