The obestatin receptor (GPR39) is expressed in human adipose tissue and is down-regulated in obesity-associated type 2 diabetes mellitus

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

Stellar Population gradients in galaxy discs from the CALIFA survey

While studies of gas-phase metallicity gradients in disc galaxies are common, very little has been done in the acquisition of stellar abundance gradients in the same regions. We present here a comparative study of the stellar metallicity and age distributions in a sample of 62 nearly face-on, spiral galaxies with and without bars, using data from the CALIFA survey. We measure the slopes of the gradients and study their relation with other properties of the galaxies. We find that the mean stellar age and metallicity gradients in the disc are shallow and negative. Furthermore, when normalized to the effective radius of the disc, the slope of the stellar population gradients does not correlate with the mass or with the morphological type of the galaxies. Contrary to this, the values of both age and metallicity at $\sim$2.5 scale-lengths correlate with the central velocity dispersion in a similar manner to the central values of the bulges, although bulges show, on average, older ages and higher metallicities than the discs. One of the goals of the present paper is to test the theoretical prediction that non-linear coupling between the bar and the spiral arms is an efficient mechanism for producing radial migrations across significant distances within discs. The process of radial migration should flatten the stellar metallicity gradient with time and, therefore, we would expect flatter stellar metallicity gradients in barred galaxies. However, we do not find any difference in the metallicity or age gradients in galaxies with without bars. We discuss possible scenarios that can lead to this absence of difference.Comment: 24 pages, 17 figures, accepted for publication in A&

Expression of caveolin-1 in human adipose tissue is upregulated in obesity and obesity-associated type 2 diabetes mellitus and related to inflammation

Caveolin-1 (CAV-1) plays important roles in many aspects of cellular biology, including vesicular transport, cholesterol homeostasis and signal transduction. The aim of the present study was to explore gene expression levels of CAV-1 in human adipose tissue in obesity and obesity-associated type 2 diabetes mellitus (T2DM) and to analyse its potential implication in the inflammatory state associated with obesity. DESIGN AND METHODS: Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) obtained from 15 females were used in the study. Patients were classified as lean (BMI 20.8 +/- 1.0 kg/m(2)) or obese (BMI 50.5 +/- 2.6 kg/m(2)). The obese group was further subclassified as normoglycaemic (NG) or patients with T2DM. Anthropometric measurements as well as circulating metabolites, hormones and adipokines were determined. Real-time polymerase chain reaction (PCR) analyses were performed to quantify transcript levels of CAV-1 and monocyte chemoattractant protein (MCP-1). RESULTS: The presence of CAV-1 protein was detected in VAT and SAT by immunohistochemistry. Both obese NG and with T2DM patients exhibited significantly higher CAV-1 expression levels in VAT and SAT compared with lean subjects (P < 0.05). No differences between obese NG and T2DM patients were observed in VAT. However, obese T2DM patients were found to have higher CAV-1 expression levels in SAT (P < 0.05) compared with obese NG patients. A significant correlation was found between CAV-1 mRNA expression levels in VAT and different circulating inflammatory markers such as sialic acid (SA) (P < 0.001) and fibrinogen (P < 0.001) as well as with MCP1 mRNA expression (P < 0.05). CONCLUSION: Our findings show for the first time the upregulation of mRNA CAV-1 expression levels in VAT and SAT of obese NG and obese T2DM patients compared with lean controls, suggesting a role for CAV-1 in obesity and T2DM development. The association with different inflammatory markers further suggests an implication of CAV-1 in the low-grade inflammation accompanying obesity

Increased circulating and visceral adipose tissue expression levels of YKL-40 in obesity-associated type 2 diabetes are related to inflammation: impact of conventional weight loss and gastric bypass

Context: Plasma YKL-40 is elevated in patients with type 2 diabetes. The potential role of visceral adipose tissue (VAT) as a significant source of YKL-40 is unknown. Objective: In the study circulating and expression levels of YKL-40 were examined in VAT analyzing the contribution of adipocytes and stromovascular fraction cells (SVFCs).Wealso explored YKL-40’s implication in insulin resistance and inflammation and the effect of weight loss on plasma YKL-40 concentrations. PatientsandMethods: Samples obtained from 53 subjects were used in the study.Geneandprotein expression levels of YKL-40 were analyzed in VAT as well as in both adipocytes and SVFCs. In addition, circulating YKL-40 concentrations were measured before and after weight loss achieved either by Roux-en-Y gastric bypass (n 26) or after a conventional dietetic program (n 20). Results: Circulating concentrations and VAT expression of YKL-40 were increased in obese patients with type 2 diabetes (P 0.01) as well as associated with variables of insulin resistance and inflammation. No differences in YKL-40 expression levels between adipocytes and SVFCs were detected. Monocyte chemoattractant protein-1 and homeostasis model assessment emerged (P 0.01) as independent factors predicting circulating YKL-40. Elevated levels of YKL-40 in obese patients decreased after weight loss following a conventional hypocaloric diet (P 0.05) but not via a surgery-induced negative energy balance mediated by the Roux-en-Y gastric bypass. Conclusions: The association of increased YKL-40 mRNA and protein levels in VAT with its circulating concentrations indicates an important contribution of VAT in YKL-40 regulation. Furthermore, our data suggest a relevant role of glucose metabolism and inflammation on YKL-40 regulation

