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Jessica González, 1 Pilar Rivera-Ortega, 1 Macarena Rodríguez-Fraile, 2 Patricia Restituto, 3 Inmaculada Colina, 4 María de los Desamparados Calleja, 5 Ana B Alcaide, 1 Aránzazu Campo, 1 Juan Bertó, 1 Luis Seijo, 6 Maria Teresa Pérez-Warnisher, 6 Javier J Zulueta, 1 Nerea Varo, 3 Juan P de-Torres 7 1Pulmonary Department, Hospital Universitari Arnau de Vilanova, Lleida, Spain; 2Nuclear Medicine Department, Clínica Universidad de Navarra, Pamplona, Spain; 3Biochemistry Department, Clínica Universitaria de Navarra, Pamplona, Spain; 4Department of Internal Medicine, Clínica Universidad de Navarra, Pamplona, Spain; 5Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain; 6Pulmonary Department, Clínica Universidad de Navarra, Madrid, Spain; 7Respirology Division, Queen’s University, Kingston, ON, CanadaCorrespondence: Jessica GonzálezPulmonary department, Hospital Universitari Arnau de Vilanova, Lleida, SpainEmail jgonzalezgutierrez@gmail.comRationale: Emphysema and osteoporosis are tobacco-related diseases. Many studies have shown that emphysema is a strong and independent predictor of low bone mineral density (BMD) in smokers; however, none of them explored its association with different emphysema subtypes.Objective: To explore the association between the different emphysema subtypes and the presence of low bone mineral density in a population of active or former smokers with and without chronic obstructive pulmonary disease (COPD).Methods: One hundred and fifty-three active and former smokers from a pulmonary clinic completed clinical questionnaires, pulmonary function tests, a low-dose chest computed tomography (LDCT) and a dual-energy absorptiometry (DXA) scans. Subjects were classified as having normal BMD or low BMD (osteopenia or osteoporosis). Emphysema was classified visually for its subtype and severity. Logistic regression analysis explored the relationship between the different emphysema subtypes and the presence of low BMD adjusting for other important factors.Results: Seventy-five percent of the patients had low BMD (78 had osteopenia and 37 had osteoporosis). Emphysema was more frequent (66.1 vs 26.3%, p=< 0.001) and severe in those with low BMD. Multivariable analysis adjusting for other significant cofactors (age, sex, FEV 1, and severity of emphysema) showed that BMI (OR=0.91, 95% CI: 0.76– 0.92) and centrilobular emphysema (OR=26.19, 95% CI: 1.71 to 399.44) were associated with low BMD.Conclusion: Low BMD is highly prevalent in current and former smokers. BMI and centrilobular emphysema are strong and independent predictors of its presence, which suggests that they should be considered when evaluating smokers at risk for low BMD.Keywords: emphysema, COPD, low bone mineral density, osteopenia, osteoporosis; smokers

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Contents With the development of the non-surgical deep uterine (Ns DU) embryo transfer ( ET) technology, the commercial applicability of ET in pigs is now possible. There are, nevertheless, many factors that influence Ns DU- ET effectiveness that need to be addressed. The aim of this study was to evaluate the effects of the weaned recipients' parity on fertility and prolificacy following Ns DU- ET. The recipients (n = 120) were selected based on their reproductive history and body condition and grouped into three categories according to their parity: primiparous sows, sows of parity 2 and sows of parities from 3 to 5. Thirty fresh embryos (morulae and unhatched blastocysts) were non-surgically transferred into one uterine horn of each recipient. It was possible to insert the Ns DU- ET catheter through the cervix along a uterine horn in 98.3% of the recipients. The parity had no influence on the difficulty grade of the insertions or on the percentage of correct insertions. The cervix and uterine wall were not perforated during the insertions, and vaginal discharge was not observed after transfer in any of the recipients. There were no differences in the pregnancy rates (74.8%), farrowing rates (71.2%) or litter sizes (9.6 ± 3.3) between groups. Also, there were no differences between groups regarding to the piglets' birthweights or piglet production efficiency. In conclusion, these results demonstrate that weaned sows from parity 1 to 5 are appropriate to be used as recipients in Ns DU- ET programs, which increase the possibilities for the utilization of ET in the recipient farms. [ABSTRACT FROM AUTHOR]

