title: A Novel Peroxisome Proliferator-activated Receptor (PPAR)α Agonist and PPARγ Antagonist, Z-551, Ameliorates High-fat Diet-induced Obesity and Metabolic Disorders in Mice.
abstract: A novel peroxisome proliferator-activated receptor (PPAR) modulator, Z-551, having both PPARα agonistic and PPARγ antagonistic activities, has been developed for the treatment of obesity and obesity-related metabolic disorders. We examined the effects of Z-551 on obesity and the metabolic disorders in wild-type mice on the high-fat diet (HFD). In mice on the HFD, Z-551 significantly suppressed body weight gain and ameliorated insulin resistance and abnormal glucose and lipid metabolisms. Z-551 inhibited visceral fat mass gain and adipocyte hypertrophy, and reduced molecules involved in fatty acid uptake and synthesis, macrophage infiltration, and inflammation in adipose tissue. Z-551 increased molecules involved in fatty acid combustion, while reduced molecules associated with gluconeogenesis in the liver. Furthermore, Z-551 significantly reduced fasting plasma levels of glucose, triglyceride, free fatty acid, insulin, and leptin. To elucidate the significance of the PPAR combination, we examined the effects of Z-551 in PPARα-deficient mice and those of a synthetic PPARγ antagonist in wild-type mice on the HFD. Both drugs showed similar, but weaker effects on body weight, insulin resistance and specific events provoked in adipose tissue compared with those of Z-551 as described above, except for lack of effects on fasting plasma triglyceride and free fatty acid levels. These findings suggest that Z-551 ameliorates HFD-induced obesity, insulin resistance, and impairment of glucose and lipid metabolisms by PPARα agonistic and PPARγ antagonistic activities, and therefore, might be clinically useful for preventing or treating obesity and obesity-related metabolic disorders such as insulin resistance, type 2 diabetes, and dyslipidemia.
authors.affiliation: From the Departments of Diabetes and Metabolic Diseases, Graduate School of Medicine and.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Shiomi
authors.affiliation: From the Departments of Diabetes and Metabolic Diseases, Graduate School of Medicine and Integrated Molecular Science on Metabolic Diseases, 22nd Century Medical and Research Center, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Yamauchi
authors.affiliation: From the Departments of Diabetes and Metabolic Diseases, Graduate School of Medicine and.
authors.forename: Masato
authors.initials: M
authors.lastname: Iwabu
authors.affiliation: From the Departments of Diabetes and Metabolic Diseases, Graduate School of Medicine and.
authors.forename: Miki
authors.initials: M
authors.lastname: Okada-Iwabu
authors.affiliation: From the Departments of Diabetes and Metabolic Diseases, Graduate School of Medicine and.
authors.forename: Ryo
authors.initials: R
authors.lastname: Nakayama
authors.affiliation: Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., Saitama 360-0111, Japan, and.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Orikawa
authors.affiliation: the Laboratory of Biofunctional Imaging, Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
authors.forename: Yoshichika
authors.initials: Y
authors.lastname: Yoshioka
authors.affiliation: Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., Saitama 360-0111, Japan, and.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: From the Departments of Diabetes and Metabolic Diseases, Graduate School of Medicine and.
authors.forename: Kohjiro
authors.initials: K
authors.lastname: Ueki
authors.affiliation: From the Departments of Diabetes and Metabolic Diseases, Graduate School of Medicine and kadowaki-3im@h.u-tokyo.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D000818:Animals; D002460:Cell Line; D059305:Diet, High-Fat / Q000009:adverse effects*; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy* / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000037:antagonists & inhibitors*
chemical_list: D007328:Insulin; D047493:PPAR alpha; D047495:PPAR gamma; D005947:Glucose
keywords: adipose tissue; diabetes; dyslipidemia; insulin resistance; liver; metabolic disorders; obesity; peroxisome proliferator-activated receptor (PPAR)