CALIFA : a diameter-selected sample for an integral field spectroscopy galaxy survey

JMA acknowledges support from the European Research Council Starting Grant (SEDmorph; P.I. V. Wild).We describe and discuss the selection procedure and statistical properties of the galaxy sample used by the Calar Alto Legacy Integral Field Area (CALIFA) survey, a public legacy survey of 600 galaxies using integral field spectroscopy. The CALIFA "mother sample" was selected from the Sloan Digital Sky Survey (SDSS) DR7 photometric catalogue to include all galaxies with an r-band isophotal major axis between 45 '' and 79 : 2 '' and with a redshift 0 : 005 M-r > -23 : 1 and over a stellar mass range between 10(9.7) and 10(11.4) M-circle dot. In particular, within these ranges, the diameter selection does not lead to any significant bias against - or in favour of - intrinsically large or small galaxies. Only below luminosities of M-r = -19 (or stellar masses <10(9.7) M-circle dot) is there a prevalence of galaxies with larger isophotal sizes, especially of nearly edge-on late-type galaxies, but such galaxies form <10% of the full sample. We estimate volume-corrected distribution functions in luminosities and sizes and show that these are statistically fully compatible with estimates from the full SDSS when accounting for large-scale structure. For full characterization of the sample, we also present a number of value-added quantities determined for the galaxies in the CALIFA sample. These include consistent multi-band photometry based on growth curve analyses; stellar masses; distances and quantities derived from these; morphological classifications; and an overview of available multi-wavelength photometric measurements. We also explore different ways of characterizing the environments of CALIFA galaxies, finding that the sample covers environmental conditions from the field to genuine clusters. We finally consider the expected incidence of active galactic nuclei among CALIFA galaxies given the existing pre-CALIFA data, finding that the final observed CALIFA sample will contain approximately 30 Sey2 galaxies.Peer reviewe

Plasma osteopontin levels and expression in adipose tissue are increased in obesity

Obesity acts as a cardiovascular risk factor by mechanisms that are not fully understood. Osteopontin (OPN) is a proinflammatory mediator involved in tissue remodeling that plays a role in atherosclerosis and diabetes. OBJECTIVE: The aim of the present study was to compare the circulating concentrations of OPN and its mRNA expression in omental adipose tissue of lean, overweight, and obese individuals and to analyze the effect of weight loss. SUBJECTS AND METHODS: Plasma concentrations of OPN were measured in 77 volunteers. OPN mRNA expression in omental adipose tissue obtained from 12 women was quantified by real-time PCR. In addition, the concentrations of OPN in 12 obese men were measured before and after weight loss following a dietetic program. SETTING: The study was conducted at a University Hospital. RESULTS: Obese and overweight patients exhibited significantly increased circulating OPN concentrations as compared with lean subjects (obese 72.6 +/- 28.5, overweight 68.2 +/- 20.8, lean 42.7 +/- 27.9 ng/ml; P < 0.001). A significant positive correlation was found between OPN levels and body fat (r = 0.45; P < 0.0001). Obese individuals showed significantly increased (P < 0.05) mRNA expression of OPN in omental adipose tissue as compared with lean volunteers, which was further increased in obese diabetic patients. Diet-induced weight loss significantly decreased OPN concentrations from 64.7 +/- 22.1 to 36.6 +/- 20.1 ng/ml (P = 0.006). CONCLUSIONS: These findings represent the first observation that plasma OPN and mRNA expression of OPN in omental adipose tissue are increased in overweight/obese patients with the latter being further elevated in obesity-associated diabetes. Moreover, weight loss reduces OPN concentrations, which may contribute to the beneficial effects accompanying weight reduction. Measurement of OPN might be useful for evaluating the outcomes of various clinical interventions for obesity-related cardiovascular disease

