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A New Thiazolidinedione, NC-2100, Which Is a Weak PPAR

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A New Thiazolidinedione, NC-2100, Which Is a Weak PPAR A New Thiazolidinedione, NC-2100, Which Is a Weak PPAR-␥ Activator, Exhibits Potent Antidiabetic Effects and Induces Uncoupling Protein 1 in White Adipose Tissue of KKAy Obese Mice Yuka Fukui, Sei-ichiro Masui, Shiho Osada, Kazuhiko Umesono, and Kiyoto Motojima Thiazolidinediones (TZDs) reduce insulin resistance in in subcutaneous WAT, although pioglitazone and trogli- type 2 diabetes by increasing peripheral uptake of glu- tazone also slightly induced UCP1 only in mesenteric cose, and they bind to and activate the transcriptional WAT. These characteristics of NC-2100 should be bene- factor peroxisome proliferator-activated receptor-␥ ficial for humans with limited amounts of brown adipose (PPAR-␥). Studies have suggested that TZD-induced tissue. Diabetes 49:759–767, 2000 activation of PPAR-␥ correlates with antidiabetic action, but the mechanism by which the activated PPAR-␥ is involved in reducing insulin resistance is not known. To examine whether activation of PPAR-␥ directly correlates ype 2 diabetes is characterized by increased blood with antidiabetic activities, we compared the effects of glucose levels that cannot be adequately con- 4 TZDs (troglitazone, pioglitazone, BRL-49653, and a trolled by insulin or insulin secretion–stimulating new derivative, NC-2100) on the activation of PPAR-␥ in sulfonylureas (1,2). To prevent diabetes-induced a reporter assay, transcription of the target genes, adi- T complications such as coronary heart disease, blindness, and pogenesis, plasma glucose and triglyceride levels, and kidney failure, new drugs that reduce peripheral insulin resis- body weight using obese KKAy mice. There were 10- to tance have been developed (3,4). Thiazolidinedione (TZD) 30-fold higher concentrations of NC-2100 required for derivatives appear to increase peripheral uptake of glucose, maximal activation of PPAR-␥ in a reporter assay system, and only high concentrations of NC-2100 weakly induced which reduces insulin resistance (3,5). However, how TZDs transcription of the PPAR-␥ but not PPAR-␣ target increase glucose uptake and their contribution to the reduc- genes in a whole mouse and adipogenesis of cultured tion of insulin resistance are unclear. On the other hand, TZDs 3T3L1 cells, which indicates that NC-2100 is a weak have recently been shown to directly bind to and activate a PPAR-␥ activator. However, low concentrations of transcriptional factor, peroxisome proliferator-activated NC-2100 efficiently lowered plasma glucose levels in receptor-␥ (PPAR-␥) (6–8). PPARs have unique tissue-specific KKAy obese mice. These results strongly suggest that roles in lipid homeostasis. PPAR-␣ is expressed at high levels TZD-induced activation of PPAR-␥ does not directly cor- in the liver (a tissue with a high capacity for ␤-oxidation of fatty relate with antidiabetic (glucose-lowering) action. Fur- acids), and its roles include involvement in fatty acid catabo- thermore, NC-2100 caused the smallest body weight lism (9,10). PPAR-␥ is most abundant in adipose tissues and increase of the 4 TZDs, which may be partly explained by the finding that NC-2100 efficiently induces uncoupling plays an important role in adipogenesis. The natural ligands protein (UCP)-2 mRNA and significantly induces UCP1 for PPARs have not been definitively identified, although bind- mRNA in white adipose tissue (WAT). NC-2100 induced ing of ligands is required for transcriptional activation. TZDs UCP1 efficiently in mesenteric WAT and less efficiently as well as prostaglandin J2 derivatives are artificial ligands for PPAR-␥ and promote adipogenesis in cell cultures (6,7,11). From the Department of Biochemistry (Y.F., K.M.), School of Pharmaceu- Studies have suggested that TZD-induced activation of tical Sciences, Toho University, Chiba; the Institute for Virus Research PPAR-␥ correlates with adipogenic activities and with antidi- (S.O., K.U.), Kyoto University, Kyoto; and the Research Laboratories (Y.F., abetic actions (12). However, these results were based on a lim- S.M.), Nippon Chemiphar Company, Saitama, Japan. ited number of TZD derivatives, and how the activated Address correspondence and reprint requests to Kiyoto Motojima, PhD, Department of Biochemistry, School of Pharmaceutical Sciences, Toho PPAR-␥ is involved in increasing peripheral glucose uptake University, Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan. E-mail: moto- activities is unclear. [email protected]. In this study, we analyzed a novel TZD, NC-2100, that weakly Received for publication 31 December 1999 and accepted in revised ␥ form 24 January 2000. activates PPAR- . By comparing the effects of TZDs with vari- A-FAB, adipocyte fatty acid binding protein; apo(E), apolipoprotein(E); ous