Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Impaired insulin action is important in the pathophysiology of multiple metabolic abnormalities such as obesity and type 2 diabetes. Protein tyrosine phosphatase 1B (PTP1B) is considered a negative regulator of insulin signalling. This is best evidenced by studies on knockout mice showing that lack of PTP1B is associated with increased insulin sensitivity as well as resistance to obesity and in vitro studies whilst studies in animals and humans have given contradictory results. However, several studies support the notion that insulin signalling can be enhanced by the inhibition of PTP1B providing an attractive target for therapy against type 2 diabetes and obesity. In addition, recent genetic studies support the association between PTP1B with insulin resistance. The development of PTP1B inhibitors has already begun although it has become clear that is not easy to find both a selective, safe and effective PTP1B inhibitor. The objective of this paper is to review the current evidence of PTP1B in the pathophysiology of obesity, type 2 diabetes and cancer as well as in the treatment of these disorders.
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PMID:Protein tyrosine phosphatase 1B: a new target for the treatment of obesity and associated co-morbidities. 1202 1

Protein tyrosine phosphatase 1B (PTP1B) has been implicated as a negative regulator of insulin action. Overexpression of PTP1B protein has been observed in insulin-resistant states associated with obesity. Mice lacking a functional PTP1B gene exhibit increased insulin sensitivity and are resistant to weight gain. To investigate the role of PTP1B in adipose tissue from obese animals, hyperglycemic obese (ob/ob) mice were treated with PTP1B antisense oligonucleotide (ISIS-113715). A significant reduction in adiposity correlated with a decrease of PTP1B protein levels in fat. Antisense treatment also influenced the triglyceride content in adipocytes, correlating with a downregulation of genes encoding proteins involved in lipogenesis, such as sterol regulatory element-binding protein 1 and their downstream targets spot14 and fatty acid synthase, as well as other adipogenic genes, lipoprotein lipase, and peroxisome proliferator-activated receptor gamma. In addition, an increase in insulin receptor substrate-2 protein and a differential regulation of the phosphatidylinositol 3-kinase regulatory subunit (p85alpha) isoforms expression were found in fat from antisense-treated animals, although increased insulin sensitivity measured by protein kinase B phosphorylation was not observed. These results demonstrate that PTP1B antisense treatment can modulate fat storage and lipogenesis in adipose tissue and might implicate PTP1B in the enlargement of adipocyte energy stores and development of obesity.
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PMID:Protein tyrosine phosphatase 1B reduction regulates adiposity and expression of genes involved in lipogenesis. 1214 51

Increased incidence of type 2 diabetes mellitus and obesity has elevated the medical need for new agents to treat these disease states. Resistance to the hormones insulin and leptin are hallmarks of both type 2 diabetes and obesity. Drugs that can ameliorate this resistance should be effective in treating type 2 diabetes and possibly obesity. Protein tyrosine phosphatase 1B (PTP1B) is thought to function as a negative regulator of insulin and leptin signal transduction. This article reviews PTP1B as a novel target for type 2 diabetes, and looks at the challenges in developing small-molecule inhibitors of this phosphatase.
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PMID:Protein tyrosine phosphatase 1B inhibitors for diabetes. 1220 50

Protein tyrosine phosphatase 1B (PTP1B) has recently been implicated in the regulation of body weight. A surprising phenotype of PTP1B-deficient mice is their resistance to diet-induced obesity. Since leptin is one of the primary hormones involved in the regulation of body weight and energy homeostasis, we investigated whether PTP1B affects leptin receptor (lepR) signaling directly. A mouse hypothalamic cell line, GT1-7, was established as a suitable cell model for the study of leptin signaling. Stimulation of GT1-7 cells by leptin caused tyrosine phosphorylation of endogenous STAT3 and activation of a STAT-dependent luciferase reporter gene. Over-expression of PTP1B in GT1-7 cells resulted in a dose-dependent decrease in endogenous JAK2 and STAT3 tyrosine phosphorylation compared with cells transfected with lepR alone. Consistent with inhibition of JAK-STAT signaling, PTP1B over-expression caused a dose-dependent decrease in leptin-induced, STAT-dependent luciferase reporter gene activation in GT1-7 cells. Furthermore, over-expression of PTP1B led to a decrease in mRNA accumulation of suppressor-of-cytokine-signalling-3 (SOCS3) and c-fos, genes that are acutely induced by leptin. Using gene microarray analysis, we confirmed that PTP1B reduces the level of gene expression of SOCS3 and showed that the expression level of other leptin-regulated genes was affected. Genes up-regulated by leptin were decreased in cells over-expressing PTP1B. Conversely, the expression of genes down-regulated by leptin was enhanced by PTP1B over-expression in GT1-7 cells. Our findings indicate that PTP1B is a negative regulator of leptin signaling and suggest that PTP1B inhibitors might be efficacious in the treatment of obesity by increasing leptin sensitivity.
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PMID:Protein tyrosine phosphatase 1B negatively regulates leptin signaling in a hypothalamic cell line. 1235 77

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin signal transduction cascade, initiated when insulin binds to the insulin receptor. PTP1B-deficient mice are more sensitive to insulin, and have improved glycemic control and resistance to diet-induced obesity than wild-type control mice. Diabetic mice treated with PTP1B antisense oligonucleotides intraperitoneally have lower PTP1B protein levels in liver and fat, reduced plasma insulin, blood glucose and hemoglobin A1c (HbA1c) levels. These studies validate PTP1B as a promising drug discovery target for the treatment of insulin resistance, diabetes and obesity. Herein we review the recent advances in the structure-based design of potent and selective small molecule inhibitors of PTP1B, and discuss th e challenge of developing compounds with improved cell permeability and bioavailability.
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PMID:Protein tyrosine phosphatase 1B as a target for the treatment of impaired glucose tolerance and type II diabetes. 1247 61

