Protein tyrosine phosphatases in hypothalamic insulin and leptin signaling

The hypothalamus is critical to the coordination of energy balance and glucose homeostasis. It responds to peripheral factors, such as insulin and leptin, that convey to the brain the degree of adiposity and the metabolic status of the organism. The development of leptin and insulin resistance in hypothalamic neurons appears to have a key role in the exacerbation of diet-induced obesity. In rodents, this has been attributed partly to the increased expression of the tyrosine phosphatases Protein Tyrosine Phosphatase 1B (PTP1B) and T cell protein tyrosine phosphatase (TCPTP), which attenuate leptin and insulin signaling. Deficiencies in PTP1B and TCPTP in the brain, or specific neurons, promote insulin and leptin signaling and prevent diet-induced obesity, type 2 diabetes mellitus (T2DM), and fatty liver disease. Although targeting phosphatases and hypothalamic circuits remains challenging, recent advances indicate that such hurdles might be overcome. Here, we focus on the roles of PTP1B and TCPTP in insulin and leptin signaling and explore their potential as therapeutic targets

A cross-cultural study on consumer preferences for olive oil

In this paper, we study consumer preferences for olive oil across four countries (Denmark, France, Tunisia, and the US). Based on a large-scale study with olive oil consumers (N = 3,462), we use the Best-Worst Scaling method to measure perceived importance for product attributes known to influence consumer choice. Our results show that consumers across all countries rate type, price, prior experience, and country of origin as important product attributes. On the other hand, packaging, label design, and brands are considered as less important product attributes. While the perceived importance for olive oil attributes differs across countries, the order of importance is almost similar for all countries. We further derive a three-segment solution and describe each segment based on its attitudinal beliefs, usage, and socio-demographic profile. We discuss implications for the study of consumer preferences for olive oil and provide managerial insights.© 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).fi=vertaisarvioitu|en=peerReviewed

Crystallization of importin alpha, the nuclear-import receptor

Crystals of recombinant importin alpha, the nuclear-import receptor, have been obtained at two different pH conditions by vapour diffusion using sodium citrate as precipitant and dithiothreitol as an additive. At pH 4-5, the crystals have the symmetry of the trigonal space group P3(1)21 or P3(2)21 (a = b = 78.0, c = 255.8 Angstrom, gamma = 120 degrees); at pH 6-7, the crystals have the symmetry of the orthorhombic space group P2(1)2(1)2(1) (a = 78.5, b = 89.7, c = 100.5 Angstrom). In both cases, there is probably one molecule of importin ct in the asymmetric unit. At least one of the crystal forms diffracts to a resolution higher than 3 Angstrom using the laboratory X-ray source; the crystals are suitable for crystal structure determination

Study of the Influence of adding styrene-ethylene/butadiene-styrene in acrylonitrile-butadiene-styrene and polyethylene blends

