Obesity and Diabetes with Ageing

Research interest

Aging in the Wistar rat associates with the development of adiposity, hyperleptinemia, whole body insulin resistance, central leptin and insulin resistance, as well as decreases in insulin sensitivity in adipose and several muscle tissues.

Our group has actively been involved studying in white adipose tissue the process of insulin resistance associated with aging, analyzing in vivo, in situ and in vitro the early steps of the insulin signaling transduction pathway in aged rats fed ad libitum and/or after three months food restriction. We have also performed in vitro studies in red and white skeletal muscle analyzing insulin action. Besides, we have extended our studies to the liver studying the crosstalk between insulin and leptin signaling on glucose and lipid metabolism, as well as gene expression studies in intracerebroventricular leptin and insulin treated rats. Finally, in the last years we have initiated the study of the role of resistin and of a nonsecretable new resistin isoform that we have named s-resistin (short-resistin) in our model of insulin resistance with aging, analyzing the gene expression of this protein in multiple tissues with aging and after three months food restriction.

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Funding

  • Título: Efectos en el hipotálamo de los ácidos grasos y las ceramidas sobre el desarrollo de resistencia a insulina y leptina con la edad
    Entidad financiadora: Consejería de Educación, Cultura y Deportes
    I.P.: Antonio Andrés Hueva
    Duración, desde: 27/09/2014   hasta: 26/09/2016
  • Título: Mecanismos implicados en la resistencia a insulina y leptina con el envejecimiento: papel de la acumulación de lípidos y el estrés del retículo del hipotálamo
    Entidad financiadora: Ministerio de Economía y Competitividad
    I.P.: Antonio Andrés Hueva
    Duración, desde: 01/01/2013   hasta: 31/12/2015
  • Título: Hepatocyte growth factor and insuline resistance
    Entidad financiadora: Research Executive Agency, Comisión Europea
    I.P.: Germán Manuel Perdomo Hernández
    Duración, desde: 15/03/2013   hasta: 31/05/2014
  • Título: Estudio de los mecanismos celulares y moleculares que vinculan al hígado graso con la obesidad, la resistencia a la insulina y la diabetes tipo 2
    Entidad financiadora: Consejería de Educación y Ciencia
    I.P.: Nilda de Carmen Gallardo Alpízar
    Duración, desde: 01/04/2010   hasta: 31/12/2013
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Publications

