title: Effects of DSP-8658, a novel selective peroxisome proliferator-activated receptors a/γ modulator, on adipogenesis and glucose metabolism in diabetic obese mice.
abstract: OBJECTIVE
  Peroxisome proliferator-activated receptors (PPARs) play a key regulating role in homeostasis. In this study, we investigated the effects of DSP-8658, a novel selective PPARa/γ modulator, on adipogenesis and glucose metabolism in diabetic obese mice and compared these effects to those of pioglitazone, a PPARγ full agonist.
  
  
  METHODS
  DSP-8658 functional activity was assessed by PPARγ-target genes expression in adipose 3T3-L1 cells and its anti-diabetic efficacy evaluated in db/db mice. The effects of DSP-8658 on adipogenesis were investigated diet induced obese (DIO) KK-A(y) mice.
  
  
  RESULTS
  DSP-8658 reduced the expression of PPARγ-target gene 11 beta hydroxysteroid dehydrogenase type 1 with an EC50 value 2.1-fold that of pioglitazone and 28.4-fold that of rosiglitazone. On the other hand, DSP-8658 increased the expression of fatty acid binding protein 4 and glycerol kinase genes with EC50 values 33-fold and >15-fold those of pioglitazone and 163-fold and >38-fold those of rosiglitazone, respectively. In db/db mice, DSP-8658, like pioglitazone, decreased blood glucose, HbA1c, and plasma triglyceride levels and increased plasma insulin concentration and pancreatic insulin contents. In DIO KK-A(y) mice, DSP-8658, unlike pioglitazone, decreased subcutaneous adipose tissue weight and mean adipocyte size. However, both DSP-8658 and pioglitazone improved blood glucose and HbA1c levels with similar efficacy. Although DSP-8658 did not change the expression levels of fatty acid transport protein 1 and glycerol kinase genes in subcutaneous adipose tissue of KK-A(y) mice, pioglitazone increased these gene expression levels.
  
  
  CONCLUSIONS
  Unlike PPARγ full agonists, DSP-8658 ameliorates blood glucose without increasing adipogenesis in diabetic obesity mice.
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd. Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Goto
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd. Osaka, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Nakayama
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd. Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Yamanaka
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd. Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Takata
authors.affiliation: Personnel, Sumitomo Dainippon Pharma Co., Ltd. Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Takazawa
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd. Osaka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Drug Development Division, Sumitomo Dainippon Pharma Co., Ltd. Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Maruta
authors.affiliation: Center for Drug Discovery and Development National Institute of Biomedical Innovation, Osaka, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Nagata
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd. Osaka, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Nagamine
authors.affiliation: Global Strategy & Business Development, Sumitomo Dainippon Pharma Co., Ltd. Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Tsuchida
authors.affiliation: Center for Drug Discovery and Development National Institute of Biomedical Innovation, Osaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kato
mesh_terms: D042842:11-beta-Hydroxysteroid Dehydrogenases; D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000378:metabolism*; D051379:Mice; D008820:Mice, Obese; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D000077205:Pioglitazone; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D047493:PPAR alpha; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D042842:11-beta-Hydroxysteroid Dehydrogenases; D005947:Glucose; D000077205:Pioglitazone