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

Resistance to the biological action of insulin in its target tissues is a cardinal feature of non-insulin-dependent diabetes mellitus. Protein-tyrosine phosphatases (PTPases) have been postulated to play a key role in the regulation of the insulin action pathway, especially in skeletal muscle, the major site of insulin-mediated glucose disposal in vivo. To evaluate whether changes in the activity and/or abundance of candidate skeletal muscle PTPases is associated with severe resistance to insulin in an animal model, we measured PTPase enzyme activity and PTPase protein level by immunoblotting in subcellular fractions of skeletal muscle in lean (+/?), insulin-resistant obese (fa/fa), and diabetic (ZDF/Drt-fa/fa) Zucker rats. Using a phosphotyrosylmyelin basic protein substrate, the solubilized-particulate fraction PTPase activity was increased by 65% and 74% (P < .05) and in vitro dephosphorylation of a recombinant rat insulin receptor kinase domain was increased by 104% and 114% in obese and diabetic animals, respectively (P < .01). These changes in PTPase activity were associated with an increase in specific immunoreactivity of leukocyte common antigen-related PTPase ([LAR] by 42% and 50%), PTPase 1B (by 61% and 69%), and the SHZ domain containing PTPase (SH-PTP2) (by 44% and 48%) in the solubilized-particulate fraction of obese and diabetic animals, respectively (P < .05). In diabetic muscle, increased SH-PTP2 abundance was also associated with a shift of SH-PTP2 to a plasma membrane component, which may have important consequences for the activation of this enzyme in the insulin-resistant state. These results provide evidence that specific PTPases play a role in the insulin resistance of this genetic model of obesity and non-insulin-dependent diabetes.
 ...
PMID:Increased abundance of specific skeletal muscle protein-tyrosine phosphatases in a genetic model of insulin-resistant obesity and diabetes mellitus. 766 92

Tumor necrosis factor-alpha (TNF-alpha) can modulate the signalling capacity of tyrosine kinase receptors; in particular, TNF-alpha has been shown to mediate the insulin resistance associated with animal models of obesity and noninsulin-dependent diabetes mellitus. In order to determine whether the effects of TNF-alpha might involve alterations in the expression of specific protein-tyrosine phosphatases (PTPases) that have been implicated in the regulation of growth factor receptor signalling, KRC-7 rat hepatoma cells were treated with TNF-alpha, and changes in overall tissue PTPase activity and the abundance of three major hepatic PTPases (LAR, PTP1B, and SH-PTP2) were measured in addition to effects of TNF-alpha on ligand-stimulated autophosphorylation of insulin and epidermal growth factor (EGF) receptors and insulin-stimulated insulin receptor substrate-1 (IRS-1) phosphorylation. TNF-alpha caused a dose-dependent decrease in insulin-stimulated IRS-1 phosphorylation and EGF-stimulated receptor autophosphorylation to 47-50% of control. Overall PTPase activity in the cytosol fraction did not change with TNF-alpha treatment, and PTPase activity in the particulate fraction was decreased by 55-66%, demonstrating that increases in total cellular PTPase activity did not account for the observed alterations in receptor signalling. However, immunoblot analysis showed that TNF-alpha treatment resulted in a 2.5-fold increase in the abundance of SH-PTP2, a 49% decrease in the transmembrane PTPase LAR, and no evident change in the expression of PTP1B. These data suggest that at least part of the TNF-alpha effect on pathways of reversible tyrosine phosphorylation may be exerted through the dynamic modulation of the expression of specific PTPases. Since SH-PTP2 has been shown to interact directly with both the EGF receptor and IRS-1, increased abundance of this PTPase, may mediate the TNF-alpha effect to inhibit signalling through these proteins. Furthermore, decreased abundance of the LAR PTPase, which has been implicated in the regulation of insulin receptor phosphorylation, may account for the less marked effect of TNF-alpha on the autophosphorylation state of the insulin receptor while postreceptor actions of insulin are inhibited.
 ...
PMID:Effect of tumor necrosis factor-alpha on the phosphorylation of tyrosine kinase receptors is associated with dynamic alterations in specific protein-tyrosine phosphatases. 901 60

