Adiposidad y carcinogénesis hepática: una aproximación epigenética

En síntesis, el trabajo realizado ha evidenciado que un exceso de adiposidad, vinculado a la manifestación de estrés oxidativo e inflamación, se asocia con la desregulación de genes implicados en la carcinogénesis, en el hígado y en el tejido adiposo de animales obesos y reflejado en los leucocitos circulantes de pacientes con obesidad. De manera relevante, se ha observado que la pérdida de peso inducida en los estudios in vivo fue capaz de revertir el patrón de expresión de los genes estudiados, ya que la disminución en el peso corporal detectada tras las intervenciones fue concomitante a la reducción en la adiposidad, lo que reportó una mejora de la esteatosis hepática y de la protección antioxidante. Estos resultados fueron reforzados con los datos obtenidos en una línea celular de hepatocitos humana, que recreó la desregulación génica relacionada con la carcinogénesis en los tratamientos con secretoma de tejido adiposo y suero de pacientes con obesidad severa, los cuales fueron capaces de reproducir el fenotipo de esteatosis hepática definido en los ensayos de las células hepáticas tratadas con oleato de sodio. Además, el tratamiento con cuerpos cetónicos en las células esteatóticas tratadas con oleato fue capaz de revertir el patrón de expresión génica ligado a la carcinogénesis, concomitante a la reducción en el acúmulo de gotas lipídicas citoplasmáticas observada en las células tras el tratamiento con el butirato de sodio, cuyos resultados se asemejan a los obtenidos en los estudios in vivo tras la pérdida de peso. Nuestros hallazgos acerca de la asociación entre la adiposidad y la desregulación de los genes implicados en la carcinogénesis, podría estar modulada por la acción de marcas epigenéticas, ya que el análisis de los perfiles de metilación del ADN de los genes diana estudiados en los leucocitos circulantes de pacientes con obesidad reveló cambios significativos en comparación a los perfiles observados en voluntarios sanos normopeso y tras la intervención nutricional de estos pacientes siguiendo una VLCKD

Oxidative Stress Induced by Excess of Adiposity Is Related to a Downregulation of Hepatic SIRT6 Expression in Obese Individuals

Sirt6 is a member of the sirtuin family involved in physiological and pathological processes including aging, cancer, obesity, diabetes, and energy metabolism. This study is aimed at evaluating the relationship between liver SIRT6 gene expression and the oxidative stress network depending on adiposity levels in Zucker rats, an animal model of metabolic syndrome. We observed that liver-specific SIRT6 expression is reduced in an in vivo model of spontaneous obesity and metabolic syndrome. We also observed that SIRT6 expression in the liver is positively associated with SIRT1 and GST-M2 expressions, two proteins involved in antioxidant protection pathways and inversely related to body weight and plasmatic oxidative status. Interestingly, the SIRT6 expression is upregulated after energy restriction-induced weight loss concomitantly with an improvement in oxidative stress markers. These results suggest that SIRT6 may be a potential therapeutic target for the treatment of obesity and associated metabolic disorders, such as liver disease.Centro de Investigacion Biomedica en Red de Fisiopatologia de la Obesidad y Nutricion (CIBERobn)Instituto de Salud Carlos IIIEuropean Regional Development Fund (FEDER

Leptin, Obesity, and Leptin Resistance: Where Are We 25 Years Later?

Leptin, a hormone that is capable of effectively reducing food intake and body weight, was initially considered for use in the treatment of obesity. However, obese subjects have since been found to have high levels of circulating leptin and to be insensitive to the exogenous administration of leptin. The inability of leptin to exert its anorexigenic effects in obese individuals, and therefore, the lack of clinical utility of leptin in obesity, is defined as leptin resistance. This phenomenon has not yet been adequately characterized. Elucidation of the molecular mechanisms underlying leptin resistance is of vital importance for the application of leptin as an effective treatment for obesity. Leptin must cross the blood–brain barrier (BBB) to reach the hypothalamus and exert its anorexigenic functions. The mechanisms involved in leptin transportation across the blood–brain barrier continue to be unclear, thereby preventing the clinical application of leptin in the treatment of obesity. In recent years, new strategies have been developed to recover the response to leptin in obesity. We have summarized these strategies in this review.This work was supported by Centro de Investigacion Biomedicaen Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn) and grants from the Instituto de Salud Carlos III (PI17/01287) cofinanced by the European Regional Development Fund (FEDER). Andrea G. Izquierdo and Marcos C Carreira are funded by CIBERobn and Ana B. Crujeiras is funded by a research contract “Miguel Servet” (CP17/00088) from the Instituto de Salud Carlos III, cofinanced by the European Regional Development Fund (FEDER)S

Temperature but not leptin prevents semi-starvation induced hyperactivity in rats: implications for anorexia nervosa treatment

