title: Peroxisome proliferator-activated receptor γ (PPARγ)-independent specific cytotoxicity against immature adipocytes induced by PPARγ antagonist T0070907.
abstract: Peroxisome proliferator-activated receptor γ (PPARγ) plays indispensable roles in adipogenesis, which is frequently impaired under pathological conditions such as non-alcoholic steatohepatitis (NASH). Thus, a potent PPARγ antagonist, T0070907 is known as a useful tool for understanding such pathological conditions, while T007097 was also suggested to have PPARγ-independent actions. In the present study, we found that T0070907 inhibited adipogenesis concomitantly with the induction of rapid apoptosis of immature adipocytes within 2 h, whereas another PPARγ antagonist, SR-202 did not show such cytotoxicity. However, T0070907 did not affect the viabilities of pre-adipocytes, mature adipocytes, and NIH-3T3 fibroblasts. The cytotoxic effect of T0070907 was not inhibited by GW1929, a PPARγ agonist, but was inhibited by α-tocopherol, which was previously shown to provide clinical benefit to NASH patients. Interestingly, treatment with high amounts of α-tocopherol alone slightly increased the cellular lipid content in mature adipocytes, but did not affect PPARγ-dependent luciferase reporter expression in COS-7 cells. Moreover, other lipophilic antioxidants, such as tocotrienols, tert-butylhydroquinone, and butylated hydroxyanisole, also inhibited T0070907-induced apoptosis like α-tocopherol. Consequently, it is suggested that T0070907 efficiently inhibits adipogenesis, not only via PPARγ-dependent manner, but also through the induction of apoptosis specifically against immature adipocytes via oxidative stress in a PPARγ-independent manner.
authors.affiliation: Department of Biophysical Chemistry, Kyoto Pharmaceutical University.
authors.forename: Arisa
authors.initials: A
authors.lastname: Kawahara
authors.forename: Naoko
authors.initials: N
authors.lastname: Haraguchi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsuchiya
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Susumu
authors.initials: S
authors.lastname: Hama
authors.forename: Kentaro
authors.initials: K
authors.lastname: Kogure
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D019556:COS Cells; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D017930:Genes, Reporter; D051379:Mice; D041681:NIH 3T3 Cells; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*
chemical_list: D001549:Benzamides; D047495:PPAR gamma; D011725:Pyridines; C458508:T 0070907