A new thiazolidinedione, NC-2100, which is a weak PPAR-gamma activator, exhibits potent antidiabetic effects and induces uncoupling protein 1 in white adipose tissue of KKAy obese mice.
Thiazolidinediones (TZDs) reduce insulin resistance in type 2 diabetes by increasing peripheral uptake of glucose, and they bind to and activate the transcriptional factor peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Studies have suggested that TZD-induced activation of PPAR-gamma correlates with antidiabetic action, but the mechanism by which the activated PPAR-gamma is involved in reducing insulin resistance is not known. To examine whether activation of PPAR-gamma directly correlates with antidiabetic activities, we compared the effects of 4 TZDs (troglitazone, pioglitazone, BRL-49653, and a new derivative, NC-2100) on the activation of PPAR-gamma in a reporter assay, transcription of the target genes, adipogenesis, plasma glucose and triglyceride levels, and body weight using obese KKAy mice. There were 10- to 30-fold higher concentrations of NC-2100 required for maximal activation of PPAR-gamma in a reporter assay system, and only high concentrations of NC-2100 weakly induced transcription of the PPAR-gamma but not PPAR-alpha target genes in a whole mouse and adipogenesis of cultured 3T3L1 cells, which indicates that NC-2100 is a weak PPAR-gamma activator. However, low concentrations of NC-2100 efficiently lowered plasma glucose levels in KKAy obese mice. These results strongly suggest that TZD-induced activation of PPAR-gamma does not directly correlate with antidiabetic (glucose-lowering) action. Furthermore, NC-2100 caused the smallest body weight increase of the 4 TZDs, which may be partly explained by the finding that NC-2100 efficiently induces uncoupling protein (UCP)-2 mRNA and significantly induces UCP1 mRNA in white adipose tissue (WAT). NC-2100 induced UCP1 efficiently in mesenteric WAT and less efficiently in subcutaneous WAT, although pioglitazone and troglitazone also slightly induced UCP1 only in mesenteric WAT. These characteristics of NC-2100 should be beneficial for humans with limited amounts of brown adipose tissue.
Fukui
Y
Y
Department of Biochemistry, School of Pharmaceutical Sciences, Toho University, Chiba, Japan.
Masui
S
S
Osada
S
S
Umesono
K
K
Motojima
K
K
D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007473:Ion Channels; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D024101:Mitochondrial Proteins; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology* / Q000627:therapeutic use*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use*; D014157:Transcription Factors / Q000502:physiology*; D000071256:Uncoupling Protein 1
D002352:Carrier Proteins; D007004:Hypoglycemic Agents; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011804:Quinolines; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D014157:Transcription Factors; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; C411578:NC 2100