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)

Protein tyrosine phosphatase (PTP)-1B antagonizes insulin signaling and is a potential therapeutic target for insulin resistance associated with obesity and type 2 diabetes. To date, studies of PTP-1B have been limited by the availability of specific antagonists; however, treatment of rodents with antisense oligonucleotides (ASOs) directed against PTP-1B improves insulin sensitivity, inhibits lipogenic gene expression, and reduces triglyceride accumulation in liver and adipose tissue. Here we investigated ASO-mediated PTP-1B inhibition in primates. First, PTP-1B ASO (ISIS 113715) dose-dependently inhibited PTP-1B mRNA and protein expression in cultured monkey hepatocytes. Subcutaneous administration of ISIS 113715 reduced PTP-1B mRNA expression in liver and adipose tissue of normal-weight monkeys by 40-50% and improved insulin sensitivity during an iv glucose tolerance test (IVGTT). In obese, insulin-resistant rhesus monkeys, treatment with 20 mg/kg ISIS 113715 for 4 wk reduced fasting concentrations of insulin and glucose and reduced insulin responses during an IVGTT. In these animals, adiponectin concentrations were also increased by 70%, most of which was an increase of high-molecular-weight oligomers. These effects were not observed in monkeys on a lower, dose-escalation regimen (1-10 mg/kg over 9 wk). Overall, the increase of adiponectin concentrations during ISIS 113715 treatment was correlated with the lowering of insulin responses during IVGTT (r = -0.47, P = 0.042). These results indicate that inhibition of PTP-1B with ASOs such as ISIS 113715 may be a viable approach for the treatment and prevention of obesity-associated insulin resistance and type 2 diabetes because they potently increase adiponectin concentrations in addition to improving insulin sensitivity.
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PMID:Inhibition of protein tyrosine phosphatase-1B with antisense oligonucleotides improves insulin sensitivity and increases adiponectin concentrations in monkeys. 1916 74

We have optimized previously discovered benzoic acids 1, which are active as inhibitors of PTP1B and LMW-PTP, two protein tyrosine phosphatases that have emerged as attractive targets for the development of novel therapeutic agents for the treatment of diabetes, obesity, and cancer. Our efforts led to the identification of new and more potent analogues with appreciable selectivity toward human PTP1B and the IF1 isoform of human LMW-PTP.
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PMID:Structure-based optimization of benzoic acids as inhibitors of protein tyrosine phosphatase 1B and low molecular weight protein tyrosine phosphatase. 1928 92

PTP1B(-/-) mice are resistant to diet-induced obesity due to leptin hypersensitivity and consequent increased energy expenditure. We aimed to determine the cellular mechanisms underlying this metabolic state. AMPK is an important mediator of leptin's metabolic effects. We find that alpha1 and alpha2 AMPK activity are elevated and acetyl-coenzyme A carboxylase activity is decreased in the muscle and brown adipose tissue (BAT) of PTP1B(-/-) mice. The effects of PTP1B deficiency on alpha2, but not alpha1, AMPK activity in BAT and muscle are neuronally mediated, as they are present in neuron- but not muscle-specific PTP1B(-/-) mice. In addition, AMPK activity is decreased in the hypothalamic nuclei of neuronal and whole-body PTP1B(-/-) mice, accompanied by alterations in neuropeptide expression that are indicative of enhanced leptin sensitivity. Furthermore, AMPK target genes regulating mitochondrial biogenesis, fatty acid oxidation, and energy expenditure are induced with PTP1B inhibition, resulting in increased mitochondrial content in BAT and conversion to a more oxidative muscle fiber type. Thus, neuronal PTP1B inhibition results in decreased hypothalamic AMPK activity, isoform-specific AMPK activation in peripheral tissues, and downstream gene expression changes that promote leanness and increased energy expenditure. Therefore, the mechanism by which PTP1B regulates adiposity and leptin sensitivity likely involves the coordinated regulation of AMPK in hypothalamus and peripheral tissues.
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PMID:Neuronal protein tyrosine phosphatase 1B deficiency results in inhibition of hypothalamic AMPK and isoform-specific activation of AMPK in peripheral tissues. 1952 36

