leptin and 2-4-thiazolidinedione

Bone mineral metabolism and bone remodeling involve a variety of molecules, for instance, bone morphogenetic proteins (BMPs) , fibroblast growth factors (FGFs) , insulin growth factors (IGFs) , interleukin-1 (IL-1) , prostagrandin E(2) (PGE(2)) , and tumor necrosis factor-alpha (TNF-alpha) . Most of them are also involved in lipid and glucose metabolism. Recent in vitro and in vivo studies have reported that therapeutic agents for diabetes and hyperlipidemia, such as insulin, thiazolidinediones, and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have pleiotropic effects on bone mineral metabolism. These agents may be useful tools for treatment of bone and mineral disorders.

Topics: Animals; Bone and Bones; Bone Density; Bone Remodeling; Calcification, Physiologic; Carbohydrate Metabolism; Glucose; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Insulin; Leptin; Lipid Metabolism; Osteogenesis; Thiazolidinediones

The peroxisome proliferator-activated receptor gamma (PPARgamma) is nuclear receptor that controls the expression of a large number of genes involved in adipocyte differentiation, lipid storage and insulin sensitization. PPARgamma is bound and activated by fatty acid derivatives and prostaglandin J2. In addition, thiazolidinediones, non-steroidal anti-inflammatory drugs are synthetic ligands and agonists of this receptor. This review addresses the role of PPARgamma in obesity and diabetes.

Topics: Adipose Tissue; Cell Differentiation; Diabetes Mellitus, Type 2; Humans; Leptin; Obesity; Receptors, Cytoplasmic and Nuclear; Thiazoles; Thiazolidinediones; Transcription Factors; Tumor Necrosis Factor-alpha

Type-II Endometrial Cancer (EMC) is one of the most common types of gynaecological cancer affecting more than 2.7 million people worldwide. Clinical evidence shows that adipokines levels are abnormally altered in Type-II EMC and reported to be one of the major responsible factor for uncontrolled proliferation and metastasis in Type-II EMC. Reversing the altered adipokine levels, therefore, help to control Type-II EMC proliferation and metastasis. In the present hypothesis we focus on the possible role of Thiazolidinediones in favourably altering the adipokine levels to benefit in the management of Type-II EMC.

Topics: Adipokines; Adiponectin; Animals; Cell Proliferation; Endometrial Neoplasms; Female; Gene Expression Regulation; Humans; Leptin; Mice; Models, Biological; Neoplasm Metastasis; Resistin; Thiazolidinediones

Small heterodimer partner (SHP, NR0B2) is involved in diverse metabolic pathways, including hepatic bile acid, lipid and glucose homeostasis, and has been implicated in effects on the peroxisome proliferator-activated receptor γ (PPARγ), a master regulator of adipogenesis and the receptor for antidiabetic drugs thiazolidinediones (TZDs). In this study, we aim to investigate the role of SHP in TZD response by comparing TZD-treated leptin-deficient (ob/ob) and leptin-, SHP-deficient (ob/ob;Shp(-/-)) double mutant mice.. Both ob/ob and double mutant ob/ob;Shp(-/-) mice developed hyperglycemia, insulin resistance, and hyperlipidemia, but hepatic fat accumulation was decreased in the double mutant ob/ob;Shp(-/-) mice. PPARγ2 mRNA levels were markedly lower in ob/ob;Shp(-/-) liver and decreased to a lesser extent in adipose tissue. The TZD troglitazone did not reduce glucose or circulating triglyceride levels in ob/ob;Shp(-/-) mice. Expression of the adipocytokines, such as adiponectin and resistin, was not stimulated by troglitazone treatment. Expression of hepatic lipogenic genes was also reduced in ob/ob;Shp(-/-) mice. Moreover, overexpression of SHP by adenovirus infection increased PPARγ2 mRNA levels in mouse primary hepatocytes.. Our results suggest that SHP is required for both antidiabetic and hypolipidemic effects of TZDs in ob/ob mice through regulation of PPARγ expression.