The hypothesis linking hyperactivity with weight loss associated hypoleptinemia in anorexia nervosa gained momentum after a study showing that leptin suppressed semi-starvation induced hyperactivity in rats. Alternatively, ambient temperature is a key modulating factor of activity in semi-starved rats. The aim of the study is to compare the efficacy of leptin with increased ambient temperature in the prevention of hyperactivity in semi-starved rats. 74 Sprague-Dawley male rats were employed in two experiments with the difference residing in the length of baseline. After an extended (28 days), or shorter (14 days) baseline with free access to food and the running wheel, housed at 21 °C, animals were either ad-lib feed or food restricted (60% of food ingested during previous week) and infused with same amount of leptin at 21 °C, 25 °C, or vehicle at 21 °C, 25 °C and 32 °C for a week. Animals housed at 32 °C significantly reduced wheel running and weight loss during food restriction while animals given leptin did not yield no differences in activity or weight loss. Moreover, unlike animals housed at 32 °C, body temperature of leptin infused animals housed at 21 °C was significantly reduced during food restriction. Furthermore, leptin treated rats without a preceding stable pattern of activity displayed a severe dysregulation of circadian rhythm in activity and a collapse of body temperature. Housing temperature plays a more critical role than leptin in the regulation of semi-starvation induced hyperactivity in rats, which may be of relevance for the management of hyperactivity in anorexia nervosaResearch leading to these results has received funding from the research budget from the Unidade Venres Clinicos (E.G., A.F.) and the Xunta de Galicia (ML: 2015-CP079 and 2016-PG068); Ministerio de Economía y Competitividad (MINECO) co-funded by the FEDER Program of EU (ML: RTI2018-101840-B-I00 and BFU2015-70454-REDT/Adipoplast) and Atresmedia Corporación (ML); MC, AGI, (CIBERobn), Xunta de Galicia and Instituto de Salud Carlos III (PI 17/01287). A.F. received a fellowship from Xunta de Galicia (Plan I2C-2014). The CiMUS is supported by the Xunta de Galicia (2016–2019, ED431G/05). CIBER de Fisiopatología de la Obesidad y Nutrición is an initiative of ISCIIIS

Novel SFRP2 DNA Methylation Profile Following Neoadjuvant Therapy in Colorectal Cancer Patients with Different Grades of BMI

The relationship between body weight and different cancers is now well-recognized and among such cancers, colorectal cancer (CRC) is reported most frequently. Our group recently published findings, through an epigenome-wide association study, suggesting that body mass index (BMI) could act as a relevant risk factor in the CRC. In addition, aberrant SFRP2 methylation is one of the major mechanisms for Wnt signaling activation in CRC. Conversely, neoadjuvant chemo-radiotherapy appears to alter the rectal cancer epigenome. This study was aimed to evaluate the effect of obesity, measured by BMI, on the methylation of SFRP2 in tumor samples of patients with CRC. Non-treated CRC patients and CRC patients treated with pre-operative neoadjuvant therapy from 2011 to 2013 were included and classified by BMI 25.0 kg/m2. SFRP2 DNA methylation in tumor samples was measured by pyrosequencing. Our findings suggest a possible interaction between SFRP2 methylation levels and BMI in CRC tumor samples. The correlation of SFRP2 hypomethylation with an elevated BMI was stronger within the non-treated CRC patient group than within the treated CRC patient group. We have successfully demonstrated that the beneficial association of tumor SFRP2 hypomethylation is dependent on patient BMI in non-treated CRC, suggesting a possible tumor suppressor role for SFRP2 in overweight and obese patients. Additional studies of clinical pathologies would be necessary to strengthen these preliminary resultsThis study was supported by “Centros de Investigación En Red” (CIBER, CB06/03/0018) of the “Instituto de Salud Carlos III” (ISCIII) and a grant from ISCIII (PI8/01399) and it was co-financed by the European Regional Development Fund (FEDER). M.M.G. was the recipient of the Nicolas Monardes Program from the “Servicio Andaluz de Salud, Junta de Andalucía”, Spain (RC-0001-2018 and C-0029-2014). S.M. was the recipient of the Nicolas Monardes Program from the “Servicio Andaluz de Salud, Junta de Andalucía”, Spain (C-0050-2017). A.B.C. was funded by a research contract “Miguel Servet” (CP17/00088) from the ISCIII. A.C.-M. was recipient of an FPU grant from Education Ministry, Madrid, SpainS

Structure and Dynamics of Large-Scale Cognitive Networks in Huntington's Disease

Altres ajuts: La Marató de TV3 (20142910).Background: Huntington's disease is a neurodegenerative disorder characterized by clinical alterations in the motor, behavioral, and cognitive domains. However, the structure and disruptions to large-scale brain cognitive networks have not yet been established. Objective: We aimed to profile changes in large-scale cognitive networks in premanifest and symptomatic patients with Huntington's disease. Methods: We prospectively recruited premanifest and symptomatic Huntington's disease mutation carriers as well as healthy controls. Clinical and sociodemographic data were obtained from all participants, and resting-state functional connectivity data, using both time-averaged and dynamic functional connectivity, was acquired from whole-brain and cognitively oriented brain parcellations. Results: A total of 64 gene mutation carriers and 23 healthy controls were included; 21 patients with Huntington's disease were classified as premanifest and 43 as symptomatic Huntington's disease. Compared with healthy controls, patients with Huntington's disease showed decreased network connectivity within the posterior hubs of the default-mode network and the medial prefrontal cortex, changes that correlated with cognitive (t = 2.25, P = 0.01) and disease burden scores (t = −2.42, P = 0.009). The salience network showed decreased functional connectivity between insular and supramarginal cortices and also correlated with cognitive (t = 2.11, P = 0.02) and disease burden scores (t = −2.35, P = 0.01). Dynamic analyses showed that network variability was decreased for default-central executive networks, a feature already present in premanifest mutation carriers (dynamic factor 8, P = 0.02). Conclusions: Huntington's disease shows an early and widespread disruption of large-scale cognitive networks. Importantly, these changes are related to cognitive and disease burden scores, and novel dynamic functional analyses uncovered subtler network changes even in the premanifest stages