This study was to explore the effects of a compound (BPG) from Balanophora polyandra Griff on metabolic syndrome in mice. The animal models, developed obesity, dyslipidemia and insulin resistance, were induced by high-fat-diet in C57BL/6 mice, and were treated orally with 100 mg/kg/day BPG and 15 mg/kg/day rosiglitazone, respectively. The age-matched C57BL/6 mice fed with standard chow were used as normal control. The blood glucose, the value of serum triglyceride and the content of triglyceride in the skeletal muscle were determined by biochemical methods. The protein expression was evaluated by western blot. BPG administration decreased body weight gain, adiposity index, serum triglyceride levels, and triglyceride accumulation in skeletal muscle significantly. At the same time, BPG administration also exhibited extensive effects on insulin resistance by improving oral glucose tolerance test, insulin tolerance test and glucose infusion rate in hyperinsulinemic-euglycemic clamp test. Furthermore, in skeletal muscle, BPG reversed the defect expression of IRbeta, IRS-1 and PTP1B, and also decreased the expression of ACCbeta and increased the expression of p-AMPK in the high-fat-diet-induced mice. All the results suggest that BPG improves metabolic syndrome may by the enhancement of insulin sensitivity and fatty acid oxidation.
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PMID:Improvement of high-fat-diet-induced metabolic syndrome by a compound from Balanophora polyandra Griff in mice. 1954 Feb 28

The selective inhibition of PTP1B has been widely recognized as a potential drug target for the treatment of type 2 diabetes and obesity. In the course of screening for PTP1B inhibitory natural products, the MeOH extract of the dried sample of the Antarctic lichen Umbilicaria antarctica was found to exhibit significant inhibitory effect, and the bioassay-guided fractionation and purification afforded three related lichen metabolites 1-3. Compounds 1-3 were identified as gyrophoric acid (1), lecanoric acid (2), and methyl orsellinate (3) mainly by analysis of NMR and MS data. These compounds inhibited PTP1B activity with 50% inhibitory concentration values of 3.6 +/- 0.04 microM, 31 +/- 2.7 microM, and 277 +/- 8.6 microM, respectively. Furthermore, the kinetic analysis of PTP1B inhibition by compound 1 suggested that the compound inhibited PTP1B activity in a non-competitive manner.
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PMID:PTP1B inhibitory effects of tridepside and related metabolites isolated from the Antarctic lichen Umbilicaria antarctica. 1961 69

The brain controls energy homeostasis and body weight by integrating various metabolic signals. Leptin, an adipose-derived hormone, conveys critical information about peripheral energy storage and availability to the brain. Leptin decreases body weight by both suppressing appetite and promoting energy expenditure. Leptin directly targets hypothalamic neurons, including AgRP and POMC neurons. These leptin-responsive neurons widely connect to other neurons in the brain, forming a sophisticated neurocircuitry that controls energy intake and expenditure. The anorexigenic actions of leptin are mediated by LEPRb, the long form of the leptin receptor, in the hypothalamus. LEPRb activates both JAK2-dependent and -independent pathways, including the STAT3, PI 3-kinase, MAPK, AMPK, and mTOR pathways. These pathways act coordinately to form a network that fully mediates leptin response. LEPRb signaling is regulated by both positive (e.g., SH2B1) and negative (e.g., SOCS3 and PTP1B) regulators and by endoplasmic reticulum stress. Leptin resistance, a primary risk factor for obesity, likely results from impairment in leptin transport, LEPRb signaling, and/or the neurocircuitry of energy balance.
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PMID:Recent advances in understanding leptin signaling and leptin resistance. 1972 19

PTP1B is a classical non-transmembrane protein tyrosine phosphatase that plays a key role in metabolic signaling and is a promising drug target for type 2 diabetes and obesity. Accumulating evidence also indicates that PTP1B is involved in cancer, but contrasting findings suggest that it can exert both tumor suppressing and tumor promoting effects depending on the substrate involved and the cellular context. In this review, we will discuss the diverse mechanisms by which PTP1B may influence tumorigenesis as well as recent in vivo data on the impact of PTP1B deficiency in murine cancer models. Together, these results highlight not only the great potential of PTP1B inhibitors in cancer therapy but also the need for a better understanding of PTP1B function prior to use of these compounds in human patients.
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PMID:The two faces of PTP1B in cancer. 1978 70