This work studies the recovery of two grades of acrylonitrile butadiene styrene (ABS) contaminated with low-density polyethylene (LDPE), by adding styrene ethylene/butadiene styrene (SEBS). To simulate contaminated ABS, virgin ABS was mixed with 1, 2, 4, and 8% of LDPE and then extruded at 220°C. After this, the ABS with the highest percentage of LDPE (8%) was mixed with 1, 2, 4, and 8% of SEBS and then extruded. Different blends were mechanically, rheologically, optically, and dimensionally characterized to study how different percentages of LDPE and SEBS modify their properties. The results obtained show how the tensile strength, Young modulus, elongation, and impact strength linearly decrease as the LDPE amount increases, for both natural and black ABS. Through the addition of SEBS to contaminated ABS, it is possible to improve its impact strength and elongation values nearly to those of virgin ABS. However, its tensile strength and Young modulus show no improvement, and even show a slight reduction. Regarding the rheological properties, the LDPE contamination in ABS causes a remarkable decrease in viscosity, and adding SEBS to the blend lowers its viscosity even further for both natural and black grades. This reduction is not a negative aspect, but rather quite the reverse, as the more fluid the material, the easier the mold injection process becomes. POLYM. ENG. SCI., 54:1313 1324, 2014. © 2013 Society of Plastics EngineersContract grant sponsor: "Subdireccion de Investigacion, Desarrollo e Innovacion de la Universitat Politecnica de Valencia" to the research project: "la investigacion de sistemas ternarios aplicados a los materiales polimericos para la mejora de residuos de estireno," Ref.: 20091056 belonging to the research program primeros proyectos de investigacion; contract grant number: PAID 06-09.Peydro, MA.; Parres, F.; Navarro Vidal, R.; Sanchez-Caballero, S. (2014). Study of the Influence of adding styrene-ethylene/butadiene-styrene in acrylonitrile-butadiene-styrene and polyethylene blends. Polymer Engineering and Science. 54(6):1313-1324. https://doi.org/10.1002/pen.23680S13131324546Adrados, A., de Marco, I., Caballero, B. M., López, A., Laresgoiti, M. F., & Torres, A. (2012). Pyrolysis of plastic packaging waste: A comparison of plastic residuals from material recovery facilities with simulated plastic waste. Waste Management, 32(5), 826-832. doi:10.1016/j.wasman.2011.06.016Brebu, M., Bhaskar, T., Murai, K., Muto, A., Sakata, Y., & Uddin, M. A. (2004). Thermal degradation of PE and PS mixed with ABS-Br and debromination of pyrolysis oil by Fe- and Ca-based catalysts. Polymer Degradation and Stability, 84(3), 459-467. doi:10.1016/j.polymdegradstab.2004.02.003Maris, E., Aoussat, A., Naffrechoux, E., & Froelich, D. (2012). Polymer tracer detection systems with UV fluorescence spectrometry to improve product recyclability. Minerals Engineering, 29, 77-88. doi:10.1016/j.mineng.2011.09.016Ta?demir, M. (2004). Properties of acrylonitrile-butadiene-styrene/polycarbonate blends with styrene-butadiene-styrene block copolymer. Journal of Applied Polymer Science, 93(6), 2521-2527. doi:10.1002/app.20708Taşdem??r, M., & Karatop, Ş. (2006). Effect of styrene–isopren–styrene addition on the recycled polycarbonate/acrylonitrile–butadiene–styrene polymer blends. Journal of Applied Polymer Science, 101(1), 559-566. doi:10.1002/app.23555Li, B., Wan, C., Zhang, Y., & Ji, J. (2010). Blends of poly(2,6-dimethyl-1,4-phenylene oxide)/polyamide 6 toughened by maleated polystyrene-based copolymers: Mechanical properties, morphology, and rheology. Journal of Applied Polymer Science, 115(6), 3385-3392. doi:10.1002/app.30742Yin, N., Zhang, Y., Zhang, Y., Zhang, X., & Zhou, W. (2007). Preparation and properties of PC/SAN alloy modified with styrene-ethylene-butylene-styrene block copolymer. Journal of Applied Polymer Science, 106(1), 637-643. doi:10.1002/app.26681Peydró, M. A., Parres, F., Crespo, J. E., & Juárez, D. (2010). Study of rheological behavior during the recovery process of high impact polystyrene using cross-WLF model. Journal of Applied Polymer Science, 120(4), 2400-2410. doi:10.1002/app.33444Tiganis, B. ., Burn, L. ., Davis, P., & Hill, A. . (2002). Thermal degradation of acrylonitrile–butadiene–styrene (ABS) blends. Polymer Degradation and Stability, 76(3), 425-434. doi:10.1016/s0141-3910(02)00045-9Arostegui, A., Sarrionandia, M., Aurrekoetxea, J., & Urrutibeascoa, I. (2006). Effect of dissolution-based recycling on the degradation and the mechanical properties of acrylonitrile–butadiene–styrene copolymer. Polymer Degradation and Stability, 91(11), 2768-2774. doi:10.1016/j.polymdegradstab.2006.03.019Karahaliou, E.-K., & Tarantili, P. A. (2009). Stability of ABS compounds subjected to repeated cycles of extrusion processing. Polymer Engineering & Science, 49(11), 2269-2275. doi:10.1002/pen.21480Karahaliou, E.-K., & Tarantili, P. A. (2009). Preparation of poly(acrylonitrile-butadiene-styrene)/montmorillonite nanocomposites and degradation studies during extrusion reprocessing. Journal of Applied Polymer Science, 113(4), 2271-2281. doi:10.1002/app.30158Chang, T. C., & Faison, E. (2001). Shrinkage behavior and optimization of injection molded parts studied by the taguchi method. Polymer Engineering & Science, 41(5), 703-710. doi:10.1002/pen.10766Shen, C., Wang, L., & Li, Q. (2007). Optimization of injection molding process parameters using combination of artificial neural network and genetic algorithm method. Journal of Materials Processing Technology, 183(2-3), 412-418. doi:10.1016/j.jmatprotec.2006.10.036Tang, S. H., Tan, Y. J., Sapuan, S. M., Sulaiman, S., Ismail, N., & Samin, R. (2007). The use of Taguchi method in the design of plastic injection mould for reducing warpage. Journal of Materials Processing Technology, 182(1-3), 418-426. doi:10.1016/j.jmatprotec.2006.08.025Ganguly, A., Saha, S., Bhowmick, A. K., & Chattopadhyay, S. (2008). Augmenting the performance of acrylonitrile–butadiene–styrene plastics for low-noise dynamic applications. Journal of Applied Polymer Science, 109(3), 1467-1475. doi:10.1002/app.2805

TCPTP-deficiency in muscle does not alter insulin signalling and glucose homeostasis.

