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)

The protein tyrosine phosphatase PTP1B, previously recognized for its role in downregulating insulin and leptin signaling, has now been shown to function as a positive regulator of signaling events associated with breast tumorigenesis. Inhibitors of PTP1B that have been developed as drug candidates for treatment of diabetes and obesity may offer new avenues for the treatment of breast cancer.
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PMID:A brake becomes an accelerator: PTP1B--a new therapeutic target for breast cancer. 1734 79

Obesity is a major public health problem associated with morbidity and mortality and continues to increase worldwide. This review focuses on the regions of the brain that are important in appetite regulation and the circulating factors implicated in the control of food intake. The hypothalamus is critical in the regulation of food intake containing neural circuits, which produce a number of peptides that influence food intake. The arcuate nucleus of the hypothalamus produces both orexigenic peptides (agouti-related protein and neuropeptide Y) and anorectic peptides (alpha-melanocyte-stimulating hormone and cocaine- and amphetamine-related transcript). The lateral hypothalamus produces the orexigenic peptides (melanin-concentrating hormone and orexins). Other hypothalamic factors recently implicated in appetite regulation include the endocannabinoids, brain-derived neurotrophic factor, nesfatin-1, AMP-activated protein kinase, mammalian target of rapamycin protein, and protein tyrosine phosphatase. Circulating factors that affect food intake mediate their effects by signaling to the hypothalamus and/or brainstem. A number of circulating factors are produced by peripheral organs, for example, leptin by adipose tissue, insulin and pancreatic polypeptide by the pancreas, gut hormones (e.g., ghrelin, obestatin, glucagon-like peptide-1, oxyntomodulin, peptide YY), and triiodothyronine by the thyroid gland. Circulating carbohydrates, lipids, and amino acids also affect appetite regulation. Knowledge regarding appetite regulation has vastly expanded in recent years providing targets for antiobesity drug design.
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PMID:Appetite regulation: an overview. 1754 73

The regulation of bone remodeling by an adipocyte-derived hormone implies that bone may exert a feedback control of energy homeostasis. To test this hypothesis we looked for genes expressed in osteoblasts, encoding signaling molecules and affecting energy metabolism. We show here that mice lacking the protein tyrosine phosphatase OST-PTP are hypoglycemic and are protected from obesity and glucose intolerance because of an increase in beta-cell proliferation, insulin secretion, and insulin sensitivity. In contrast, mice lacking the osteoblast-secreted molecule osteocalcin display decreased beta-cell proliferation, glucose intolerance, and insulin resistance. Removing one Osteocalcin allele from OST-PTP-deficient mice corrects their metabolic phenotype. Ex vivo, osteocalcin can stimulate CyclinD1 and Insulin expression in beta-cells and Adiponectin, an insulin-sensitizing adipokine, in adipocytes; in vivo osteocalcin can improve glucose tolerance. By revealing that the skeleton exerts an endocrine regulation of sugar homeostasis this study expands the biological importance of this organ and our understanding of energy metabolism.
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PMID:Endocrine regulation of energy metabolism by the skeleton. 1769 52

Diabetes mellitus is a disorder characterized by hyperglycemia in both the fasting and post-prandial states. The two most common forms of diabetes mellitus, type 1 and type 2 (previously called juvenile-onset and adult-onset, respectively), comprise the vast majority of cases. Type 1 diabetes (T1DM) has been shown to be a disease characterized by immune-mediated destruction of the insulin-secreting cells of the pancreas; it comprises the majority of cases of diabetes seen in childhood and approximately, 5-10% of all cases of diabetes mellitus in the USA and perhaps accounts for an even higher percentage in those nations with lower rates of obesity. The process of beta-cell destruction, marked by the production of autoantibodies to the beta-cell, occurs over many years and ultimately results in metabolic abnormalities first manifested as impaired glucose tolerance and then progressing to symptomatic hyperglycemia. It has been reported that approximately 50% of the genetic risk for T1DM can be attributed to the HLA region. The highest risk HLA-DR3/4 DQ8 genotype has been shown to be highly associated with beta-cell autoimmunity. The first antibodies described in association with the development of T1DM were islet cell autoantibodies (ICA). Subsequently, antibodies to insulin (IAA), glutamic acid decarboxylase (GAA or GAD) and protein tyrosine phosphatase (IA2 or ICA512) have all been defined. The number of antibodies, rather than the individual antibody, is thought to be most predictive of progression to overt diabetes.
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PMID:Autoantibodies in type 1 diabetes. 1817 60

PTP1B and T cell PTP (TC-PTP) are protein tyrosine phosphatases (PTPs) that share high sequence and structural homology yet play distinct physiological roles. While PTP1B plays a central role in metabolism and is an attractive drug target for obesity and type 2 diabetes, TC-PTP is necessary for the control of inflammation. In this review, we will discuss the growing evidence for the involvement of PTP1B in cancer, while proposing a role for TC-PTP in inflammation-induced tumorigenesis. Given the challenge of developing inhibitors specific for PTP1B alone, it is necessary to consider both enzymes and their roles in various cancer models.
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PMID:PTP1B and TC-PTP: regulators of transformation and tumorigenesis. 1823 7