  • Rodríguez M, Moltó E, Aguado L, Gallardo N, Andrés A, Arribas C. S-resistin, a non secretable resistin isoform, impairs the insulin signalling pathway in 3T3-L1 adipocytes. J Physiol Biochem. 2015 Jun 4. [Epub ahead of print]. (A).
  • Salamanca A, Bárcena B, Arribas C, Fernández-Agulló T, Martínez C, Carrascosa JM, Ros M, Andrés A, Gallardo N. Aging impairs the hepatic subcellular distribution of ChREBP in response to fasting/feeding in rats: Implications on hepatic steatosis. Exp Gerontol. 2015 May 21. pii: S0531-5565(15)00157-6. doi: 10.1016/j.exger.2015.05.009. (A).
  • Visiedo F, Bugatto F, Carrasco-Fernández C, Sáez-Benito A, Mateos RM, Cózar-Castellano I, Bartha JL, Perdomo G. Hepatocyte growth factor is elevated in amniotic fluid from obese women and regulates placental glucose and fatty acid metabolism. Placenta. 2015 Apr;36(4):381-8. doi: 10.1016/j.placenta.2015.01.199. (A).
  • Jiménez-Palomares M, López-Acosta JF, Villa-Pérez P, Moreno-Amador JL, Muñoz-Barrera J, Fernández-Luis S, Heras-Pozas B, Perdomo G, Bernal-Mizrachi E, Cózar-Castellano I.. Cyclin C stimulates ?-cell proliferation in rat and human pancreatic ?-cells. Am J Physiol Endocrinol Metab. 2015 Mar 15;308(6):E450-9. doi: 10.1152/ajpendo.00260.2014. (A).
  • Rueda CB, Traba J, Amigo I, Llorente-Folch I, González-Sánchez P, Pardo B, Esteban JA, Del Arco A, Satrústegui J. Mitochondrial ATP-Mg/Pi Carrier SCaMC-3/Slc25a23 Counteracts PARP-1-Dependent Fall in Mitochondrial ATP Caused by Excitotoxic Insults in Neurons. J Neurosci. 2015 Feb 25;35(8):3566-81. doi: 10.1523/JNEUROSCI.2702-14.2015. (A).
  • Bühler KM, Huertas E, Echeverry-Alzate V, Giné E, Moltó E, Montoliu L, López-Moreno JA. Risky alcohol consumption in young people is associated with the fatty acid amide hydrolase gene polymorphism C385A and affective rating of drug pictures. Mol Genet Genomics. 2014; 289(3):279-89. doi: 10.1007/s00438-013-0809-x. (A).
  • Ramos-Rodriguez JJ, Molina-Gil S, Ortiz-Barajas O, Jimenez-Palomares M, Perdomo G, Cozar-Castellano I, Lechuga-Sancho AM, Garcia-Alloza M. Central proliferation and neurogenesis is impaired in type 2 diabetes and prediabetes animal models. PLoS One. 2014 Feb 20;9(2):e89229. (A).
  • Calero R, Morchon E, Johnsen JI, Serrano R. Sunitinib Suppress Neuroblastoma Growth through Degradation of MYCN and Inhibition of Angiogenesis. PLoS One. 2014 Apr 23;9(4):e95628. (A).
  • Rueda CB, Llorente-Folch I, Amigo I, Contreras L, González-Sánchez P, Martínez-Valero P, Juaristi I, Pardo B, Del Arco A, Satrústegui J. Ca2+ regulation of mitochondrial function in neurons. Biochim Biophys Acta. 2014;1837(10):1617-24. doi: 10.1016/j.bbabio.2014.04.010. (A).
  • López-Acosta JF, Moreno-Amador JL, Jiménez-Palomares M, Díaz-Marrero AR, Cueto M, Perdomo G, Cózar-Castellano I. Epoxypukalide induces proliferation and protects against cytokine-mediated apoptosis in primary cultures of pancreatic ?-cells. PLoS One. 2013; 8(1):e52862. (A).
  • Jimenez-Gomez G, Benavente-Fernandez I, Lubian-Lopez SP, Matias-Vega M, Lechuga-Campoy JL, Saez-Benito A, Lechuga-Sancho AM, Perdomo G. Hepatocyte growth factor as an indicator of neonatal maturity. J Pediatr Endocrinol Metab. 2013;26(7-8):709-14. (A).
  • Ramos-Rodriguez JJ, Ortiz O, Jimenez-Palomares M, Kay KR, Berrocoso E, Murillo-Carretero MI, Perdomo G, Spires-Jones T, Cozar-Castellano I, Lechuga-Sancho AM, Garcia-Alloza M.. Differential central pathology and cognitive impairment in pre-diabetic and diabetic mice. Psychoneuroendocrinology. 2013;38(11):2462-75. (A).
