Papel de la leptina y su resistencia en el síndrome de ovario poliquístico y la diabetes gestacional

La resistencia a la insulina y el síndrome metabólico al que se asocia es un problema sociosanitario de primer nivel. En la mujer el síndrome metabólico produce dos alteraciones fisiopatológicas propias que son el síndrome de ovario poliquístico (PCOS) y la diabetes gestacional (DMG). La leptina es la adipocina más importante y su resistencia está asociada tanto a obesidad como a la resistencia a la insulina. Nuestra hipótesis era que la resistencia a la leptina en células de la granulosa humana podría conllevar una menor expresión de aromatasa y por tanto una menor síntesis de estrógenos. Como hemos estudiado en otros sistemas quisimos comprobar la importancia de la expresión de la proteína Sam68 en la señal del receptor de leptina y su resistencia en PCOS. En el embarazo, los niveles de leptina aumentan por la síntesis de leptina, una hormona trofoblástica autocrina para el crecimiento placentario. La función trófica y antiapoptótica ha sido descrita por nuestro grupo. La hipótesis propuesta en esta tesis es el efecto antiapoptótico de la leptina frente a dos circunstancias fisiopatológicas, la hipertermia y la acidosis. Nuestro grupo también ha demostrado que la hiperleptinemia en la DMG se debe a una mayor expresión de leptina en el trofoblasto. Además, el receptor de leptina está activado en esta patología. Nuestra hipótesis es que la macrosomía del feto de la mujer con DMG estaría favorecida por una mayor expresión de transportadores de nutrientes, como AQP-9 que es un transportador de agua y glicerol. Los resultados de la Tesis han confirmado la presencia de resistencia a la leptina en la granulosa de mujeres con PCOS, donde se expresa menos aromatasa y menos proteína Sam68, una molécula de señalización necesaria para la señal del receptor de leptina, por lo que proponemos nuevas dianas terapéuticas en el PCOS. El papel antiapoptótico de la leptina en células trofoblásticas ha sido confirmado con las situaciones fisiopatológicas de hipertermia y acidosis, lo que incide en la importancia del sistema leptina/receptor de leptina en el mantenimiento de la placenta Por último, hemos demostrado que la leptina induce la expresión de AQP-9, la cual está sobreexpresada en el trofoblasto de mujeres con DMG. Esta Tesis confirma la importancia de la leptina y su resistencia en el PCOS y DMG, e incide en los mecanismos de acción, apuntando a nuevas dianas terapéuticas como la proteína Sam68

Role of leptin in inflammation and vice versa

Inflammation is an essential immune response for the maintenance of tissue homeostasis. In a general sense, acute and chronic inflammation are different types of adaptive response that are called into action when other homeostatic mechanisms are insufficient. Although considerable progress has been made in understanding the cellular and molecular events that are involved in the acute inflammatory response to infection and tissue injury, the causes and mechanisms of systemic chronic inflammation are much less known. The pathogenic capacity of this type of inflammation is puzzling and represents a common link of the multifactorial diseases, such as cardiovascular diseases and type 2 diabetes. In recent years, interest has been raised by the discovery of novel mediators of inflammation, such as microRNAs and adipokines, with different effects on target tissues. In the present review, we discuss the data emerged from research of leptin in obesity as an inflammatory mediator sustaining multifactorial diseases and how this knowledge could be instrumental in the design of leptin-based manipulation strategies to help restoration of abnormal immune responses. On the other direction, chronic inflammation, either from autoimmune or infectious diseases, or impaired microbiota (dysbiosis) may impair the leptin response inducing resistance to the weight control, and therefore it may be a cause of obesity. Thus, we are reviewing the published data regarding the role of leptin in inflammation, and the other way around, the role of inflammation on the development of leptin resistance and obesity

Nutrients and Dietary Approaches in Patients with Type 2 Diabetes Mellitus and Cardiovascular Disease: A Narrative Review

Cardiovascular disease (CVD) is the most common cause of morbidity and mortality in developed countries. The prevalence of CVD is much higher in patients with type 2 diabetes mellitus (T2DM), who may benefit from lifestyle changes, which include adapted diets. In this review, we provide the role of different groups of nutrients in patients with T2DM and CVD, as well as dietary approaches that have been associated with better and worse outcomes in those patients. Many different diets and supplements have proved to be beneficial in T2DM and CVD, but further studies, guidelines, and dietary recommendations are particularly required for patients with both diseases