Anthropometric data from three groups of adolescent girls - preoperative adolescent idiopathic scoliosis (AIS), screened for scoliosis and normals were analysed by comparing skeletal data between higher and lower body mass index subsets. Unexpected findings for each of skeletal maturation, asymmetries and overgrowth are not explained by prevailing theories of AIS pathogenesis. A speculative pathogenetic theory for girls is formulated after surveying evidence including: (1) the thoracospinal concept for right thoracic AIS in girls; (2) the new neuroskeletal biology relating the sympathetic nervous system to bone formation/resorption and bone growth; (3) white adipose tissue storing triglycerides and the adiposity hormone leptin which functions as satiety hormone and sentinel of energy balance to the hypothalamus for long-term adiposity; and (4) central leptin resistance in obesity and possibly in healthy females. The new theory states that AIS in girls results from developmental disharmony expressed in spine and trunk between autonomic and somatic nervous systems. The autonomic component of this double neuro-osseous theory for AIS pathogenesis in girls involves selectively increased sensitivity of the hypothalamus to circulating leptin (genetically-determined up-regulation possibly involving inhibitory or sensitizing intracellular molecules, such as SOC3, PTP-1B and SH2B1 respectively), with asymmetry as an adverse response (hormesis); this asymmetry is routed bilaterally via the sympathetic nervous system to the growing axial skeleton where it may initiate the scoliosis deformity (leptin-hypothalamic-sympathetic nervous system concept = LHS concept). In some younger preoperative AIS girls, the hypothalamic up-regulation to circulating leptin also involves the somatotropic (growth hormone/IGF) axis which exaggerates the sympathetically-induced asymmetric skeletal effects and contributes to curve progression, a concept with therapeutic implications. In the somatic nervous system, dysfunction of a postural mechanism involving the CNS body schema fails to control, or may induce, the spinal deformity of AIS in girls (escalator concept). Biomechanical factors affecting ribs and/or vertebrae and spinal cord during growth may localize AIS to the thoracic spine and contribute to sagittal spinal shape alterations. The developmental disharmony in spine and trunk is compounded by any osteopenia, biomechanical spinal growth modulation, disc degeneration and platelet calmodulin dysfunction. Methods for testing the theory are outlined. Implications are discussed for neuroendocrine dysfunctions, osteopontin, sympathoactivation, medical therapy, Rett and Prader-Willi syndromes, infantile idiopathic scoliosis, and human evolution. AIS pathogenesis in girls is predicated on two putative normal mechanisms involved in trunk growth, each acquired in evolution and unique to humans.
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PMID:Pathogenesis of adolescent idiopathic scoliosis in girls - a double neuro-osseous theory involving disharmony between two nervous systems, somatic and autonomic expressed in the spine and trunk: possible dependency on sympathetic nervous system and hormones with implications for medical therapy. 1987 75

As the insulin and leptin signaling pathway can be regulated by PTP1B, it has been suggested that compounds that reduce PTP1B activity or expression levels can be used for treating type 2 diabetes and obesity. In the course of our screening efforts on new PTP1B inhibitors, six new flavanones ( 1- 6) with dihydrofuran moiety and two known flavanones ( 7 and 8) were isolated from the stem bark of Erythrina abyssinica (Leguminosae). Their structures were elucidated on the basis of spectroscopic (including UV, CD, MS, 1D, and 2D NMR) and physicochemical analyses. With the exception of 3 and 5, the compounds inhibited PTP1B activity in an IN VITRO assay with IC (50) values ranging from 15.2 +/- 1.2 to 19.6 +/- 2.3 microM, whereas RK-682 as a positive control displayed an IC (50) value of 4.7 +/- 0.5 microM.
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PMID:New prenylated flavanones from Erythrina abyssinica with protein tyrosine phosphatase 1B (PTP1B) inhibitory activity. 1996 Apr 12

Insulin is an inducer of brown fat adipogenesis through the activation of a signalling network that involves positive/negative modulators. Given the importance of brown adipose tissue (BAT) for basal thermogenic energy expenditure, we investigated the role of PTP1B in the acquisition of terminal differentiated phenotype and in the apoptotic responses of brown adipocytes. Immortalized brown preadipocytes lacking (PTP1B(-/-)) or expressing (PTP1B(+/+)) PTP1B have been generated. PTP1B deficiency accelerated a full program of brown adipogenesis including induction of transcription factors, coactivators, adipogenic markers and signalling molecules. Fully differentiated PTP1B(-/-) brown adipocytes were resistant to tumor necrosis factor (TNFalpha)-induced apoptosis as these cells were protected against caspase-8 activation, FLIP degradation, Bid cleavage and caspase-3 activation compared to wild-type controls. These events were recovered by PTP1B rescue. Survival signalling including phosphorylation of IRS-1 and Akt/PKB and BclxL expression were decreased in TNFalpha-treated PTP1B(-/-) cells but not in the wild-type. Similarly, PTP1B(-/-) brown adipocytes were protected against resveratrol-induced apoptosis. Phosphorylation of Akt/PKB and Foxo1 phosphorylation/acetylation decreased exclusively in resveratrol-treated wild-type cells, leading to nuclear localization of Foxo1 and up-regulation of Bim. Thus, PTP1B inhibition could be of benefit against obesity by counteracting TNFalpha-induced brown fat atrophy, and combined with resveratrol might improve low-grade inflammation.
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PMID:Beneficial effects of PTP1B deficiency on brown adipocyte differentiation and protection against apoptosis induced by pro- and anti-inflammatory stimuli. 2002


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