  • Visiedo F, Bugatto F, Sánchez V, Cózar-Castellano I, Bartha JL, Perdomo G. High glucose levels reduce fatty acid oxidation and increase triglyceride accumulation in human placenta. Am J Physiol Endocrinol Metab. 2013; 305(2):E205-12. (A).
  • Horrillo D, Gallardo N, Lauzurica N, Barrus MT, San Frutos MG, Andres A, Ros M, Fernandez-Agullo T. Development of liver fibrosis during aging: effects of caloric restriction. J Biol Regul Homeost Agents. 2013;27(2):377-88. (A).
  • Llorente-Folch I, Rueda CB, Amigo I, Del Arco A, Saheki T, Pardo B, Satrústegui J. Calcium-Regulation of Mitochondrial Respiration Maintains ATP Homeostasis and Requires ARALAR/AGC1-Malate Aspartate Shuttle in Intact Cortical Neurons. J Neurosci. 2013;33(35):13957-71. (A).
  • Amigo I, Traba J, González-Barroso MM, Rueda CB, Fernández M, Rial E, Sánchez A, Satrústegui J, Del Arco A.. Glucagon regulation of oxidative phosphorylation requires an increase in matrix adenine nucleotide content through Ca2+ activation of the mitochondrial ATP-Mg/Pi carrier SCaMC-3. J Biol Chem. 2013; 288[11]: 7791-7802. (A).
  • Traba J, Del Arco A, Duchen MR, Szabadkai G, Satrústegui J. SCaMC-1 promotes cancer cell survival by desensitizing mitochondrial permeability transition via ATP/ADP-mediated matrix Ca(2+) buffering. Cell Death Differ. 2012;19(4):650-660. [Epub 2011]. (A).
  • Amigo I, Traba J, Satrústegui J, del Arco A. SCaMC-1Like a member of the mitochondrial carrier (MC) family preferentially expressed in testis and localized in mitochondria and chromatoid body. PLoS One. 2012;7(7):e40470. (A).
  • Pintado C, Gavilán MP, Gavilán E, García-Cuervo L, Gutiérrez A, Vitorica J, Castaño A, Ríos RM, Ruano D. Lipopolysaccharide-induced neuroinflammation leads to the accumulation of ubiquitinated proteins and increases susceptibility to neurodegeneration induced by proteasome inhibition in rat hippocampus. J Neuroinflammation. 2012;9(1):87. (A).
  • Gavilán MP, Pintado C, Gavilán E, García-Cuervo LM, Castaño A, Ríos RM, Ruano D. Age-related differences in the dynamics of hippocampal proteasome recovery. J Neurochem. 2012;123(4):635-644. (A).
  • De Solís AJ, Fernández-Agulló T, García-SanFrutos M, Pérez-Pardo P, Bogónez E, Andrés A, Ros M, Carrascosa JM. Impairment of skeletal muscle insulin action with aging in Wistar rats: role of leptin and caloric restriction.Mech Ageing Dev. 2012. 133[5]: 306-316. (A).
  • Horrillo D, Sierra J, Arribas C, García-San Frutos M, Carrascosa JM, Lauzurica N, Fernández-Agulló T, Ros M. Age-associated development of inflammation in Wistar rats: Effects of caloric restriction. Arch Physiol Biochem. 2011. 117[3]: 140-150. (A).
  • Carrascosa JM, Andrés A, Ros M, Bogónez E, Arribas C, Fernández-Agulló T, De Solís AJ, Gallardo N, Martínez C. Development of insulin resistance during aging: involvement of central processes and role of adipokines. Curr Protein Pept Sci. 2011. 12[4]: 305-315. (A).
  • Bonzón-Kulichenko E, Fernández-Agulló T, Moltó E, Serrano R, Fernández A, Ros M, Carrascosa JM, Arribas C, Martínez C, Andrés A, Gallardo N. Regulation of Insulin-Stimulated Glucose Uptake in Rat White Adipose Tissue upon Chronic Central Leptin Infusion: Effects on Adiposity. Endocrinology. 2011. 152[4]: 1366-1377. (A).
  • Fernández CM, Del Arco A, Gallardo N, Aguado L, Rodriguez M, Ros M, Carrascosa JM, Andrés A, Arribas C. S-resistin inhibits adipocyte differentiation and increases TNFalpha expression and secretion in 3T3-L1 cells.Biochim Biophys Acta. 2010. 1803[10]: 1131-1141. (A).
  • Traba J, Satrústegui J, del Arco A. Transport of adenine nucleotides in the mitochondria of Saccharomyces cerevisiae: interactions between the ADP/ATP carriers and the ATP-Mg/Pi carrier. Mitochondrion. 2009. 9[2]: 79-85. (A).
