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.

Key words

glucose metabolism - pancreas function - type 2 diabetes

• References

• 1 Lehmann JM, Moore LB, Smith-Oliver TA et al. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem 1995; 270: 12953-12956
• 2 Yki-Järvinen H. Thiazolidinediones. New England Journal of Medicine 2004; 351: 1106-1118
• 3 Fonseca V, Foyt HL, Shen K et al. Long-term effects of troglitazone: open-label extension studies in type 2 diabetic patients. Diabetes Care 2000; 23: 354-359
• 4 Elasy TA, Griffin M. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association: response to Nesto. Diabetes Care 2004; 27: 2096 author reply 2096
• 5 Ferre P. The biology of peroxisome proliferator-activated receptors: relationship with lipid metabolism and insulin sensitivity. Diabetes 2004; 53 (Suppl. 01) S43-S50
• 6 Lehrke M, Lazar MA. The many faces of PPARgamma. Cell 2005; 123: 993-999
• 7 Berger JP, Petro AE, Macnaul KL et al. Distinct properties and advantages of a novel peroxisome proliferator-activated protein [gamma] selective modulator. Mol Endocrinol 2003; 17: 662-676
• 8 Ushiroda K, Maruta K, Kitoh M et al. Development of a new class of benzoylpyrrole-based PPARα/γ activators. Bioorganic & Medicinal Chemistry Letters 2011; 21: 220-224
• 9 Kubota N, Terauchi Y, Yamauchi T et al. Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem 2002; 277: 25863-25866
• 10 Tsuchida A, Yamauchi T, Takekawa S et al. Peroxisome proliferator-activated receptor (PPAR)alpha activation increases adiponectin receptors and reduces obesity-related inflammation in adipose tissue: comparison of activation of PPARalpha, PPARgamma, and their combination. Diabetes 2005; 54: 3358-3370
• 11 Yamanaka M, Ishikawa T, Griep A et al. PPARgamma/RXRalpha-induced and CD36-mediated microglial amyloid-beta phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice. J Neurosci 2012; 32: 17321-17331
• 12 Orasanu G, Ziouzenkova O, Devchand PR et al. The peroxisome proliferator-activated receptor-gamma agonist pioglitazone represses inflammation in a peroxisome proliferator-activated receptor-alpha-dependent manner in vitro and in vivo in mice. J Am Coll Cardiol 2008; 52: 869-881
• 13 Diani AR, Sawada G, Wyse B et al. Pioglitazone preserves pancreatic islet structure and insulin secretory function in three murine models of type 2 diabetes. Am J Physiol Endocrinol Metab 2004; 286: E116-E122
• 14 Larsen TM, Toubro S, Astrup A. PPARgamma agonists in the treatment of type II diabetes: is increased fatness commensurate with long-term efficacy?. Int J Obes Relat Metab Disord 2003; 27: 147-161
• 15 Zhang F, Lavan BE, Gregoire FM. Selective Modulators of PPAR-gamma Activity: Molecular Aspects Related to Obesity and Side-Effects. PPAR Res 2007; 2007: 32696
• 16 Higa M, Zhou YT, Ravazzola M et al. Troglitazone prevents mitochondrial alterations, beta cell destruction, and diabetes in obese prediabetic rats. Proc Natl Acad Sci U S A 1999; 96: 11513-11518
• 17 Campbell IW, Mariz S. Beta-cell preservation with thiazolidinediones. Diabetes Res Clin Pract 2007; 76: 163-176
• 18 Kawasaki F, Matsuda M, Kanda Y et al. Structural and functional analysis of pancreatic islets preserved by pioglitazone in db/db mice. Am J Physiol Endocrinol Metab 2005; 288: E510-E518
• 19 Robertson RP. Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes. J Biol Chem 2004; 279: 42351-42354
• 20 Inoue I, Goto S, Matsunaga T et al. The ligands/activators for peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARgamma increase Cu2+,Zn2+-superoxide dismutase and decrease p22phox message expressions in primary endothelial cells. Metabolism 2001; 50: 3-11
• 21 Koh EH, Kim MS, Park JY et al. Peroxisome proliferator-activated receptor (PPAR)-alpha activation prevents diabetes in OLETF rats: comparison with PPAR-gamma activation. Diabetes 2003; 52: 2331-2337
• 22 Chen W, Zhou XB, Liu HY et al. P633H, a novel dual agonist at peroxisome proliferator-activated receptors alpha and gamma, with different anti-diabetic effects in db/db and KK-Ay mice. Br J Pharmacol 2009; 157: 724-735
• 23 Iwatsuka H, Shino A, Suzuoki Z. General survey of diabetic features of yellow KK mice. Endocrinol Jpn 1970; 17: 23-35
• 24 Castle CK, Colca JR, Melchior GW. Lipoprotein profile characterization of the KKA(y) mouse, a rodent model of type II diabetes, before and after treatment with the insulin-sensitizing agent pioglitazone. Arterioscler Thromb 1993; 13: 302-309
• 25 Guan HP, Li Y, Jensen MV et al. A futile metabolic cycle activated in adipocytes by antidiabetic agents. Nat Med 2002; 8: 1122-1128
• 26 Lobo S, Wiczer BM, Smith AJ et al. Fatty acid metabolism in adipocytes: functional analysis of fatty acid transport proteins 1 and 4. J Lipid Res 2007; 48: 609-620
• 27 Staels B, Dallongeville J, Auwerx J et al. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 1998; 98: 2088-2093