Nonesterified fatty acids (NEFAs) are acutely liberated during lipolysis and are chronically elevated in pathological conditions, such as insulin resistance, hypertension, and obesity, which are known risk factors for atherosclerosis. The purpose of this study was to investigate the effect and mechanism of action of NEFAs on the epithelial growth factor (EGF) receptor (EGFR). In the ECV-304 endothelial cell line, unsaturated fatty acids triggered a time- and dose-dependent tyrosine phosphorylation of EGFR (polyunsaturated fatty acids [PUFAs] were the most active), whereas saturated FAs were inactive. Although less potent than PUFAs, oleic acid (OA) was used because it is prominent in the South European diet and is only slightly oxidizable (thus excluding oxidation derivatives). EGFR is activated by OA independent of any autocrine secretion of EGF or other related mediators. OA-induced EGFR autophosphorylation triggered EGFR signaling pathway activation (as assessed through coimmunoprecipitation of SH2 proteins such as SHC, GRB2, and SHP-2) and subsequent p42/p44 mitogen-activated protein kinase (as shown by the use of EGFR- deficient B82L and EGFR- transduced B82LK(+) cell lines). OA induced in vitro both autophosphorylation and activation of intrinsic tyrosine kinase of immunopurified EGFR, thus suggesting that EGFR is a primary target of OA. EGFR was also activated by mild surfactants, Tween-20 and Triton X-100, both in vitro (on immunopurified EGFR) and in intact living cells, thus indicating that EGFR is sensitive to amphiphilic molecules. These data suggest that EGFR is activated by OA and PUFAs, acts as a sensor for unsaturated fatty acids (and amphiphilic molecules), and is a potential transducer by which diet composition may influence vascular wall biology.
 ...
PMID:Activation of epithelial growth factor receptor pathway by unsaturated fatty acids. 1055 35

The role of leptin and its receptor on the regulation of appetite and body fat was summarized. Leptin directly exerts its anorexigenic effects on arcuate nucleus via proopiomelanocortin and neuropeptide Y neurons. The anorexia and sympathetic nerve activation result in the reduction of body fat. But physiological concentrations of leptin could not reduce body fat in obese people, while genetic loss of central leptin effects induces obesity in children. Melanin concentrating hormone, orexin, and corticotropin-releasing hormone may be directly regulated by leptin. Serotonergic neurons may be separate from leptin effects. Phosphorylation of 985- and 1138-tyrosine of long-form leptin receptor activates SHP-2 and STAT3, respectively. Soluble leptin receptor concentrations in serum are negatively correlated with BMI. Clinical usefulness of leptin is now in progress.
 ...
PMID:[Role of leptin and its receptor in the regulation of appetite and body fat]. 1126 87

Protein-tyrosine phosphatases (PTPases) form a large family of enzymes that serve as key regulatory components in signal transduction pathways. Defective or inappropriate regulation of PTPase activity leads to aberrant tyrosine phosphorylation, which contributes to the development of many human diseases including cancers and diabetes. For example, recent gene knockout studies in mice identify PTP1B as a promising target for anti-diabetes/obesity drug discovery. Thus, there is intense interest in obtaining specific and potent PTPase inhibitors for biological studies and pharmacological development. However, given the highly conserved nature of the PTPase active site, it is unclear whether selectivity in PTPase inhibition can be achieved. We describe a combinatorial approach that is designed to target both the active site and a unique peripheral site in PTP1B. Compounds that can simultaneously associate with both sites are expected to exhibit enhanced affinity and specificity. We also describe a novel affinity-based high-throughput assay procedure that can be used for PTPase inhibitor screening. The combinatorial library/high-throughput screen protocols furnished a small molecule PTP1B inhibitor that is both potent (K(i) = 2.4 nm) and selective (little or no activity against a panel of phosphatases including Yersinia PTPase, SHP1, SHP2, LAR, HePTP, PTPalpha, CD45, VHR, MKP3, Cdc25A, Stp1, and PP2C). These results demonstrate that it is possible to acquire potent, yet highly selective inhibitors for individual members of the large PTPase family of enzymes.
 ...
PMID:Acquisition of a specific and potent PTP1B inhibitor from a novel combinatorial library and screening procedure. 1158 2