  • Serrano R, Barrenetxe J, Orbe J, Rodríguez JA, Gallardo N, Martinez C, Andres A, Páramo JA. Tissue-specific PAI-1 gene expression and glycosylation pattern in insulin-resistant old rats. Am J Physiol Regul Integr Comp Physiol. 2009. 297[5]: 1563-1569. (A).
  • Traba J, Satrústegui J, del Arco A. Characterization of SCaMC-3-like/slc25a41, a novel calcium-independent mitochondrial ATP-Mg/Pi carrier. Biochem J. 2009. 418[1]: 125-133. (A).
  • Mármol P, Pardo B, Wiederkehr A, del Arco A, Wollheim CB, Satrústegui J. Requirement for aralar and its Ca2+-binding sites in Ca2+ signal transduction in mitochondria from INS-1 clonal beta-cells. J Biol Chem. 2009. 284[1]: 515-524. [Epub 2008]. (A).
  • Serrano R, Villar M, Gallardo N, Carrascosa JM, Martinez C, Andrés A. The effect of aging on insulin signalling pathway is tissue dependent: Central role of adipose tissue in the insulin resistance of aging. Mech Ageing Dev. 2009. 130[3]: 189-197. [Epub 2008]. (A).
  • Fernández CM, Moltó E, Gallardo N, del Arco A, Martínez C, Andrés A, Ros M, Carrascosa JM, Arribas C. The expression of rat resistin isoforms is differentially regulated in visceral adipose tissues: effects of aging and food restriction. Metabolism. 2009. 58[2]: 204-211. (A).
  • Carrascosa JM, Ros M, Andrés A, Fernández-Agulló T, Arribas C. Changes in the neuroendocrine control of energy homeostasis by adiposity signals during aging. Exp Gerontol. 2009. 44[1-2]: 20-25. [Epub 2008]. (A).
  • Bonzón-Kulichenko E, Schwudke D, Gallardo N, Moltó E, Fernández-Agulló T, Shevchenko A, Andrés A.. Central Leptin Regulates Total Ceramide Content and Sterol Regulatory Element Binding Protein-1C Proteolytic Maturation in Rat White Adipose Tissue. Endocrinology. 2009. 150[1]: 169-178. [Epub 2008]. (A).
  • Traba J, Froschauer EM, Wiesenberger G, Satrústegui J, Del Arco A. Yeast mitochondria import ATP through the calcium-dependent ATP-Mg/Pi carrier Sal1p, and are ATP consumers during aerobic growth in glucose. Mol Microbiol. 2008. 69[3]: 570-585. (A).
  • Pérez C, Fernández-Agulló T, De Solís AJ, Ros M, Andrés A, Carrascosa JM. Effects of chronic acarbose treatment on adipocyte insulin responsiveness, serum levels of leptin and adiponectin and hypothalamic NPY expression in obese diabetic Wistar rats. Clin Exp Pharmacol Physiol. 2008. 35[3]: 253-261. (A).
  • Satrústegui J, Pardo B, Del Arco A. Mitochondrial transporters as novel targets for intracellular calcium signaling. Physiol Rev. 2007. 87[1]: 29-67. (A).
  • Satrústegui J, Contreras L, Ramos M, Marmol P, del Arco A, Saheki T, Pardo B. Role of aralar, the mitochondrial transporter of aspartate-glutamate, in brain N-acetylaspartate formation and Ca(2+) signaling in neuronal mitochondria. J Neurosci Res. 2007. 85[15]: 3359-3366. (A).
  • Molto E, Bonzon-Kulichenko E, Gallardo N, Andres A. MTPA: A crustacean metallothionein that affects hepatopancreatic mitochondrial functions. Arch Biochem Biophys. 2007. 467[1]: 31-40. (A).
  • Escriva F, Gavete ML, Fermin Y, Perez C, Gallardo N, Alvarez C, Andres A, Ros M, Carrascosa JM. Effect of age and moderate food restriction on insulin sensitivity in Wistar rats: role of adiposity. J Endocrinol. 2007. 194[1]: 131-141. (A).
  • Garcia-San Frutos M, Fernandez-Agullo T, De Solis AJ, Andres A, Arribas C, Carrascosa JM, Ros M.. Impaired central insulin response in aged wistar rats: role of adiposity. Endocrinology. 2007. 148: 5238-5247. (A).
  • Gallardo N, Bonzon-Kulichenko E, Fernandez-Agullo T, Molto E, Gomez-Alonso S, Blanco P, Carrascosa JM, Ros M, Andres A. Tissue-specific effects of central leptin on the expression of genes involved in lipid metabolism in liver and white adipose tissue. Endocrinology. 2007. 148[12]: 5604-4610. (A).