Phase Variation in HMW1A Controls a Phenotypic Switch in Haemophilus influenzae Associated with Pathoadaptation during Persistent Infection

Genetic variants arising from within-patient evolution shed light on bacterial adaptation during chronic infection. Contingency loci generate high levels of genetic variation in bacterial genomes, enabling adaptation to the stringent selective pressures exerted by the host. A significant gap in our understanding of phase-variable contingency loci is the extent of their contribution to natural infections. The human-adapted pathogen nontypeable Haemophilus influenzae (NTHi) causes persistent infections, which contribute to underlying disease progression. The phase-variable high-molecular-weight (HMW) adhesins located on the NTHi surface mediate adherence to respiratory epithelial cells and, depending on the allelic variant, can also confer high epithelial invasiveness or hyperinvasion. In this study, we characterize the dynamics of HMW-mediated hyperinvasion in living cells and identify a specific HMW binding domain shared by hyperinvasive NTHi isolates of distinct pathological origins. Moreover, we observed that HMW expression decreased over time by using a longitudinal set of persistent NTHi strains collected from chronic obstructive pulmonary disease (COPD) patients, resulting from increased numbers of simple-sequence repeats (SSRs) downstream of the functional P2hmw1A promoter, which is the one primarily driving HMW expression. Notably, the increased SSR numbers at the hmw1 promoter region also control a phenotypic switch toward lower bacterial intracellular invasion and higher biofilm formation, likely conferring adaptive advantages during chronic airway infection by NTHi. Overall, we reveal novel molecular mechanisms of NTHi pathoadaptation based on within-patient lifestyle switching controlled by phase variation. IMPORTANCE Human-adapted bacterial pathogens have evolved specific mechanisms to colonize their host niche. Phase variation is a contingency strategy to allow adaptation to changing conditions, as phase-variable bacterial loci rapidly and reversibly switch their expression. Several NTHi adhesins are phase variable. These adhesins are required for colonization but also immunogenic, in such a way that bacteria with lower adhesin levels are better equipped to survive an immune response, making their contribution to natural infections unclear. We show here that the major NTHi adhesin HMW1A displays allelic variation, which can drive a phase-variable epithelial hyperinvasion phenotype. Over time, hmw1A phase variation lowers adhesin expression, which controls an NTHi lifestyle switch from high epithelial invasiveness to lower invasion and higher biofilm formation. This reversible loss of function aligns with the previously stated notion that epithelial infection is essential for NTHi infection establishment, but once established, persistence favors gene inactivation, in this case facilitating biofilm growth

Increased tenascin C and Toll-like receptor 4 levels in visceral adipose tissue as a link between inflammation and extracellular matrix remodeling in obesity

CONTEXT: Obesity is associated with an altered inflammatory and extracellular matrix (ECM) profile. Tenascin C (TNC) is an ECM glycoprotein with proinflammatory effects. OBJECTIVE: We aimed to explore the expression levels of TNC in adipose tissue analyzing the contribution of adipocytes and stromovascular fraction cells (SVFC) as well as its impact on inflammation and ECM regulation. We also analyzed the effect of the stimulation with TNF-α and lipopolysaccharide (LPS) on both SVFC and adipocytes. PATIENTS AND METHODS: Samples obtained from 75 subjects were used in the study. Expression levels of TNC, TLR4, MMP2, and MMP9 were analyzed in visceral adipose tissue (VAT) as well as in both adipocytes and SVFC. In addition, Tnc expression was measured in two mice models of obesity. RESULTS: We show, for the first time, that VAT expression levels of TNC are increased in normoglycemic and type 2 diabetic obese patients (P<0.01) as well as in obese patients with nonalcoholic steatohepatitis (P<0.01). Furthermore, expression levels of Tnc in epididymal adipose tissue from two different mice models of obesity were significantly increased (P<0.01). TNC and TLR4 were mainly expressed by SVFC, and its expression was significantly enhanced (P<0.01) by TNF-α treatment. LPS treatment also increased mRNA levels of TNC. Moreover, the addition of exogenous TNC induced (P<0.05) TLR4 and CCL2 mRNA expression in human adipocyte cultures. CONCLUSIONS: These findings indicate that TNC is involved in the etiopathology of obesity via visceral adipose tissue inflammation representing a link with ECM remodeling

Más allá de la hiperglucemia: la variabilidad glucémica como factor pronóstico en el infarto cerebral agudo