Aims/Hypothesis: Insulin activates the insulin receptor (IR) protein tyrosine kinase and downstream phosphatidylinositol-3-kinase (PI3K)/Akt signalling in muscle to promote glucose uptake. The IR can serve as a substrate for the protein tyrosine phosphatases (PTP) 1B and TCPTP, which share a striking 74% sequence identity in their catalytic domains. PTP1B is a validated therapeutic target for the alleviation of insulin resistance in type 2 diabetes. PTP1B dephosphorylates the IR in liver and muscle to regulate glucose homeostasis, whereas TCPTP regulates IR signalling and gluconeogenesis in the liver. In this study we have assessed for the first time the role of TCPTP in the regulation of IR signalling in muscle. Methods: We generated muscle-specific TCPTP-deficient (MCK-Cre;Ptpn2lox/lox) mice and assessed the impact on glucose homeostasis and muscle IR signalling in chow versus high fat fed mice. Results: Blood glucose and insulin levels, insulin and glucose tolerances and insulininduced muscle IR activation and downstream PI3K/Akt signalling remained unaltered in chow fe

Regulation of insulin signaling through reversible oxidation of the protein-tyrosine phosphatases TC45 and PTP1B

Many studies have illustrated that the production of reactive oxygen species (ROS) is important for optimal tyrosine phosphorylation and signaling in response to diverse stimuli. Protein-tyrosine phosphatases (PTPs), which are important regulators of signal transduction, are exquisitely sensitive to inhibition after generation of ROS, and reversible oxidation is becoming recognized as a general physiological mechanism for regulation of PTP function. Thus, production of ROS facilitates a tyrosine phosphorylation-dependent cellular signaling response by transiently inactivating those PTPs that normally suppress the signal. In this study, we have explored the importance of reversible PTP oxidation in the signaling response to insulin. Using a modified ingel PTP assay, we show that stimulation of cells with insulin resulted in the rapid and transient oxidation and inhibition of two distinct PTPs, which we have identified as PTP1B and TC45, the 45-kDa spliced variant of the T cell protein-tyrosine phosphatase. We investigated further the role of TC45 as a regulator of insulin signaling by combining RNA interference and the use of substrate-trapping mutants. We have shown that TC45 is an inhibitor of insulin signaling, recognizing the beta-subunit of the insulin receptor as a substrate. The data also suggest that this strategy, using ligand-induced oxidation to tag specific PTPs and using interference RNA and substrate-trapping mutants to illustrate their role as regulators of particular signal transduction pathways, may be applied broadly across the PTP family to explore function

T-Cell Protein Tyrosine Phosphatase Attenuates STAT3 and Insulin Signaling in the Liver to Regulate Gluconeogenesis

OBJECTIVE: Insulin-induced phosphatidylinositol 3-kinase (PI3K)/Akt signaling and interleukin-6 (IL-6)-instigated JAK/STAT3-signaling pathways in the liver inhibit the expression of gluconeogenic genes to decrease hepatic glucose output. The insulin receptor (IR) and JAK1 tyrosine kinases and STAT3 can serve as direct substrates for the T-cell protein tyrosine phosphatase (TCPTP). Homozygous TCPTP-deficiency results in perinatal lethality prohibiting any informative assessment of TCPTP's role in glucose homeostasis. Here we have used Ptpn2+/- mice to investigate TCPTP's function in glucose homeostasis. RESEARCH DESIGN AND METHODS: We analyzed insulin sensitivity and gluconeogenesis in chow versus high-fat-fed (HFF) Ptpn2+/- and Ptpn2+/+ mice and insulin and IL-6 signaling and gluconeogenic gene expression in Ptpn2+/- and Ptpn2+/+ hepatocytes. RESULTS: HFF Ptpn2+/- mice exhibited lower fasted blood glucose and decreased hepatic glucose output as determined in hyperinsulinemic euglycemic clamps and by the decreased blood glucose levels in pyruvate tolerance tests. The reduced hepatic glucose output coincided with decreased expression of the gluconeogenic genes G6pc and Pck1 and enhanced hepatic STAT3 phosphorylation and PI3K/Akt signaling in the fasted state. Insulin-induced IR-beta-subunit Y1162/Y1163 phosphorylation and PI3K/Akt signaling and IL-6-induced STAT3 phosphorylation were also enhanced in isolated Ptpn2+/- hepatocytes. The increased insulin and IL-6 signaling resulted in enhanced suppression of G6pc and Pck1 mRNA. CONCLUSIONS: Liver TCPTP antagonises both insulin and STAT3 signaling pathways to regulate gluconeogenic gene expression and hepatic glucose output

