diazepinylbenzoic-acid and Insulin-Resistance

PPARgamma is a molecular target of thiazolidinedione class of antidiabetic drugs. Although activation of PPARgamma by thiazolidinedione improves insulin resistance in obese subjects, PPARgamma heterozygous knockout mice were resistant to a high-fat diet induced obesity and insulin resistance, suggesting that a moderate reduction of PPARgamma activity could be beneficial for the treatment of obesity and insulin resistance. This hypothesis was supported by genetic evidences consistently showing that the common Pro12Ala variant of PPARgamma2, which causes a moderate reduction in transcriptional activity and adipogenic potential, has been associated with reduced weight gain and improved insulin sensitivity. We here review PPARgamma antagonism as a potential remedy for obesity and diabetes.

Topics: Animals; Benzoates; Biphenyl Compounds; Humans; Insulin Resistance; Obesity; PPAR gamma

Topics: Adipocytes; Animals; Benzoates; Biphenyl Compounds; Cell Differentiation; Diabetes Mellitus, Type 2; Fatty Acids; Humans; Insulin Resistance; Polymorphism, Genetic; Receptors, Cytoplasmic and Nuclear; Transcription Factors

Topics: Animals; Benzoates; Biphenyl Compounds; Clinical Trials as Topic; Drug Design; Humans; Hypoglycemic Agents; Insulin Resistance; Pioglitazone; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Retinoid X Receptors; Thiazoles; Thiazolidinediones; Transcription Factors

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.

Topics: Adipocytes; Adiponectin; Animals; Benzoates; Biphenyl Compounds; Cell Differentiation; Diabetes Mellitus, Type 2; Energy Metabolism; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Polymorphism, Genetic; Proteins; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Retinoid X Receptors; Transcription Factors; Triglycerides; Up-Regulation

PPARgamma is a ligand-activated transcription factor and functions as a heterodimer with a retinoid X receptor (RXR). Supraphysiological activation of PPARgamma by thiazolidinediones can reduce insulin resistance and hyperglycemia in type 2 diabetes, but these drugs can also cause weight gain. Quite unexpectedly, a moderate reduction of PPARgamma activity observed in heterozygous PPARgamma-deficient mice or the Pro12Ala polymorphism in human PPARgamma, has been shown to prevent insulin resistance and obesity induced by a high-fat diet. In this study, we investigated whether functional antagonism toward PPARgamma/RXR could be used to treat obesity and type 2 diabetes. We show herein that an RXR antagonist and a PPARgamma antagonist decrease triglyceride (TG) content in white adipose tissue, skeletal muscle, and liver. These inhibitors potentiated leptin's effects and increased fatty acid combustion and energy dissipation, thereby ameliorating HF diet-induced obesity and insulin resistance. Paradoxically, treatment of heterozygous PPARgamma-deficient mice with an RXR antagonist or a PPARgamma antagonist depletes white adipose tissue and markedly decreases leptin levels and energy dissipation, which increases TG content in skeletal muscle and the liver, thereby leading to the re-emergence of insulin resistance. Our data suggested that appropriate functional antagonism of PPARgamma/RXR may be a logical approach to protection against obesity and related diseases such as type 2 diabetes.

Topics: 3T3 Cells; Adipose Tissue; Animals; Benzhydryl Compounds; Benzoates; Biphenyl Compounds; Diabetes Mellitus, Type 2; Epoxy Compounds; Fatty Acids; Hyperglycemia; Hypoglycemic Agents; Insulin Resistance; Leptin; Mice; Mice, Knockout; Nicotinic Acids; Obesity; Receptors, Adrenergic, beta-3; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Retinoid X Receptors; Rosiglitazone; Tetrahydronaphthalenes; Thiazoles; Thiazolidinediones; Transcription Factors