Type 2 diabetes is increasing at an alarming rate worldwide, and there has been a considerable effort in several laboratories to identify suitable targets for the design of drugs against the disease. To this end, the protein tyrosine phosphatases that attenuate insulin signaling by dephosphorylating the insulin receptor (IR) have been actively pursued. This is because inhibiting the phosphatases would be expected to prolong insulin signaling and thereby facilitate glucose uptake and, presumably, result in a lowering of blood glucose. Targeting the IR protein tyrosine phosphatase, therefore, has the potential to be a significant disease-modifying strategy. Several protein tyrosine phosphatases (PTPs) have been implicated in the dephosphorylation of the IR. These phosphatases include PTPalpha, LAR, CD45, PTPepsilon, SHP2, and PTP1B. In most cases, there is evidence for and against the involvement of the phosphatases in insulin signaling. The most convincing data, however, support a critical role for PTP1B in insulin action. PTP1B knockout mice are not only insulin sensitive but also maintain euglycemia (in the fed state), with one-half the level of insulin observed in wild-type littermates. Interestingly, these mice are also resistant to diet-induced obesity when fed a high-fat diet. The insulin-sensitive phenotype of the PTP1B knockout mouse is reproduced when the phosphatase is also knocked down with an antisense oligonucleotide in obese mice. Thus PTP1B appears to be a very attractive candidate for the design of drugs for type 2 diabetes and obesity.
 ...
PMID:Protein tyrosine phosphatases: the quest for negative regulators of insulin action. 1262 22

DHEA improves insulin sensitivity and has anti-obesity effect in animal models and men. However, the molecular mechanisms by which DHEA improves insulin action have not been clearly understood. In the present study, we examined the protein levels and phosphorylation state of insulin receptor (IR), IRS-1 and IRS-2, the association between IRSs and PI3K and SHP2, the insulin-induced IRSs associated PI 3-kinase activities, and the phosphorylation status of AKT and atypical PKCzeta/lambda in the liver and the muscle of 6 month-old Wistar rats treated with DHEA. There was no change in IR, IRS-1 and IRS-2 protein levels in both tissues of treated rats analysed by immunoblotting. On the other hand, insulin-induced IRS-1 tyrosine phosphorylation was increased in both tissues while IRS-2 tyrosyl phosphorylation was increased in liver of DHEA treated group. The PI3-kinase/AKT pathway was increased in the liver and the PI3K/atypical PKCzeta/lambda pathway was increased in the muscle of DHEA treated rats. These data indicate that these regulations of early steps of insulin action may play a role in the intracellular mechanism for the improved insulin sensitivity observed in this animal model.
 ...
PMID:The phosphatidylinositol/AKT/atypical PKC pathway is involved in the improved insulin sensitivity by DHEA in muscle and liver of rats in vivo. 1550 80

Adipose tissue secretes different adipokines, including interleukin-6 (IL-6), that have been implicated in the insulin resistance and inflammatory state characterizing obesity. We examined the putative cross-talk between insulin and IL-6 in adipose cells and found that insulin exerts an inhibitory effect on the IL-6 signaling pathway by altering the post-translational modifications of the signal transducer and activator of transcription 3 (STAT3). Insulin reduces the tyrosine phosphorylation and increases the serine phosphorylation of STAT3, thereby reducing its nuclear localization and transcriptional activity. Signaling through the MEK/MAPK pathway plays an important role as treatment with the MEK inhibitor PD98059 reduces the effects of insulin on IL-6 signaling. We also show that the protein tyrosine phosphatase SHP2 is activated upon insulin signaling and is required for the dephosphorylation of STAT3 and that insulin exerts a synergistic effect with IL-6 on suppressor of cytokine signaling 3 expression. As a consequence, the IL-6-induced expression of the inflammatory markers serum amyloid A 3 and haptoglobin are significantly decreased in cells incubated with both IL-6 and insulin. Thus, insulin exerts an important anti-inflammatory effect in adipose cells by impairing the IL-6 signal at several levels.
 ...
PMID:Insulin antagonizes interleukin-6 signaling and is anti-inflammatory in 3T3-L1 adipocytes. 1726 1