Glycaemic variability (GV) refers to variations in blood glucose levels, and may affect stroke outcomes. This study aims to assess the effect of GV on acute ischaemic stroke progression. We performed an exploratory analysis of the multicentre, prospective, observational GLIAS-II study. Capillary glucose levels were measured every 4 hours during the first 48 hours after stroke, and GV was defined as the standard deviation of the mean glucose values. The primary outcomes were mortality and death or dependency at 3 months. Secondary outcomes were in-hospital complications, stroke recurrence, and the impact of the route of insulin administration on GV. Results: A total of 213 patients were included. Higher GV values were observed in patients who died (n = 16; 7.8%; 30.9 mg/dL vs 23.3 mg/dL; p = 0.05). In a logistic regression analysis adjusted for age and comorbidity, both GV (OR = 1.03; 95% CI, 1.003-1.06; p = 0.03) and stroke severity (OR = 1.12; 95% CI, 1.04-1.2; p = 0.004) were independently associated with mortality at 3 months. No association was found between GV and the other outcomes. Patients receiving subcutaneous insulin showed higher GV than those treated with intravenous insulin (38.95 mg/dL vs 21.34 mg/dL; p < 0.001). Conclusions: High GV values during the first 48 hours after ischaemic stroke were independently associated with mortality. Subcutaneous insulin may be associated with higher VG levels than intravenous administration.La variabilidad glucémica (VG) hace referencia a las oscilaciones en los niveles de glucosa en sangre y podría influir en el pronóstico del ictus. Analizar el efecto de la VG en la evolución del infarto cerebral agudo (IC). Análisis exploratorio del estudio GLIAS-II (multicéntrico, prospectivo y observacional). Se midieron los niveles de glucemia capilar cada cuatro horas durante las primeras 48 horas y la VG se definió como la desviación estándar de los valores medios. Variables principales: mortalidad y muerte o dependencia a los tres meses. Variables secundarias: porcentaje de complicaciones intrahospitalarias y de recurrencia de ictus, e influencia de la vía de administración de insulina sobre la VG. Se incluyeron 213 pacientes. Los pacientes que fallecieron (N = 16;7,8%) presentaron mayores valores de VG (30,9 mg/dL vs. 23,3 mg/dL; p = 0,05). En el análisis de regresión logística ajustado por edad y comorbilidad, tanto la VG (OR = 1,03; IC del 95%: 1,003-1,06: p = 0,03) como la gravedad del IC (OR = 1,12; IC del 95%: 1,04-1,2; p = 0,004) se asociaron de forma independiente con la mortalidad a los tres meses. No se encontró asociación entre la VG y las demás variables de estudio. Los pacientes que recibieron tratamiento con insulina subcutánea mostraron una mayor VG que los tratados con insulina intravenosa (38,9 mg/dL vs. 21,3 mg/dL; p < 0,001). Conclusiones: Valores elevados de VG durante las primeras 48 horas tras el IC se asociaron de forma independiente con la mortalidad. La administración subcutánea de insulina podría condicionar una mayor VG que la vía intravenosaFinanciado por el Instituto de Salud Carlos III (ISCIII) y el FEDER (PI 09/01781). Promovido por el Proyecto Ictus del Grupo de Estudio de Enfermedades Cerebrovasculares de la Sociedad Espanola ˜ de Neurología, y las Redes de Investigación temática RETICS INVICTUS e INVICTUS Plus (RD12/0014/0006, RD16/0019/0005

Factor von Willebrand como intermediario entre la hemostasia y la angiogénesis de origen tumoral

Cancer patients often show an imbalance condition between coagulation system and fibrinolysis which causes a prothrombotic state. Different molecular factors like von Willebrand factor (vWf), presenting higher plasmatic rates in these patients, play an important role in this situation. During active angiogenesis taking place in tumor growth, the vascular endothelial growth factor (VEGF) and the fibroblast growth factor (FGF-2) contribute to the proliferation and differentiation of endothelial tissue, the main vWf producer, promoting increased rates of vWf in the serum of neoplastic patients. Recently vWf's contribution to tumor cells and platelet adhesion has been described. In this process, the discovery of platelet, endothelial and tumor cell membrane integrins and their implication in cellular adhesion has represented a major step in demonstrating how blood clotting and platelet aggregation are mediated by tumor cell and platelet linkage. Migration properties acquired by tumor cells as a result of this binding have been also pointed out. Clinical trials show higher rates of plasmatic vWf in cancer patients the more advanced clinical and radiological stage they present (metastasic versus localized). Moreover, higher pre-surgical serum vWf rates in patients can be used to predict poorer survival after resection surgery. vWf high molecular weight multimers have been also related to a cleavage protease deficiency in the serum of the oncologic population. The promising results of antiaggregation/anticoagulation therapies in these patients permit us to envisage new therapeutic target