Topics: Animals; Bile Acids and Salts; Diabetes Mellitus; Gene Expression Regulation; Glucose; Hepatocytes; Humans; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Mice; Mice, Obese; PPAR gamma; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Thiazolidinediones

Administration of peroxisome proliferator-activated receptor gamma (PPARγ) ligands, thiazolidinediones (TZD), to prepartum dairy cattle has been shown to improve dry matter intake and decrease circulating nonesterified fatty acids (NEFA) around the time of calving. The objective of this work was to elucidate mechanisms of TZD action in transition dairy cattle by investigating changes in plasma leptin, tumor necrosis factor-α (TNFα), the revised quantitative insulin sensitivity check index (RQUICKI), and adipose tissue gene expression of leptin, PPARγ, lipoprotein lipase (LPL), and fatty acid synthase (FAS). Multiparous Holstein cows (n=40) were administered 0, 2.0, or 4.0 mg of TZD/kg of body weight (BW) by intrajugular infusion once daily from 21 d before expected parturition until parturition. Plasma samples collected daily from 22 d before expected parturition through 21 d postpartum were analyzed for glucose, NEFA, and insulin. Plasma samples collected on d -14, -3, -1, 1, 3, 7, 14, and 49 relative to parturition were also analyzed for leptin and TNFα. Adipose tissue was collected on d 7 before expected parturition from a subset of cows, and gene expression was examined via quantitative real-time PCR. A tendency for a treatment by time effect on plasma leptin prepartum was observed such that values were similar on d -14 but cows receiving 2.0 mg/kg of BW of TZD tended to have lower circulating leptin as calving approached. Postpartum leptin tended to be increased linearly (2.3, 2.4, and 2.5±0.1 ng/mL for 0, 2.0, and 4.0 mg/kg treatments, respectively) in cows that received TZD prepartum. Plasma TNFα increased linearly (2.6, 3.7, and 4.0±0.1 pg/mL) in response to TZD treatment and decreased through the first week postpartum. Calculation of RQUICKI 1/[log(glucose)+log(insulin)+log(NEFA)] suggested altered insulin sensitivity in cows administered TZD that may depend on day relative to calving. Administration of TZD increased adipose tissue expression of PPARγ mRNA (11.0, 13.3, and 12.8±1.9). Administration of TZD had a quadratic effect on gene expression of leptin (16.2, 10.7, and 17.4±1.6) and no effect on LPL expression, and expression of FAS was lower for TZD-treated cows than for controls (8.2, 4.2, and 6.1±1.8, respectively). Results imply altered expression and plasma concentrations of leptin, increased plasma TNFα concentrations, and increased expression of PPARγ in adipose tissue as potential mechanisms for the effects of TZD administration on tr

Topics: Adipose Tissue; Animals; Cattle; Female; Gene Expression Regulation; Hypoglycemic Agents; Insulin Resistance; Leptin; Pregnancy; Thiazolidinediones; Tumor Necrosis Factor-alpha

We evaluated the efficacy of a thiazolidinedione in the treatment of diabetes induced by glucocorticoids. We examined the effectiveness of troglitazone in seven patients with long-standing steroid-induced diabetes. Five of the seven subjects were treated with insulin alone, one was treated with both insulin and oral therapy and one was treated with oral therapy alone. The mean insulin dose in six of the seven subjects was 0.66+/-0.09 units/kg per day. Diabetes status was assessed by measuring serum fructosamine, HgbA1c, oral glucose and meal tolerance tests (OGTT and MTT) at baseline and after treatment for 5-8 weeks with troglitazone 400 mg/day. Troglitazone caused a significant decrease in fructosamine (274+/-32 vs. 217+/-22 mmol/l; P<0.01) and HgbA1C (7.8+/-0.4 vs. 7.2+/-0.4%; P<0.01) as well as decrements in the areas under the OGTT 2,308+/-156 vs. 1,937+/-127 mmol/l; P<0.05) and MTT glucose curves (4694+/-449 vs. 4057+/-437 mmol/l; P<0.05). In addition, the area under the insulin curve for the oral glucose tolerance test showed a significant increase from 27,438+/-4,488 to 41,946+/-6,048 pmol/l (P<0.05). Total and LDL cholesterol were also significantly decreased (6.4+/-0.9 vs. 5.0+/-0.6 mmol/l and 3.8+/-0.7 vs. 2.7+/-0.4 mmol/l, respectively, P<0.05). Fasting leptin values decreased by 23% despite an increase in body weight. Troglitazone is effective in the treatment of glucocorticoid-induced diabetes as manifested by lower measures of glycemia, HgbA1c, and post-prandial glucose values, while the doses of other diabetes medications remained unchanged or were reduced. The insulin-sensitizing drug also produced a marked increase in endogenous insulin secretion in response to glucose, lower total and LDL cholesterol, and decreased fasting leptin despite weight gain. Thiazolidinediones may improve diabetes-related parameters by antagonizing pathways of glucocorticoid-induced insulin resistance and by reversing adverse effects of glucocorticoids on beta cell function.