Leptin and Gestational Diabetes Mellitus

Emerging research has highlighted the importance of leptin in fetal growth and development, independent of its essential role in the regulation of feeding and energy metabolism. Leptin is now considered an important signaling molecule of the reproductive system, since it regulates the production of gonadotropins, the blastocyst formation and implantation, the normal placentation, as well as the feto-placental communication. Placental leptin is an important cytokine which regulates placental functions in an autocrine or paracrine manner. Leptin seems to play a crucial role during the first stages of pregnancy as it modulates critical processes like proliferation, protein synthesis, invasion, and apoptosis in placental cells. Furthermore, deregulation of leptin levels has been correlated with the pathogenesis of various disorders associated with reproduction and gestation, including gestational diabetes mellitus (GDM). Due to the relevant incidence of the GDM and the importance of leptin, we decided to review the latest information available about leptin action in normal and GDM pregnancies to support the idea of leptin as an important factor and/or predictor of diverse disorders associated with reproduction and pregnancy

Randomized Clinical Trial to Determine the Effectiveness of CO-Oximetry and Anti-Smoking Brief Advice in a Cohort of Kidney Transplant Patients who Smoke

[Abstract] Background: measure the efficacy of exhaled carbon monoxide (CO) measurement plus brief advisory sessions to reduce smoking exposure and smoking behaviour in kidney transplant recipients. Methods: Randomized, controlled, open-label clinical trial at a Spanish hospital.Smoking kidney transplant recipients giving their consent to participate were randomized to control (brief advice, n=63) or intervention group (brief advisory session plus measuring exhaled CO, n=59). Measurements: Sociodemographic characteristics, cardiovascular risk factors, treatment, rejection episodes, infections, self-reported smoking, drug use, level of dependence and motivation to stop smoking (Fagerström's and Richmond's test) and stage of change (Prochaska and DiClemente's Stages). Efficacy was assessed at 3, 6, 9 and 12 months as: cotinine test, CO levels in exhaled air, nicotine dependence, motivational stages of change, motivation to stop smoking, pattern of tobacco use and smoking cessation rates. Logistic regression models were computed. Results: At 12 months of follow-up, differences were found in exhaled CO between the intervention and control group(6.1±6.8vs.10.2±9.7ppm;p=0.028). Carboxyhemoglobin levels were lower in the intervention group as well as the positive cotinine test (1.2±1.2%vs.2.0±2.4%;p=0.039),(53.4%vs.74.2%). At 12 months, intervention reduces the probability of a positive urine test by 28%. Conclusions: Co-oximetry is a clinically relevant intervention for reduction of tobacco exposure in kidney transplant recipients.Instituto de Salud Carlos III; PI11 /0135

Nutrients and Dietary Approaches in Patients with Type 2 Diabetes Mellitus and Cardiovascular Disease: A Narrative Review

Cardiovascular disease (CVD) is the most common cause of morbidity and mortality in developed countries. The prevalence of CVD is much higher in patients with type 2 diabetes mellitus (T2DM), who may benefit from lifestyle changes, which include adapted diets. In this review, we provide the role of different groups of nutrients in patients with T2DM and CVD, as well as dietary approaches that have been associated with better and worse outcomes in those patients. Many different diets and supplements have proved to be beneficial in T2DM and CVD, but further studies, guidelines, and dietary recommendations are particularly required for patients with both diseases

Gal-1 Expression Analysis in the GLIOCAT Multicenter Study: Role as a Prognostic Factor and an Immune-Suppressive Biomarker

Glioblastoma (GBM) is the most frequent primary malignant brain tumor and has a dismal prognosis. Unfortunately, despite the recent revolution of immune checkpoint inhibitors in many solid tumors, these have not shown a benefit in overall survival in GBM patients. Therefore, new potential treatment targets as well as diagnostic, prognostic, and/or predictive biomarkers are needed to improve outcomes in this population. The beta-galactoside binding protein Galectin-1 (Gal-1) is a protein with a wide range of pro-tumor functions such as proliferation, invasion, angiogenesis, and immune suppression. Here, we evaluated Gal-1 expression by immunohistochemistry in a homogenously treated cohort of GBM (the GLIOCAT project) and correlated its expression with clinical and molecular data. We observed that Gal-1 is a negative prognostic factor in GBM. Interestingly, we observed higher levels of Gal-1 expression in the mesenchymal/classical subtypes compared to the less aggressive proneural subtype. We also observed a Gal-1 expression correlation with immune suppressive signatures of CD4 T-cells and macrophages, as well as with several GBM established biomarkers, including SHC1, PD-L1, PAX2, MEOX2, YKL-40, TCIRG1, YWHAG, OLIG2, SOX2, Ki-67, and SOX11. Moreover, Gal-1 levels were significantly lower in grade 4 IDH-1 mutant astrocytomas, which have a better prognosis. Our results confirm the role of Gal-1 as a prognostic factor and also suggest its value as an immune-suppressive biomarker in GBM

