Catalan, V. (Victoria)
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- Deletion of inducible nitric-oxide synthase in leptin-deficient mice improves brown adipose tissue function(Public Library Science, 2010-05-16) Collantes, M. (María); Peñuelas-Sanchez, I. (Ivan); Ramirez, B. (Beatriz); Catalan, V. (Victoria); Becerril, S. (Sara); Frühbeck, G. (Gema); Gomez-Ambrosi, J. (Javier); Rodriguez, A. (Amaia); Sainz, N. (Neira)Abstract Background: Leptin and nitric oxide (NO) on their own participate in the control of non-shivering thermogenesis. However, the functional interplay between both factors in this process has not been explored so far. Therefore, the aim of the present study was to analyze the impact of the absence of the inducible NO synthase (iNOS) gene in the regulation of energy balance in ob/ob mice. Methods and Findings: Double knockout (DBKO) mice simultaneously lacking the ob and iNOS genes were generated, and the expression of molecules involved in the control of brown fat cell function was analyzed by real-time PCR, western-blot and immunohistochemistry. Twelve week-old DBKO mice exhibited reduced body weight (p,0.05), decreased amounts of total fat pads (p,0.05), lower food efficiency rates (p,0.05) and higher rectal temperature (p,0.05) than ob/ob mice. Ablation of iNOS also improved the carbohydrate and lipid metabolism of ob/ob mice. DBKO showed a marked reduction in the size of brown adipocytes compared to ob/ob mutants. In this sense, in comparison to ob/ob mice, DBKO rodents showed an increase in the expression of PR domain containing 16 (Prdm16), a transcriptional regulator of brown adipogenesis. Moreover, iNOS deletion enhanced the expression of mitochondria-related proteins, such as peroxisome proliferatoractivated receptor c coactivator-1 a (Pgc-1a), sirtuin-1 (Sirt-1) and sirtuin-3 (Sirt-3). Accordingly, mitochondrial uncoupling proteins 1 and 3 (Ucp-1 and Ucp-3) were upregulated in brown adipose tissue (BAT) of DBKO mice as compared to ob/ob rodents. Conclusion: Ablation of iNOS improved the energy balance of ob/ob mice by decreasing food efficiency through an increase in thermogenesis. These effects may be mediated, in part, through the recovery of the BAT phenotype and brown fat cell function improvement.
- The obestatin receptor (GPR39) is expressed in human adipose tissue and is down-regulated in obesity-associated type 2 diabetes mellitus(Society for Endocrinology, 2007) Rotellar, F. (Fernando); Catalan, V. (Victoria); Álvarez-Cienfuegos, J. (Javier); Frühbeck, G. (Gema); Silva, C. (Camilo); Gomez-Ambrosi, J. (Javier); Salvador, J. (Javier); Rodriguez, A. (Amaia); Gil, M.J. (María José)The G protein-coupled receptor 39 (GPR39) has recently been identified as the receptor for obestatin, a peptidic hormone involved in energy homeostasis. However, the expression levels of this receptor in human adipose tissue in obesity and obesity-associated type 2 diabetes mellitus (T2DM) remain unknown. Therefore, we evaluated the actual presence of GPR39 mRNA in human adipose tissue and whether GPR39 expression levels are altered in obesity and obesity-associated T2DM. DESIGN: Omental adipose tissue biopsies obtained from 15 women were used in the study. Patients were classified as lean (body mass index 20.8 +/- 1.0 kg/m(2)), obese normoglycaemic (body mass index 48.4 +/- 2.1 kg/m(2)) and obese T2DM patients (body mass index 52.6 +/- 4.9 kg/m(2)). Anthropometric measurements and biochemical profiles were assessed for each subject. Real-time RT-PCR analyses were performed to quantify transcript levels of GPR39 and adiponectin. RESULTS: Obese T2DM patients exhibited significantly lower GPR39 expression levels compared to lean (P = 0.016) and obese normoglycaemic subjects (P = 0.008), while no differences between lean and obese normoglycaemic patients were observed. The mRNA expression levels of GPR39 were negatively correlated to fasting glucose concentrations (r = -0.581, P = 0.023), while exhibiting a positive correlation to adiponectin mRNA expression levels (r = 0.674, P = 0.006). CONCLUSION: GPR39 is expressed in human adipose tissue. The reduced expression levels of GPR39 in omental adipose tissue observed in obese patients with T2DM suggest an involvement of obestatin signalling in glucose homeostasis and T2DM development.