  • Villar M, Serrano R, Gallardo N, Carrascosa JM, Martínez C, Andrés A. Altered subcellular distribution of IRS-1 and IRS-3 is associated with defective Akt activation and GLUT4 translocation in insulin-resistant old rat adipocytes. Biochim. Biophys. Acta-Mol. Cell Res.. 2006. 1763[2]: 197-206. (A).
  • Arco AD, Satrustegui J. New mitochondrial carriers: an overview. CMLS-Cell Mol Life Sci. 2005. 62(19-20): 2204-2227. (R).
  • Molto E, Bonzon-Kulichenko E, del Arco A, Lopez-Alanon DM, Carrillo O, Gallardo N, Andres A. Cloning, tissue expression and metal inducibility of an ubiquitous metallothionein from Panulirus argus. Gene. 2005. 361: 140-148. (A).
  • Del Arco A. Novel variants of human SCaMC-3, an isoform of the ATP-Mg/P(i) mitochondrial carrier, generated by alternative splicing from 3′-flanking transposable elements. Biochem J. 2005. 389(Pt 3): 647-655. (A).
  • Cavero S, Traba J, Del Arco A, Satrustegui J. The calcium-dependent ATP-Mg/Pi mitochondrial carrier is a target of glucose-induced calcium signalling in Saccharomyces cerevisiae. Biochem J. 2005. 392(Pt 3): 537-544. (A).
  • Jalil MA, Begum L, Contreras L, Pardo B, Iijima M, Li MX, Ramos M, Marmol P, Horiuchi M, Shimotsu K, Nakagawa S, Okubo A, Sameshima M, Isashiki Y, Del Arco A, Kobayashi K, Satrustegui J, Saheki T. Reduced N-acetylaspartate levels in mice lacking aralar, a brain- and muscle-type mitochondrial aspartate-glutamate carrier. J Biol Chem. 2005. 280[35]: 31333-31339. (A).
  • Serrano R, Villar M, Martinez C, Carrascosa JM, Gallardo N, Andres A.. Differential gene expression of insulin receptor isoforms A and B and insulin receptor substrates 1, 2 and 3 in rat tissues: modulation by aging and differentiation in rat adipose tissue. J Mol Endocrinol. 2005. 34[1]: 153-161. (A).
  • Gallardo N, Arribas C, Villar M, Ros M, Carrascosa JM, Martinez C, Andres A. ObRa and ObRe are differentially expressed in adipose tissue in aged food restricted rats: Effects on circulating soluble leptin receptor levels.Endocrinology. 2005. 146[11]: 4934-4942. (A).
  • Ruiz MA, Albasanz JL, Leon D, Ros M, Andres A, Martin M. Different modulation of inhibitory and stimulatory pathways mediated by adenosine after chronic in vivo agonist exposure. Brain Res. 2005. 1031[2]: 211-221. (A).
  • Rubi B, del Arco A, Bartley C, Satrustegui J, Maechler P. The malate-aspartate NADH shuttle member Aralar1 determines glucose metabolic fate, mitochondrial activity, and insulin secretion in beta cells. J Biol Chem. 2004. 279[53]: 55659-55666. (A).
  • del Arco A, Satrustegui J. Identification of a novel human subfamily of mitochondrial carriers with calcium-binding domains. J Biol Chem. 2004. 279[23]: 24701-24713. (A).
  • Perez C, Fernandez-Galaz C, Fernandez-Agullo T, Arribas C, Andres A, Ros M, Carrascosa JM. Leptin impairs insulin signaling in rat adipocytes. Diabetes. 2004. 53[2]: 347-353. (A).
  • Cavero S, Vozza A, Del Arco A, Palmieri L, Villa A, Blanco E, Runswick MJ, Walker JE, Cerdan S, Palmieri F, Satrustegui J. Identification and metabolic role of the mitochondrial aspartate-glutamate transporter in Saccharomyces cerevisiae. Mol Microbiol. 2003. 50[4]: 1257-1269. (A).
  • Ramos M, Del Arco A, Pardo B, Martinez-Serrano A, Martinez-Morales JR, Kobayashi K, Yasuda T, Bogonez E, Bovolenta P, Saheki T, Satrustegui J. Developmental changes in the Ca2+-regulated mitochondrial aspartate-glutamate carrier aralar1 in brain and prominent expression in the spinal cord. Brain Res Dev Brain Res. 2003. 143[1]: 33-46. (A).