Strain-Dependent Differences in Bone Development, Myeloid Hyperplasia, Morbidity and Mortality in Ptpn2-Deficient Mice

Single nucleotide polymorphisms in the gene encoding the protein tyrosine phosphatase TCPTP (encoded by PTPN2) have been linked with the development of autoimmunity. Here we have used Cre/LoxP recombination to generate Ptpn2ex2−/ex2− mice with a global deficiency in TCPTP on a C57BL/6 background and compared the phenotype of these mice to Ptpn2−/− mice (BALB/c-129SJ) generated previously by homologous recombination and backcrossed onto the BALB/c background. Ptpn2ex2−/ex2− mice exhibited growth retardation and a median survival of 32 days, as compared to 21 days for Ptpn2−/− (BALB/c) mice, but the overt signs of morbidity (hunched posture, piloerection, decreased mobility and diarrhoea) evident in Ptpn2−/− (BALB/c) mice were not detected in Ptpn2ex2−/ex2− mice. At 14 days of age, bone development was delayed in Ptpn2−/− (BALB/c) mice. This was associated with increased trabecular bone mass and decreased bone remodeling, a phenotype that was not evident in Ptpn2ex2−/ex2− mice. Ptpn2ex2−/ex2− mice had defects in erythropoiesis and B cell development as evident in Ptpn2−/− (BALB/c) mice, but not splenomegaly and did not exhibit an accumulation of myeloid cells in the spleen as seen in Ptpn2−/− (BALB/c) mice. Moreover, thymic atrophy, another feature of Ptpn2−/− (BALB/c) mice, was delayed in Ptpn2ex2−/ex2− mice and preceded by an increase in thymocyte positive selection and a concomitant increase in lymph node T cells. Backcrossing Ptpn2−/− (BALB/c) mice onto the C57BL/6 background largely recapitulated the phenotype of Ptpn2ex2−/ex2− mice. Taken together these results reaffirm TCPTP's important role in lymphocyte development and indicate that the effects on morbidity, mortality, bone development and the myeloid compartment are strain-dependent

Leptin and Insulin Act on POMC Neurons to Promote the Browning of White Fat

SummaryThe primary task of white adipose tissue (WAT) is the storage of lipids. However, “beige” adipocytes also exist in WAT. Beige adipocytes burn fat and dissipate the energy as heat, but their abundance is diminished in obesity. Stimulating beige adipocyte development, or WAT browning, increases energy expenditure and holds potential for combating metabolic disease and obesity. Here, we report that insulin and leptin act together on hypothalamic neurons to promote WAT browning and weight loss. Deletion of the phosphatases PTP1B and TCPTP enhanced insulin and leptin signaling in proopiomelanocortin neurons and prevented diet-induced obesity by increasing WAT browning and energy expenditure. The coinfusion of insulin plus leptin into the CNS or the activation of proopiomelanocortin neurons also increased WAT browning and decreased adiposity. Our findings identify a homeostatic mechanism for coordinating the status of energy stores, as relayed by insulin and leptin, with the central control of WAT browning

Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance

Reactive oxygen species (ROS) generated during exercise are considered integral for the health-promoting effects of exercise. However, the precise mechanisms by which exercise and ROS promote metabolic health remain unclear. Here, we demonstrate that skeletal muscle NADPH oxidase 4 (NOX4), which is induced after exercise, facilitates ROS-mediated adaptive responses that promote muscle function, maintain redox balance, and prevent the development of insulin resistance. Conversely, reductions in skeletal muscle NOX4 in aging and obesity contribute to the development of insulin resistance. NOX4 deletion in skeletal muscle compromised exercise capacity and antioxidant defense and promoted oxidative stress and insulin resistance in aging and obesity. The abrogated adaptive mechanisms, oxidative stress, and insulin resistance could be corrected by deleting the H2O2-detoxifying enzyme GPX-1 or by treating mice with an agonist of NFE2L2, the master regulator of antioxidant defense. These findings causally link NOX4-derived ROS in skeletal muscle with adaptive responses that promote muscle function and insulin sensitivity