title: Timcodar (VX-853) Is a Non-FKBP12 Binding Macrolide Derivative That Inhibits PPARγ and Suppresses Adipogenesis.
abstract: Nutrient overload and genetic factors have led to a worldwide epidemic of obesity that is the underlying cause of diabetes, atherosclerosis, and cardiovascular disease. In this study, we used macrolide drugs such as FK506, rapamycin, and macrolide derived, timcodar (VX-853), to determine their effects on lipid accumulation during adipogenesis. Rapamycin and FK506 bind to FK506-binding proteins (FKBPs), such as FKBP12, which causes suppression of the immune system and inhibition of mTOR. Rapamycin has been previously reported to inhibit the adipogenic process and lipid accumulation. However, rapamycin treatment in rodents caused immune suppression and glucose resistance, even though the mice lost weight. Here we show that timcodar (1 μM), a non-FKBP12-binding drug, significantly (p < 0.001) inhibited lipid accumulation during adipogenesis. A comparison of the same concentration of timcodar (1 μM) and rapamycin (1 μM) showed that both are inhibitors of lipid accumulation during adipogenesis. Importantly, timcodar potently (p < 0.01) suppressed transcriptional regulators of adipogenesis, PPARγ and C/EBPα, resulting in the inhibition of genes involved in lipid accumulation. These studies set the stage for timcodar as a possible antiobesity therapy, which is rapidly emerging as a pandemic.
authors.affiliation: Center for Hypertension and Personalized Medicine, Department of Physiology & Pharmacology, University of Toledo College of Medicine, Toledo, OH 43614, USA.
authors.forename: Terry D
authors.identifier: 0000-0002-7599-1529
authors.initials: TD
authors.lastname: Hinds
authors.affiliation: Center for Hypertension and Personalized Medicine, Department of Physiology & Pharmacology, University of Toledo College of Medicine, Toledo, OH 43614, USA.
authors.forename: Kezia
authors.identifier: 0000-0002-1974-7740
authors.initials: K
authors.lastname: John
authors.affiliation: Center for Hypertension and Personalized Medicine, Department of Physiology & Pharmacology, University of Toledo College of Medicine, Toledo, OH 43614, USA.
authors.forename: Lucien
authors.initials: L
authors.lastname: McBeth
authors.affiliation: Center for Drug Design and Development, Department of Medicinal & Biological Chemistry, University of Toledo College of Pharmacy and Pharmaceutical Sciences, Toledo, OH 43606, USA.
authors.forename: Christopher J
authors.identifier: 0000-0003-2353-3013
authors.initials: CJ
authors.lastname: Trabbic
authors.affiliation: Center for Diabetes and Endocrine Research, Department of Physiology & Pharmacology, University of Toledo College of Medicine, Toledo, OH 43614, USA.
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Sanchez