Protein tyrosine phosphatase 1B (PTP1B) has been implicated as one of the key negative regulators of insulin and leptin signal transduction pathways. PTP1B deficient mice are more sensitive to insulin, and have improved glycemic control and resistance to diet-induced obesity than the wild-type control mice. Inhibiting PTP1B action using antisense oligonucleotides and small molecule inhibitors represents novel therapeutic approach for the treatment of insulin resistance, type II diabetes, and obesity. The rapid development of this field is evidenced by the increasing number of patents and publications in recent years. This review will highlight the recent advances in various approaches for attenuating PTP1B action, particularly small molecule PTP1B inhibitors, and the challenges associated with developing PTP1B inhibitors with drug like properties.
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PMID:Protein tyrosine phosphatase 1B inhibition: opportunities and challenges. 1287 Nov 38

Protein tyrosine phosphatase 1B (PTP1B) has been implicated in the regulation of the insulin signaling pathway and represents an attractive target for the design of inhibitors in the treatment of type 2 diabetes and obesity. Inspection of the structure of PTP1B indicates that potent PTP1B inhibitors may be obtained by targeting a secondary aryl phosphate-binding site as well as the catalytic site. We report here the crystal structures of PTP1B in complex with first and second generation aryldifluoromethyl-phosphonic acid inhibitors. While all compounds bind in a previously unexploited binding pocket near the primary binding site, the second generation compounds also reach into the secondary binding site, and exhibit moderate selectivity for PTP1B over the closely related T-cell phosphatase. The molecular basis for the selectivity has been confirmed by single point mutation at position 52, where the two phosphatases differ by a phenylalanine-to-tyrosine switch. These compounds present a novel platform for the development of potent and selective PTP1B inhibitors.
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PMID:The structural basis for the selectivity of benzotriazole inhibitors of PTP1B. 1451 96

In Type 2 diabetes, glucose homeostasis is impaired due to either a decrease in insulin secretion or insulin action. In this symposium, molecular targets that could have an impact on either or both of these defects were discussed and data related to specific compounds were presented. Protein tyrosine phosphatase 1B inhibitors that relieve the negative control on insulin action and are active in cell assays, dipeptidyl peptidase IV inhibitors that raise postprandial glucagon-like peptide 1 levels in animals and humans, and pyruvate dehydrogenase kinase inhibitors that increase the levels of pyruvate dehydrogenase, which in turn improve insulin sensitivity, were all discussed. Roche presented for the first time their novel glucokinase activators and discussed both the in vitro and in vivo activity profiles of representative glucokinase activators as potential therapy for Type 2 diabetes. Second generation retinoid X receptor modulators that retain the desirable effects of full agonists, while devoid of their negative attributes, such as triglyceride accumulation, were discussed. Also, clinical efficacy results of synthetic exendin-4, Exenatide trade mark, a glucagon-like peptide 1 analogue, were presented. In the area of obesity, agonists of several central (melanocortin type 4, serotonin subtype 2C and cannabinoid receptor 1) receptors and one peripheral G-protein-coupled receptor, cholecystokinin receptor-A, all of which lead to reduced food intake in animals, were discussed.
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PMID:Metabolic diseases drug discovery world summit. July 28-29, 2003, San Diego, CA, USA. 1451 91

Protein tyrosine phosphatase 1B (PTP1B) has been implicated as a negative regulator of multiple signaling pathways downstream of receptor tyrosine kinases. Gene-targeting studies in mice have established PTP1B as a major target in diabetes and obesity. Initially, inhibition of this enzyme was thought to potentially lead to increased oncogenic signaling, but mice lacking PTP1B do not develop tumors. Our recent results show that loss of PTP1B can lead to decreased Ras signaling, despite enhanced signaling of other pathways. Here, we discuss how these findings implicate PTP1B as a positive and negative regulator of oncogenesis.
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PMID:Beyond the metabolic function of PTP1B. 1504 56

Protein tyrosine phosphatase 1B (PTP1B) plays a key role as a negative regulator of insulin and leptin signalling and is therefore considered to be an important molecular target for the treatment of type 2 diabetes and obesity. Detailed structural information about the structure of PTP1B, including the conformation and flexibility of active-site residues as well as the water-molecule network, is a key issue in understanding ligand binding and enzyme kinetics and in structure-based drug design. A 1.95 A apo PTP1B structure has been obtained, showing four highly coordinated water molecules in the active-site pocket of the enzyme; hence, the active site is highly solvated in the apo state. Three of the water molecules are located at positions that approximately correspond to the positions of the phosphate O atoms of the natural substrate phosphotyrosine and form a similar network of hydrogen bonds. The active-site WPD-loop was found to be in the closed conformation, in contrast to previous observations of wild-type PTPs in the apo state, in which the WPD-loop is open. The closed conformation is stabilized by a network of hydrogen bonds. These results provide new insights into and understanding of the active site of PTP1B and form a novel basis for structure-based inhibitor design.
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PMID:Water-molecule network and active-site flexibility of apo protein tyrosine phosphatase 1B. 1533 22


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