  • Vacas J, Fernandez M, Ros M, Blanco P. Adenosine modulation of [Ca2+]i in cerebellar granular cells: multiple adenosine receptors involved. Brain Res. 2003. 992[2]: 272-280. (A).
  • Del Arco A, Peralta S, Carrascosa JM, Ros M, Andres A, Arribas C. Alternative splicing generates a novel non-secretable resistin isoform in Wistar rats. FEBS Lett. 2003. 555[2]: 243-249. (A).
  • Gallardo N, Carrillo O, Molto E, Deas M, Gonzalez-Suarez R, Carrascosa JM, Ros M, Andres A. Isolation and biological characterization of a 6-kDa protein from hepatopancreas of lobster Panulirus argus with insulin-like effects. Gen Comp Endocr. 2003. 131[3]: 284-290. (A).
  • Begum L, Jalil MA, Kobayashi K, Iijima M, Li MX, Yasuda T, Horiuchi M, del Arco A, Satrustegui J, Saheki T. Expression of three mitochondrial solute carriers, citrin, aralar1 and ornithine transporter, in relation to urea cycle in mice. Biochim Biophys Acta. 2002. 1574[3]: 283-292. (A).
  • del Arco A, Morcillo J, Martinez-Morales JR, Galian C, Martos V, Bovolenta P, Satrustegui J. Expression of the aspartate/glutamate mitochondrial carriers aralar1 and citrin during development and in adult rat tissues. Eur J Biochem. 2002. 269[13]: 3313-3320. (A).
  • Molero JC, Perez C, Martinez C, Villar M, Andres A, Fermin Y, Carrascosa JM. Activation of MAP kinase by insulin and vanadate in adipocytes from young and old rats. Mol Cell Endocrinol. 2002. 189[1-2]: 77-84. (A).
  • Fernandez-Galaz C, Fernandez-Agullo T, Perez C, Peralta S, Arribas C, Andres A, Carrascosa JM, Ros M.. Long-term food restriction prevents ageing-associated central leptin resistance in wistar rats. Diabetologia. 2002. 45[7]: 997-1003. (A).
  • Peralta S, Carrascosa JM, Gallardo N, Ros M, Arribas C. Ageing increases SOCS-3 expression in rat hypothalamus: effects of food restriction. Biochem Biophys Res Commun. 2002. 296[2]: 425-428. (A).
  • Palmieri L, Pardo B, Lasorsa FM, del Arco A, Kobayashi K, Iijima M, Runswick MJ, Walker JE, Saheki T, Satrustegui J, Palmieri F. Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. EMBO J. 2001. 20[18]: 5060-5069. (A).
  • Carrascosa JM, Molero JC, Fermin Y, Martinez C, Andres A, Satrustegui J. Effects of chronic treatment with acarbose on glucose and lipid metabolism in obese diabetic Wistar rats. Diabetes Obes Metab. 2001. 3[4]: 240-248. (A).
  • Fernandez-Galaz C, Fernandez-Agullo T, Campoy F, Arribas C, Gallardo N, Andres A, Ros M, Carrascosa JM. Decreased leptin uptake in hypothalamic nuclei with ageing in Wistar rats. J Endocrinol. 2001. 171[1]: 23-32. (A).
  • del Arco A, Agudo M, Satrustegui J. Characterization of a second member of the subfamily of calcium-binding mitochondrial carriers expressed in human non-excitable tissues. Biochem J. 2000. 345 Pt 3: 725-732. (A).
  • Sanz R, del Arco A, Ayuso C, Ramos C, Satrustegui J. Assignment of the calcium-binding mitochondrial carrier Aralar1 gene (SLC25A12) to human chromosome band 2q31 by in situ hybridization. Cytogenet Cell Genet. 2000. 89[3-4]: 143-144. (A).

Antonio Andrés Hueva

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Phone: (+34) 926 295 300

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Facultad de Ciencias y Tecnologías Químicas de Ciudad Real

Universidad de Castilla-La Mancha

Avenida de Camilo José Cela, 10

13071 Ciudad Real

Facultad de Ciencias Ambientales y Bioquímica

Universidad de Castilla-La Mancha

Avenida de Carlos III s/n

45071 Toledo

telefono  (+34) 926 295 300, Ext. 3435

telefono (+34)  925 268 800, Ext. 5411 y 5472

fax  (+34) 902 204 130

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