diazepinylbenzoic-acid and Obesity

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

The peroxisome proliferator activated receptor-γ (PPARγ) agonist, pioglitazone (PIO), exerts anti-diabetic properties associated with increased fat mass, whereas the retinoid X receptor (RXR) antagonist HX531 demonstrates anti-obesity and anti-diabetic effects with reduced body weight and fat pad mass. The cell cycle abnormality in adipocytes has not been well-investigated in obesity or during treatment with modulators of nuclear receptors. We therefore investigated cell size and cell cycle distributions of adipocytes in vivo and examined the expression of cell cycle regulators in cultured human visceral preadipocytes. The cell size distribution and cell cycle analyses of in vivo adipocytes derived from OLETF rats demonstrated that HX531 brought about G0/G1 cell cycle arrest associated with the inhibition of cellular hypertrophy, which resulted in the reduction of fat pad mass. In contrast, PIO promoted proliferation activities associated with the increase in M + late M:G0 + G1 ratio and the appearance of both small and hypertrophied adipocytes. In cultured human visceral preadipocytes HX531 up-regulated cell cycle regulators, p53, p21(Cip1), cyclin D1, Fbxw7 and Skp2, which are known contributors towards G0 /G1 cell cycle arrest. The knockdown of p53 with a shRNA lentivirus reversed the HX531-induced up-regulation of p21(Cip1), which is one of the major p53-effector molecules. We conclude that HX531 exerts anti-obesity and anti-diabetes properties by up-regulating the p53-p21(Cip1) pathway, resulting in G0/G1 cell cycle arrest and the inhibition of cellular hypertrophy of adipocytes.

Topics: Adipocytes; Animals; Anti-Obesity Agents; Benzoates; Biphenyl Compounds; Cell Proliferation; Cell Size; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p21; Diabetes Mellitus, Type 2; Disease Models, Animal; G1 Phase Cell Cycle Checkpoints; Humans; Hypertrophy; Hypoglycemic Agents; Kidney Glomerulus; Male; Obesity; Pioglitazone; PPAR gamma; Rats; Rats, Inbred OLETF; Resting Phase, Cell Cycle; Retinoid X Receptors; RNA Interference; Signal Transduction; Thiazolidinediones; Time Factors; Transfection; Tumor Suppressor Protein p53; 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