Effects of DSP-8658, a novel selective peroxisome proliferator-activated receptors a/γ modulator, on adipogenesis and glucose metabolism in diabetic obese mice.

Abstract

AIMS/INTRODUCTION:

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.

MATERIALS AND 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.

CONCLUSION:

Unlike PPARγ full agonists, DSP-8658 ameliorates blood glucose without increasing adipogenesis in diabetic obesity mice.

• Authors: T Goto, R Nakayama, M Yamanaka, M Takata, T Takazawa, K Watanabe, K Maruta, R Nagata, J Nagamine, A Tsuchida, H Kato
• Journal: Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association (Exp Clin Endocrinol Diabetes) Vol. 123 Issue 8 Pg. 492-9 (Sep 2015) ISSN: 1439-3646 [Electronic] Germany
• PMID: 26011171 (Publication Type: Journal Article)
• Copyright: © Georg Thieme Verlag KG Stuttgart · New York.

Chemical References

• PPAR alpha
• PPAR gamma
• Thiazolidinediones
• Rosiglitazone
• 11-beta-Hydroxysteroid Dehydrogenases
• Glucose
• Pioglitazone

Topics

• 11-beta-Hydroxysteroid Dehydrogenases
• 3T3-L1 Cells
• Adipogenesis (drug effects)
• Animals
• Diabetes Mellitus, Experimental (drug therapy, metabolism, pathology)
• Glucose (metabolism)
• Mice
• Mice, Obese
• PPAR alpha (agonists, metabolism)
• PPAR gamma (agonists, metabolism)
• Pioglitazone
• Rosiglitazone
• Thiazolidinediones (pharmacology)