PPAR-␥ agonist activities on the plasma glucose levels of BAT, brown adipose tissue; CTE-1, cytosolic acyl-CoA thioesterase; DMEM, KKAy obese mice (13), we examined whether TZD-induced Dulbecco’s modified Eagle’s medium; FATP, fatty acid transport protein; ␥ FCS, fetal calf serum; GPDH, glycerol-3-phosphate dehydrogenase; HD, per- activation of PPAR- directly correlates with adipogenic activ- oxisomal hydratase-dehydrogenase; H-FAB, heart muscle–type fatty acid ities and with antidiabetic action. We also examined possible binding protein; LBD, ligand binding domain; LPL, lipoprotein lipase; PCR, mechanisms to explain why some but not all TZDs do not pro- polymerase chain reaction; PPAR-␥, peroxisome proliferator-activated mote obesity despite their similar antidiabetic activities receptor-␥; RT, reverse transcription; TZD, thiazolidinedione; UCP, uncoupling protein; VLACS, very-long-chain acyl-CoA synthetase; WAT, white adipose tis- because the TZDs had diverse effects on body and fat weights, sue; WY14,643, [4-choloro-6-(2,3-xylidino)-2-pyrimidinyl-thio]acetic acid. and some reports have shown that troglitazone, the first TZD to DIABETES, VOL. 49, MAY 2000 759 A NEW TZD INDUCES UCP1 IN WAT a control powder diet (MF; Oriental Kobo, Tokyo) or a diet containing 0.5% clofibrate, 0.01 or 0.03% pioglitazone, 0.1 or 0.3% troglitazone, or 0.03 or 0.1% NC-2100 for 8 or 14 days, respectively. All of the animals were killed at day 9 to extract total RNA or at day 15 for the determination of fat mass. Food intake was measured every day. Cell culture and adipocyte differentiation assay. NIH3T3L1 mouse fibro- blasts (American Type Culture Collection, Rockville, MD) were maintained in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal calf serum (FCS) and 1 mg/l gentamicin. The cells were seeded and grown to con- fluence in a 24-well culture plate in a 5% CO2 atmosphere at 37°C. At post- confluence, the medium was changed to DMEM/5% FCS supplemented with 0.5 mmol/l 1-methyl-3-isobutylxanthin, 0.5 µmol/l dexamethasone, and 1 mg/l gentamicin for 48h. The medium was then treated with test chemicals in DMEM/5% FCS (23). The activities of glycerol-3-phosphate dehydrogenase (GPDH) in the cells were measured at 9 days postconfluence as described (24). Transient transfection reporter assay. CV-1 cells were tranfected with the (GAL4-UASx4)-TK-luciferase reporter vector (25), sPG-GAL4-mPPAR-␣-ligand binding domain (LBD) or sPG-GAL4-mPPAR-␥-LBD (26) expression vectors, or pCMX-␤GAL-␤-galactosidase expression vector by liposomal delivery (1,2- dimyristyloxypropyl-3-dimethyl-hydroxy ethyl ammonium bromide [Gibco BRL, Rockville, MD]). NC-2100 or typical PPAR activators were added 6 h after transfection at concentrations described in the figure legends. At 10 h after the addition of the compounds, the transfected cells were lysed, and luciferase and ␤-galactosidase activities were determined. Results were normalized to ␤-galac- tosidase activity (26). RNA preparation and Northern blot analysis. The animals were killed by decapitation. Liver, intestine, lumbar subcutaneous WAT, mesenteric WAT, and interscapular BAT were removed and were quickly frozen in liquid nitrogen. The samples were stored at –80°C until extraction of total RNA. Total RNA was prepared from the liver, intestine, adipose tissues, or the cultured NIH3T3L1 cells by the acid guanidium thiocyanate-phenol-chloroform extraction method (27). Northern blot analysis was carried out essentially as previously described (28). The cDNA probes included peroxisomal hydratase-dehydrogenase (HD) bifunctional enzyme, apolipoprotein(E) [apo(E)], apo (AIV), adipocyte fatty acid binding protein (A-FAB), fatty acid transport protein (FATP), lipoprotein lipase (LPL), and UCP2 and have been previously described (29). The cDNAs for UCP1, UCP3, cytosolic acyl-CoA thioesterase (CTE-1), very-long-chain acyl-CoA synthetase (VLACS), and ribosomal protein S14 were obtained by cloning polymerase chain reaction (PCR) products of cDNA synthesized from the livers of mice fed with [4-choloro-6-(2,3-xylidino)-2-pyrimidinyl-thio]acetic acid (WY14,643) (Tokyo- Kasei, Tokyo) as previously described (29). The synthetic oligonucleotides used to amplify respective cDNA sequences were 5Ј-TACACGGGGACCTAC AATGCT and 5Ј-TCGCACAGCTTGGTACGCTT for UCP1 (corresponding to nucleotide numbers from 691 to 978 of the published mouse sequence) (30) (GenBank accession number U63419), 5Ј-TGCACCGCCAGATGAGTTTTG and 5Ј-GGGAGCGTTCATGTATCGGG for UCP3 (corresponding to nucleo- tide numbers from 432 to 931 of the published mouse sequence) (31) (Gen- Ј FIG. 1. Structures of NC-2100, troglitazone, pioglitazone, and Bank accession number AB01742), 5 -AACCTGGACCCTTTCCTGGGATCA Ј BRL-49653. and 5 -GGCTCCCCTCCAAAGGTGATGTTG for CTE-1 (corresponding to nucleotide numbers from 466 to 1165 of the published
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