title: 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.
authors.affiliation: Department of Biology, Metabolex, Inc., 3876 Bay Center Place, Hayward, CA 94545, USA.
authors.forename: Apurva
authors.initials: A
authors.lastname: Chandalia
authors.forename: Holly J
authors.initials: HJ
authors.lastname: Clarke
authors.forename: L Edward
authors.initials: LE
authors.lastname: Clemens
authors.forename: Bindu
authors.initials: B
authors.lastname: Pandey
authors.forename: Vic
authors.initials: V
authors.lastname: Vicena
authors.forename: Paul
authors.initials: P
authors.lastname: Lee
authors.forename: Brian E
authors.initials: BE
authors.lastname: Lavan
authors.forename: Francine M
authors.initials: FM
authors.lastname: Gregoire