Current strategies to treat type 2 diabetes (DMT2) include reducing insulin resistance using glitazones, supplementing with exogenous insulin, increasing endogenous insulin production with sulfonylureas and meglitinides, reducing hepatic glucose production through biguanides, and limiting postprandial glucose absorption with alpha-glucosidase inhibitors. In all of these areas, new generations of molecules with improved efficacy and safety profiles, are being investigated. Promising biological targets are rapidly emerging such as the role of lipotoxicity as a cause of glucometabolic insulin resistance, leading to a host of new molecular drug targets such as AMP-activated protein kinase (AMPK) activators, recombinant adiponectin derivatives, and fatty acid synthase (FAS) inhibitors. Insulin action can be enhanced in muscle, liver and fat, with small-molecule activators of the insulin receptor or inhibitors of protein tyrosine phosphatase (FTP)-IB. Defective glucose-stimulated insulin secretion by pancreatic B-cells could be alleviated with recombinant glucagon-like peptide (GLP-1) or agonists to the GLP-1 receptor. This review presents a new approach for obesity and DMT2 drug discovery through pharmacogenomics. Several compounds have already been validated through genetic engineering in animal models or the preliminary use of therapeutic compounds in humans.
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PMID:[Molecular targets for new drug discovery to treat type 2 diabetes and obesity]. 1848 61

The protein tyrosine phosphatase nonreceptor type1 (PTPN1) gene encodes for the protein tyrosine phosphatase 1B, which suppresses the signaling pathway of leptin. Variations of the PTPN1 gene may lead to changes in leptin sensitivity and thereby influence eating behavior and measures of obesity. This study investigated the association between single-nucleotide polymorphisms (SNPs) of the PTPN1 gene and eating behavior and different measures of obesity, including visceral fat. We used data from a population-based, cross-sectional study of 382 Dutch white men aged 40-80 years. Self-reported macronutrient intake was collected with a food frequency questionnaire. Anthropometrical measurements included BMI, waist and hip circumference, total lean and fat mass measured with dual-energy X-ray absorptiometry, and visceral and subcutaneous fat measured with ultrasound. Associations were studied using linear regression analysis. There were no statistically significant associations of SNPs in the PTPN1 gene with dietary phenotypes or measures of obesity.
Obesity (Silver Spring) 2008 Dec
PMID:No association of PTPN1 polymorphisms with macronutrient intake and measures of adiposity. 1884 48

Mesenchymal stem cells (MSCs) are self-renewable multipotent progenitor cells with the capacity to differentiate into several distinct mesenchymal lineages. While MSCs display significant potential in tissue engineering and therapeutic applications, the regulatory mechanisms underlying the differentiation of these cells are yet to be established. Phosphorylation is a post-translational modification that plays a significant role in diverse biological phenomena. In this study, to mine the protein tyrosine phosphatases (PTPs) involved in adipogenesis of human MSCs, differential expression of human PTPs was examined using RT-PCR analysis. Among the 107 human PTPs, PTP-RQ was dramatically downregulated during the early phase of adipogenesis. PTP-RQ is classified as a receptor-type III PTP with phosphatidylinositol phosphatase (PIPase) activity. Overexpression of PTP-RQ consistently led to reduced differentiation of MSCs into adipocytes via decreasing the phosphatidyl inositol phosphate level in cells, and consequently downregulating Akt/PKB phosphorylation. Our results collectively suggest that PTP-RQ is a useful target protein for regulating the differentiation of MSCs into adipocytes, and may be used to develop novel drugs for the treatment of obesity.
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PMID:Involvement of PTP-RQ in differentiation during adipogenesis of human mesenchymal stem cells. 1935 28

Erythrocyte acid phosphatase (ACP locus 1), also known as low-molecular-weight protein tyrosine phosphatase, has previously been associated to glycemia, dyslipidemia, and obesity. In this study, ACP1 genotype and activity were tested in 318 women aged 19 to 83 (mean, 51.74 +/- 13.44) years. ACP1 genotype was found to directly correlate to glutathione reductase activity (P < .001) and levels of low-density lipoprotein cholesterol (P = .038). Glutathione reductase activity was in turn found to correlate to a series of cardiovascular risk factors such as systolic arterial pressure (P < .001), total cholesterol levels (P = .018), and low-density lipoprotein cholesterol levels (P = .039). A possible protective effect of ACP1 genotype AA against these cardiovascular risk factors was observed in this study. Furthermore, this work hypothesizes that nutritional riboflavin uptake becomes more crucial as body mass index increases, to counteract oxidative stress and minimize cardiovascular risk. This might be especially true in ACP1 genotypes AC, BC, and CC, which might possibly show the least endogenous protection against oxidative stress.
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PMID:ACP1 genotype, glutathione reductase activity, and riboflavin uptake affect cardiovascular risk in the obese. 1957 May 51

Reversible protein tyrosine phosphorylation, catalysed by the counter-actors protein tyrosine phosphatases (PTPs) and protein tyrosine kinases (PTKs), is a fundamentally important regulatory mechanism of proteins in living cells, controlling cell communication, proliferation, differentiation, motility, and molecular trafficking. The activities of PTPs and PTKs are derailed in several diseases such as cancer and type II diabetes, making them attractive drug targets. Developing drugs against PTKs has started a decade earlier than that on PTPs, and at present there are several molecules targeting PTKs on the market. PTPs in turn are of raising interest, with PTP1B on the lead for its effects on type II diabetes and obesity. In the search for modulators of PTP activity, high-throughput methods are important as the initial step to find suitable lead compounds for drug development. Also, high-throughput methods are very useful in elucidating the specific function of different PTPs. In this review, the different high-throughput studies performed to find inhibitors and activators of classical PTPs are discussed.
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PMID:High-throughput methods in identification of protein tyrosine phosphatase inhibitors and activators. 2128 96


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