- Leptin inhibits the proliferation of vascular smooth muscle cells induced by angiotensin II through nitric oxide-dependent mechanisms(Hindawi Publishing Corporation, 2010) Fortuño, A. (Ana); Catalan, V. (Victoria); Frühbeck, G. (Gema); Gomez-Ambrosi, J. (Javier); Rodriguez, A. (Amaia)OBJECTIVE: This study was designed to investigate whether leptin modifies angiotensin (Ang) II-induced proliferation of aortic vascular smooth muscle cells (VSMCs) from 10-week-old male Wistar and spontaneously hypertensive rats (SHR), and the possible role of nitric oxide (NO). METHODS: NO and NO synthase (NOS) activity were assessed by the Griess and (3)H-arginine/citrulline conversion assays, respectively. Inducible NOS (iNOS) and NADPH oxidase subutnit Nox2 expression was determined by Western-blot. The proliferative responses to Ang II were evaluated through enzymatic methods. RESULTS: Leptin inhibited the Ang II-induced proliferative response of VSMCs from control rats. This inhibitory effect of leptin was abolished by NOS inhibitor, NMMA, and iNOS selective inhibitor, L-NIL, and was not observed in leptin receptor-deficient fa/fa rats. SHR showed increased serum leptin concentrations and lipid peroxidation. Despite a similar leptin-induced iNOS up-regulation, VSMCs from SHR showed an impaired NOS activity and NO production induced by leptin, and an increased basal Nox2 expression. The inhibitory effect of leptin on Ang II-induced VSMC proliferation was attenuated. CONCLUSION: Leptin blocks the proliferative response to Ang II through NO-dependent mechanisms. The attenuation of this inhibitory effect of leptin in spontaneous hypertension appears to be due to a reduced NO bioavailability in VSMCs.
- The ‘new normality’ in research? What message are we conveying our medical students?(Wiley, 2021) Unamuno, X. (Xabier); Catalan, V. (Victoria); Mentxaka, A. (Amaia); Becerril, S. (Sara); Frühbeck, G. (Gema); Gomez-Ambrosi, J. (Javier); Rodriguez, A. (Amaia)The impact of COVID-19 on medical education has been mainly viewed from the perspective of the imposed transition from face-to- face to online delivery of information and the inforced stopping of practical teaching in hospitals.1-5 However, unfortunately, the deleterious effects of COVID-19 on how research findings are obtained, communicated and valued needs also careful consideration. Whilst teaching students that it is a genuinely exciting and unique time to be in medicine, as teachers of a subject entitled ‘Introduction to Research’ to second-year medical students, we feel particularly worried about what the handling of the pandemia is transmitting our future physicians. Now, more than ever before, scholars need to reaffirm the importance on how research findings are obtained and communicated.
- Obesity and prostate cancer: gene expression signature of human periprostatic adipose tissue(BioMed Central, 2012) Principe, P. (Paulo); Pina, F. (Francisco); Monteiro, C. (Cátia); Medeiros, R. (Rui); Sanches-Magalhães, J. (José); Catalan, V. (Victoria); Fraga, A. (Avelino); Morais, A. (Antonio); Oliveira, J. (Jorge); Ribeiro, R. (Ricardo); Frühbeck, G. (Gema); Lobato, C. (Carlos); Gomez-Ambrosi, J. (Javier); Lobo, F. (Francisco); Rodriguez, A. (Amaia); Cunha, V. (Virginia); Lopes, C. (Carlos); Hu, P. (Pingzhao); Silva, V. (Vitor)Obesity and excess adiposity modified the expression of PP adipose tissue genes to ultimately foster fat mass growth. In patients with prostate cancer the expression profile of PP adipose tissue accounted for hypercellularity and reduced immunosurveillance. Both findings may be liable to promote a favorable environment for prostate cancer progression.