Leptin and Nutrition in Gestational Diabetes

Leptin is highly expressed in the placenta, mainly by trophoblastic cells, where it has an important autocrine trophic effect. Moreover, increased leptin levels are found in the most frequent pathology of pregnancy: gestational diabetes, where leptin may mediate the increased size of the placenta and the fetus, which becomes macrosomic. In fact, leptin mediates the increased protein synthesis, as observed in trophoblasts from gestational diabetic subjects. In addition, leptin seems to facilitate nutrients transport to the fetus in gestational diabetes by increasing the expression of the glycerol transporter aquaporin-9. The high plasma leptin levels found in gestational diabetes may be potentiated by leptin resistance at a central level, and obesity-associated inflammation plays a role in this leptin resistance. Therefore, the importance of anti-inflammatory nutrients to modify the pathology of pregnancy is clear. In fact, nutritional intervention is the first-line approach for the treatment of gestational diabetes mellitus. However, more nutritional intervention studies with nutraceuticals, such as polyphenols or polyunsaturated fatty acids, or nutritional supplementation with micronutrients or probiotics in pregnant women, are needed in order to achieve a high level of evidence. In this context, the Mediterranean diet has been recently found to reduce the risk of gestational diabetes in a multicenter randomized trial. This review will focus on the impact of maternal obesity on placental inflammation and nutrients transport, considering the mechanisms by which leptin may influence maternal and fetal health in this setting, as well as its role in pregnancy pathologies

Sam68 mediates leptin signaling and action in human granulosa cells: possible role in leptin resistance in PCOS.

Polycystic ovary syndrome (PCOS) is a complex metabolic disorder associated with ovulatory dysfunction, hyperandrogenism, obesity, and insulin resistance, that leads to subfertility. Sam68 is an RNA-binding protein with signaling functions that is ubiquitously expressed, including gonads. Sam68 is recruited to leptin signaling, mediating different leptin actions. We aimed to investigate the role of Sam68 in leptin signaling, mediating the effect on aromatase expression in granulosa cells and the posible implication of Sam68 in the leptin resistance in PCOS. Granulosa cells were from healthy donors (n = 25) and women with PCOS (n = 25), within the age range of 20 to 40 years, from Valencian Infertility Institute (IVI), Seville, Spain. Sam68 expression was inhibited by siRNA method and overexpressed by expression vector. Expression level was analysed by qPCR and immunoblot. Statistical significance was assessed by ANOVA followed by different post-hoc tests. A P value of We have found that leptin stimulation increases phosphorylation and expression level of Sam68 and aromatase in granulosa cells from normal donors. Downregulation of Sam68 expression resulted in a lower activation of MAPK and PI3K pathways in response to leptin, whereas overexpression of Sam68 increased leptin stimulation of signaling, enhancing aromatase expression. Granulosa cells from women with PCOS presented lower expression of Sam68 and were resistant to the leptin effect on aromatase expression. These results suggest the participation of Sam68 in leptin receptor signaling, mediating the leptin effect on aromatase expression in granulosa cells, and point to a new target in leptin resistance in PCOS

Decreased Expression of Sam68 Is Associated with Insulin Resistance in Granulosa Cells from PCOS Patients

Background and objective: Polycystic ovary syndrome (PCOS) is a complex metabolic disorder associated with ovulatory dysfunction, hyperandrogenism, obesity, and insulin resistance, which leads to subfertility. PCOS is the most frequent metabolic disorder in women and the major cause of infertility. Susceptibility to developing PCOS is determined by a complex interaction between environmental and genetic factors. Although different mechanisms have been proposed to explain PCOS manifestations, defects in insulin actions or in the insulin signaling pathways are central in the pathogenesis of the syndrome. However, the mechanisms (molecular players and signaling pathways) underlying its primary origin still remain an unsolved issue. Current research is increasingly focusing on the discovery of novel biomarkers to further elucidate the complex pathophysiology of PCOS. Sam68, an RNA-binding protein, is recruited to insulin signaling, mediating different insulin actions. We aimed to investigate the role of Sam68 in insulin signaling and the possible implications of Sam68 in the insulin resistance in PCOS. Materials and methods: Granulosa cells were taken from women with PCOS (n = 25) and healthy donors (n = 25) and, within the age range of 20 to 42 years, from GINEMED, Assisted Reproduction Centre, Seville, Spain. The Sam68 expression level was analyzed both by qPCR and immunoblot. Statistical significance was assessed by one-way ANOVA, followed by a post-hoc test. A p value of < 0.05 was considered statistically significant. Results: We found that insulin stimulation increases the phosphorylation and expression level of Sam68 in granulosa cells from normal donors. The downregulation of Sam68 expression resulted in a lower activation of both the MAPK and the PI3K pathways in response to insulin. Moreover, the granulosa cells from the women with PCOS presented a lower expression of Sam68, as well as insulin receptor and insulin receptor substrate-1 (IRS-1). In these cells, the overexpression of Sam68 resulted in an increased activation of both the MAPK and the PI3K pathways in response to insulin. Conclusions: These results suggest the participation of Sam68 in insulin receptor signaling, mediating the insulin effect in granulosa cells, and they suggest the possible role of Sam68 in the insulin resistance of PCOS