The insulin signaling pathway is critical in regulating glucose levels and is associated with diabetes, obesity, and longevity. A tyrosine phosphorylation cascade creates docking sites for protein interactions, initiating subsequent propagation of the signal throughout the cell. The phosphotyrosine interactome of this medically important pathway has not yet been studied comprehensively. We therefore applied quantitative interaction proteomics to exhaustively profile all potential phosphotyrosine-dependent interaction sites in its key players. We targeted and compared insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) as central distributors of the insulin signal, the insulin receptor, the insulin-like growth factor 1 receptor, and the insulin receptor-related receptor. Using the stable isotope labeling by amino acids in cell culture (SILAC) approach with phosphorylated versus non-phosphorylated bait peptides, we found phosphorylation-specific interaction partners for 52 out of 109 investigated sites. In addition, doubly and triply phosphorylated motifs provided insight into the combinatorial effects of phosphorylation events in close proximity to each other. Our results retrieve known interactions and substantially broaden the spectrum of potential interaction partners of IRS-1 and IRS-2. A large number of common interactors rationalize their extensive functional redundancy. However, several proteins involved in signaling and metabolism interact differentially with IRS-1 and IRS-2 and thus provide leads into their different physiological roles. Differences in interactions at the receptor level are reflected in multisite recruitment of SHP2 by the insulin-like growth factor 1 receptor and limited but exclusive interactions with the IRR. In common with other recent reports, our data furthermore hint at non-SH2 or phosphotyrosine-binding domain-mediated phosphotyrosine binding.
 ...
PMID:The phosphotyrosine interactome of the insulin receptor family and its substrates IRS-1 and IRS-2. 1900 11

Protein Tyrosine Phosphatases (PTPs) that function as negative regulators of the insulin signaling cascade have been identified as novel targets for the therapeutic enhancement of insulin action in insulin resistant disease states. Reducing Protein Tyrosine Phosphatase1B (PTP1B) abundance not only enhances insulin sensitivity and improves glucose metabolism but also protects against obesity induced by high fat feeding. PTP1B inhibitors such as Formylchromone derivatives, 1, 2-Naphthoquinone derivatives and Oxalyl aryl amino benzoic derivatives may eventually find an important clinical role as insulin sensitizers in the management of Type-II Diabetes and metabolic syndrome. We have carried out docking of modified oxalyl aryl amino benzoic acid derivatives into three dimensional structure of PTP1B using BioMed CAChe 6.1. These compounds exhibit good selectivity for PTP1B over most of phosphatases in selectivity panel such as SHP-2, LAR, CD45 and TCPTP found in literature. This series of compounds identified the amino acid residues such as Gly220 and Arg221 are important for achieving specificity via H-bonding interactions. Lipophilic side chain of methionine in modified oxalyl aryl amino benzoic acid derivative [1b (a2, b2, c1, d)] lies in closer vicinity of hydrophobic region of protein consisted of Meth258 and Phe52 in comparison to active ligand. Docking Score in [1b (a2, b2, c1, d)] is -131.740Kcal/mol much better than active ligand score -98.584Kcal/mol. This information can be exploited to design PTP1B specific inhibitors.
 ...
PMID:Docking of oxalyl aryl amino benzoic acid derivatives into PTP1B. 1923 34


1 2 3 Next >>