- Uroguanylin prevents hepatic steatosis, mitochondrial dysfunction and fibrosis in obesity-associated NAFLD(Elsevier, 2023) Valenti, V. (Víctor); Colina, I. (Inmaculada); Catalan, V. (Victoria); Becerril, S. (Sara); Frühbeck, G. (Gema); Fernández-Sáez, E.M. (Eva M.); Losarcos, M. (Maite); Burrell, M.A. (María Ángela); Martín, M. (Mariana); Moncada, R. (Rafael); Mugueta, C. (Carmen); Silva, C. (Camilo); Gomez-Ambrosi, J. (Javier); Rodriguez, A. (Amaia); Escalada, J. (Javier)Background: The biological mediators supporting the resolution of liver steatosis, inflammation and fibrosis after bariatric surgery in patients with obesity and NAFLD remain unclear. We sought to analyze whether uroguanylin and guanylin, two gut hormones involved in the regulation of satiety, food preference and adiposity, are involved in the amelioration of obesity-associated NAFLD after bariatric surgery. Methods: Proguanylin (GUCA2A) and prouroguanylin (GUCA2B) were measured in 214 participants undergoing bariatric surgery with biopsy-proven NAFLD diagnosis. Pathways involved in lipid metabolism, mitochondrial network and fibrogenesis were evaluated in liver biopsies (n = 137). The effect of guanylin and uroguanylin on these metabolic functions was assessed in HepG2 hepatocytes and LX-2 hepatic stellate cells (HSC) under lipotoxic and profibrogenic conditions. Results: Plasma and hepatic expression of GUCA2B were decreased in obesity-associated NAFLD. Both GUCA2A and GUCA2B levels were increased after sleeve gastrectomy and Roux-en-Y gastric bypass in parallel to the improved liver function. The liver of patients with type 2 diabetes showed impaired mitochondrial β-oxidation, biogenesis, dynamics as well as increased fibrosis. Uroguanylin diminished the lipotoxicity in palmitate-treated HepG2 hepatocytes, evidenced by decresased steatosis and lipogenic factors, as well as increased mitochondrial network expression, AMPK-induced β-oxidation and oxygen consumption rate. Additionally, uroguanylin, but not guanylin, reversed HSC myofibroblast transdifferentiation as well as fibrogenesis after TGF-β1 stimulation. Conclusions: Uroguanylin constitutes a protective factor against lipotoxicity, mitochondrial dysfunction and fibrosis. Increased GUCA2B levels might contribute to improve liver injury in patients with obesity-associated NAFLD after bariatric surgery.
- Prevalencia de diabesidad en España: depende de cómo se defina la obesidad(Gobierno de Navarra, 2022) Catalan, V. (Victoria); Gomez-Ambrosi, J. (Javier)La obesidad representa la enfermedad metabólica más prevalente a nivel mundial, conllevando un aumento de la morbi-mortalidad y la consiguiente disminución en la esperanza de vida1. A pesar de la magnitud del problema y de la atención que recibe en las publicaciones científicas, la pandemia sigue creciendo de forma imparable. Según un estudio reciente llevado a cabo en 200 países, la prevalencia de la obesidad en el mundo se ha multiplicado por seis en los últimos 40 años4. La prevalencia de obesidad en Europa varía entre el 12 y el 26%5, rango dentro del cual se encuentran también las cifras en la población adulta española, entorno al 22%6. La obesidad se ha convertido en una de las principales causas de muerte, ya que constituye el principal factor de riesgo para una serie de enfermedades no transmisibles, en particular la diabetes tipo 2 (DT2)7,8. Esta estrecha relación llevó hace unos años a acuñar el término diabesidad, destacando el hecho de que la mayoría de las personas con DT2 tienen obesidad.