Topics: Administration, Oral; Adult; Biomarkers; Blood Glucose; Chromans; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Fructosamine; Glucocorticoids; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin; Leptin; Middle Aged; Prednisone; Thiazoles; Thiazolidinediones; Troglitazone

Peroxisome proliferator-activated receptor-gamma (PPARgamma) has been shown to play an important role in the regulation of expression of a subclass of adipocyte genes and to serve as the molecular target of the thiazolidinedione (TZD) and certain non-TZD antidiabetic agents. Hypercorticosteroidism leads to insulin resistance, a variety of metabolic dysfunctions typically seen in diabetes, and hypertrophy of visceral adipose tissue. In adipocytes, the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) converts inactive cortisone into the active glucocorticoid cortisol and thereby plays an important role in regulating the actions of corticosteroids in adipose tissue. Here, we show that both TZD and non-TZD PPARgamma agonists markedly reduced 11beta-HSD-1 gene expression in 3T3-L1 adipocytes. This diminution correlated with a significant decrease in the ability of the adipocytes to convert cortisone to cortisol. The half-maximal inhibition of 11beta-HSD-1 mRNA expression by the TZD, rosiglitazone, occurred at a concentration that was similar to its K(d) for binding PPARgamma and EC(50) for inducing adipocyte differentiation thereby indicating that this action was PPARgamma-dependent. The time required for the inhibitory action of the TZD was markedly greater for 11beta-HSD-1 gene expression than for leptin, suggesting that these genes may be down-regulated by different molecular mechanisms. Furthermore, whereas regulation of PPARgamma-inducible genes such as phosphoenolpyruvate carboxykinase was maintained when cellular protein synthesis was abrogated, PPARgamma agonist inhibition of 11beta-HSD-1 and leptin gene expression was ablated, thereby supporting the conclusion that PPARgamma affects the down-regulation of 11beta-HSD-1 indirectly. Finally, treatment of diabetic db/db mice with rosiglitazone inhibited expression of 11beta-HSD-1 in adipose tissue. This decrease in enzyme expression correlated with a significant decline in plasma corticosterone levels. In sum, these data indicate that some of the beneficial effects of PPARgamma antidiabetic agents may result, at least in part, from the down-regulation of 11beta-HSD-1 expression in adipose tissue.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; 3T3 Cells; Adipocytes; Animals; Cycloheximide; Diabetes Mellitus, Experimental; DNA-Binding Proteins; Gene Expression Regulation, Enzymologic; Hydroxysteroid Dehydrogenases; Kinetics; Leptin; Ligands; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Rosiglitazone; Thiazoles; Thiazolidinediones; Transcription Factors; Transcription, Genetic

The biological role of peroxisome proliferator-activated receptor gamma (PPARgamma) was investigated by gene targeting and case-control study of the Pro12Ala PPARgamma2 polymorphism. Homozygous PPARgamma-deficient embryos died at 10.5-11.5 days post conception (dpc) due to placental dysfunction. Heterozygous PPARgamma-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy under a high-fat diet, whose phenotypes were abrogated by PPARgamma agonist treatment. Heterozygous PPARgamma-deficient mice showed overexpression and hypersecretion of leptin despite the smaller size of adipocytes and decreased fat mass, which may explain these phenotypes at least in part. This study reveals a hitherto unpredicted role for PPARgamma in high-fat diet-induced obesity due to adipocyte hypertrophy and insulin resistance, which requires both alleles of PPARgamma. A Pro12Ala polymorphism has been detected in the human PPARgamma2 gene. Since this amino acid substitution may cause a reduction in the transcriptional activity of PPARgamma, this polymorphism may be associated with decreased insulin resistance and decreased risk of type 2 diabetes. To investigate this hypothesis, we performed a case-control study of the Pro12Ala PPARgamma2 polymorphism. In an obese group, subjects with Ala12 were more insulin sensitive than those without. The frequency of Ala12 was significantly lower in the diabetic group, suggesting that this polymorphism protects against type 2 diabetes. These results revealed that in both mice and humans, PPARgamma is a thrifty gene mediating type 2 diabetes.

Topics: Adipose Tissue; Animals; Case-Control Studies; Diabetes Mellitus, Type 2; Dietary Fats; Humans; Hypertrophy; Insulin Resistance; Leptin; Mice; Mice, Knockout; Models, Biological; Obesity; Polymorphism, Genetic; Receptors, Cytoplasmic and Nuclear; Thiazoles; Thiazolidinediones; Transcription Factors