[The molecular mechanisms by which PPAR gamma/RXR inhibitors improve insulin resistance].
Potent activation of PPAR gamma by thiazolidinediones(TZD) increases TG content of WAT, thereby decreasing TG content of liver/muscle, leading to amelioration of insulin resistance at the expense of obesity. Moderate reduction of PPAR gamma activity by PPAR gamma/RXR inhibitors decreases TG content of WAT/muscle/liver due to increased leptin and increase in fatty-acid combustion and decrease in lipogenesis, thereby ameliorating HF diet-induced obesity and insulin resistance. Moreover, PPAR gamma/RXR inhibitors decrease lipogenesis in WAT, while TZD stimulate adipocyte differentiation and apoptosis, thereby both preventing adipocyte hypertrophy, which is associated with alleviation of insulin resistance presumably due to decreases in FFA, and TNF alpha, and upregulation of adiponectin. We conclude that although by different mechanisms, both PPAR gamma/RXR inhibitors and PPAR gamma agonist improve insulin resistance, which is associated with decreased TG content of muscle/liver and prevention of adipocyte hypertrophy.
Yamauchi
T
T
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo.
Kadowaki
T
T
D017667:Adipocytes / Q000166:cytology; D052242:Adiponectin; D000818:Animals; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D002454:Cell Differentiation; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D004734:Energy Metabolism / Q000235:genetics; D006801:Humans; D007333:Insulin Resistance; D036341:Intercellular Signaling Peptides and Proteins; D011110:Polymorphism, Genetic; D011506:Proteins / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors*; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics; D014280:Triglycerides / Q000378:metabolism; D015854:Up-Regulation
D052242:Adiponectin; D001565:Benzoates; D001713:Biphenyl Compounds; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014280:Triglycerides; C438269:diazepinylbenzoic acid