- Farmacogenómica en el cáncer colorrectal(Servicio de Publicaciones de la Universidad de Navarra, 2003) García, F. (F.); Martin-Algarra, S. (Salvador); Zarate, R. (Ruth); Catalan, V. (Victoria); Bandres, E. (Eva); Escalada, A. (A.); Garcia-Foncillas, J. (Jesús); Andión, E. (E.); Honorato-Cía, B. (Beatriz); Zabalegui, N. (Natalia)La investigación en el proyecto genoma humano va a favorecer en los próximos años el desarrollo farmacoterapias más personalizadas. La Farmacogenómica es una nueva disciplina que se ha desarrollado en los últimos años y cuyos objetivos se dirigen a conocer aquellos mecanismos que permitan explicar cómo la base genética de cada individuo afecta a la respuesta obtenida a las drogas. La posibilidad de predecir qué terapias son más efectivas para un determinado paciente va a constituir una poderosa herramienta médica, particularmente en el ámbito de la oncología. Es probable que estas predic- ciones deriven de una mejor comprensión de la enfermedad tanto a nivel celular como molecular. Por lo que respecta al cáncer colorrectal, los avances en el conocimiento de la etiología de la enfermedad a nivel molecular no se han asociado con una mejora en el tratamiento del paciente. La eficacia clínica y la toxicidad de las drogas más utilizadas en el tratamiento del cáncer colorrectal de cada paciente son por el momento impredecibles. Entre otras muchas variables, se han descrito determinados polimorfismos en genes implicados en el metabolismo de estas drogas que determinan la variabilidad interindividual tanto en la eficacia terapeútica como en la toxicidad. La investigación de las características moleculares del cáncer colorrectal y el desarrollo de nuevas terapias dirigidas a dianas específicas van a permitir en el futuro predecir la respuesta de la neoplasia y, por tanto, modificar la opción terapeútica buscando aquella que mejor se ajuste al perfil biológico.
- Adipokine dysregulation and adipose tissue inflammation in human obesity(Wiley, 2018) Unamuno, X. (Xabier); Catalan, V. (Victoria); Becerril, S. (Sara); Frühbeck, G. (Gema); Gomez-Ambrosi, J. (Javier); Rodriguez, A. (Amaia)Obesity, a worldwide epidemic, confers increased risk for multiple serious conditions, including type 2 diabetes, cardiovascular diseases, nonalcoholic fatty liver disease and cancer. Adipose tissue is considered one of the largest endocrine organs in the body as well as an active tissue for cellular reactions and metabolic homeostasis rather than an inert tissue for energy storage. The functional pleiotropism of adipose tissue relies on its ability to synthesize and release a large number of hormones, cytokines, extracellular matrix proteins and growth and vasoactive factors, collectively termed adipokines that influence a variety of physiological and pathophysiological processes. In the obese state, excessive visceral fat accumulation causes adipose tissue dysfunctionality that strongly contributes to the onset of obesity-related comorbidities. The mechanisms underlying adipose tissue dysfunction include adipocyte hypertrophy and hyperplasia, increased inflammation, impaired extracellular matrix remodelling and fibrosis together with an altered secretion of adipokines. This review describes how adipose tissue becomes inflamed in obesity and summarizes key players and molecular mechanisms involved in adipose inflammation.
- Leptin administration favors muscle mass accretion by decreasing FoxO3a and increasing PGC-1alpha in ob/ob mice(Public Library of Science, 2009) Ramirez, B. (Beatriz); Catalan, V. (Victoria); Becerril, S. (Sara); Frühbeck, G. (Gema); Gomez-Ambrosi, J. (Javier); Rodriguez, A. (Amaia); Sainz, N. (Neira)Absence of leptin has been associated with reduced skeletal muscle mass in leptin-deficient ob/ob mice. The aim of our study was to examine the effect of leptin on the catabolic and anabolic pathways regulating muscle mass. Gastrocnemius, extensor digitorum longus and soleus muscle mass as well as fiber size were significantly lower in ob/ob mice compared to wild type littermates, being significantly increased by leptin administration (P<0.001). This effect was associated with an inactivation of the muscle atrophy-related transcription factor forkhead box class O3 (FoxO3a) (P<0.05), and with a decrease in the protein expression levels of the E3 ubiquitin-ligases muscle atrophy F-box (MAFbx) (P<0.05) and muscle RING finger 1 (MuRF1) (P<0.05). Moreover, leptin increased (P<0.01) protein expression levels of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), a regulator of muscle fiber type, and decreased (P<0.05) myostatin protein, a negative regulator of muscle growth. Leptin administration also activated (P<0.01) the regulators of cell cycle progression proliferating cell nuclear antigen (PCNA) and cyclin D1, and increased (P<0.01) myofibrillar protein troponin T. The present study provides evidence that leptin treatment may increase muscle mass of ob/ob mice by inhibiting myofibrillar protein degradation as well as enhancing muscle cell proliferation.