Epigenetic effects of healthy foods and lifestyle habits from the southern european atlantic diet pattern: a narrative review

Recent scientific evidence has shown the importance of diet and lifestyle habits for the proper functioning of the human body. A balanced and healthy diet, physical activity, and psychological well-being have a direct beneficial effect on health and can have a crucial role in the development and prognosis of certain diseases. The Southern European Atlantic diet, also named the Atlantic diet, is a unique dietary pattern that occurs in regions that present higher life expectancy, suggesting that this specific dietary pattern is associated with positive health effects. In fact, it is enriched with nutrients of high biological value, which, together with its cooking methods, physical activity promotion, reduction in carbon footprint, and promoting of family meals, promote these positive effects on health. The latest scientific advances in the field of nutri-epigenetics have revealed that epigenetic markers associated with food or nutrients and environmental factors modulate gene expression and, therefore, are involved with both health and disease. Thus, in this review, we evaluated the main aspects that define the Southern European Atlantic diet and the potential epigenetic changes associated with them based on recent studies regarding the main components of these dietary patterns. In conclusion, based on the information existing in the literature, we postulate that the Southern European Atlantic diet could promote healthy aging by means of epigenetic mechanisms. This review highlights the necessity of performing longitudinal studies to demonstrate this proposalS

Aortic disease in Marfan syndrome is caused by overactivation of sGC-PRKG signaling by NO

AbstractThoracic aortic aneurysm, as occurs in Marfan syndrome, is generally asymptomatic until dissection or rupture, requiring surgical intervention as the only available treatment. Here, we show that nitric oxide (NO) signaling dysregulates actin cytoskeleton dynamics in Marfan Syndrome smooth muscle cells and that NO-donors induce Marfan-like aortopathy in wild-type mice, indicating that a marked increase in NO suffices to induce aortopathy. Levels of nitrated proteins are higher in plasma from Marfan patients and mice and in aortic tissue from Marfan mice than in control samples, indicating elevated circulating and tissue NO. Soluble guanylate cyclase and cGMP-dependent protein kinase are both activated in Marfan patients and mice and in wild-type mice treated with NO-donors, as shown by increased plasma cGMP and pVASP-S239 staining in aortic tissue. Marfan aortopathy in mice is reverted by pharmacological inhibition of soluble guanylate cyclase and cGMP-dependent protein kinase and lentiviral-mediated Prkg1 silencing. These findings identify potential biomarkers for monitoring Marfan Syndrome in patients and urge evaluation of cGMP-dependent protein kinase and soluble guanylate cyclase as therapeutic targets.</jats:p

Active commuting to and from university, obesity and metabolic syndrome among Colombian university students

Background: There is limited evidence concerning how active commuting (AC) is associated with health benefits in young. The aim of the study was to analyze the relationship between AC to and from campus (walking) and obesity and metabolic syndrome (MetS) in a sample of Colombian university students. Methods: A total of 784 university students (78.6% women, mean age = 20.1 ± 2.6 years old) participated in the study. The exposure variable was categorized into AC (active walker to campus) and non-AC (non/infrequent active walker to campus: car, motorcycle, or bus) to and from the university on a typical day. MetS was defined in accordance with the updated harmonized criteria of the International Diabetes Federation criteria. Results: The overall prevalence of MetS was 8.7%, and it was higher in non-AC than AC to campus. The percentage of AC was 65.3%. The commuting distances in this AC from/to university were 83.1%, 13.4% and 3.5% for < 2 km, 2- 5 km and > 5 km, respectively. Multiple logistic regressions for predicting unhealthy profile showed that male walking commuters had a lower probability of having obesity [OR = 0.45 (CI 95% 0.25–0.93)], high blood pressure [OR = 0.26 (CI 95% 0.13–0.55)] and low HDL cholesterol [OR = 0.29 (CI 95% 0.14–0.59)] than did passive commuters. Conclusions: Our results suggest that in young adulthood, a key life-stage for the development of obesity and MetS, AC could be associated with and increasing of daily physical activity levels, thereby promoting better cardiometabolic health.This study was part of the project entitled “Body Adiposity Index and Biomarkers of Endothelial and Cardiovascular Health in Adults”, which was funded by Centre for Studies on Measurement of Physical Activity, School of Medicine and Health Sciences, Universidad del Rosario (Code N° FIUR DNBG001) and Universidad de Boyacá (Code N° RECT 60)