Metabolic pathways are affected by the impacts of environmental contaminants underlying a large variability of toxic effects across different species. However, the systematic reconstruction of metabolic pathways remains limited in environmental sentinel species due to the lack of available genomic data in many taxa of animal diversity. In this study we used a multi-omics approach to reconstruct the most comprehensive map of metabolic pathways for a crustacean model in biomonitoring, the amphipod Gammarus fossarum in order to improve the knowledge of the metabolism of this sentinel species. We revisited the assembly of RNA-seq data by de novo approaches to reduce RNA contaminants and transcript redundancy. We also acquired extensive mass spectrometry shotgun proteomic data on several organs from a reference population of G. fossarum males and females to identify organ-specific metabolic profiles. The G. fossarum metabolic pathway reconstruction (available through the metabolic database GamfoCyc) was performed by adapting the genomic tool CycADS and we identified 377 pathways representing 7630 annotated enzymes, 2610 enzymatic reactions and the expression of 858 enzymes was experimentally validated by proteomics. To our knowledge, our analysis provides for the first time a systematic metabolic pathway reconstruction and the proteome profiles of these pathways at the organ level in this sentinel species. As an example, we show an elevated abundance in enzymes involved in ATP biosynthesis and fatty acid beta-oxidation indicative of the high-energy requirement of the gills, or the key anabolic and detoxification role of the hepatopancreatic caeca, as exemplified by the specific expression of the retinoid biosynthetic pathways and glutathione synthesis. In conclusion, the multi-omics data integration performed in this study provides new resources to investigate metabolic processes in crustacean amphipods and their role in mediating the effects of environmental contaminant exposures in sentinel species. SYNOPSIS: This study provide the first evidence that it is possible to combine multiple omics data to exhaustively describe the metabolic network of a model species in ecotoxicology, Gammarus fossarum, for which a reference genome is not yet available., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: The molecular mediators responsible for the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) to steatohepatitis (MASH) have not yet been completely disentangled. We sought to analyze whether FNDC4, an hepatokine and adipokine with anti-inflammatory properties, is involved in TNF-α-induced inflammatory cell death in patients with MASLD., Methods: Plasma FNDC4 (n = 168) and hepatic FNDC4 and inflammatory cell death (n = 65) were measured in samples from patients with severe obesity with available liver biopsy-proven MASLD diagnosis. The effect of FNDC4 on TNF-α-induced pyroptosis, apoptosis and necroptosis (PANoptosis) and mitochondrial dysfunction was studied in vitro using human HepG2 hepatocytes., Results: Compared with individuals with normal liver, patients with type 2 diabetes and MASLD exhibited decreased hepatic FNDC4 mRNA and protein levels, which were related to liver inflammation. An overexpression of TNF-α, its receptor TNF-R1 and factors involved in inflammatory cell death was also found in the liver of these patients. FNDC4-knockdown in HepG2 hepatocytes increased apoptotic cell death, while FNDC4 treatment blunted NLRP3 inflammasome-induced pyroptosis, apoptosis and necroptosis in TNF-α-stimulated hepatocytes. Moreover, FNDC4 improved TNF-α-induced hepatocyte mitochondrial dysfunction by enhancing mitochondrial DNA (mtDNA) copy number and OXPHOS complex subunits I, II, III and V protein expression. Mechanistically, AMP-activated protein kinase α (AMPKα) was required for the FNDC4-mediated inhibition of cell death and increase in mtDNA content., Conclusions: FNDC4 acts as a hepatocyte survival factor favouring mitochondrial homeostasis and decreasing inflammatory cell death via AMPKα. Collectively, our study identifies FNDC4 as an attractive target to prevent hepatocellular damage in patients with MASLD., Competing Interests: Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Albuminuria is considered an early and sensitive marker of kidney dysfunction, but also an independent cardiovascular risk factor. Considering the possible relationship among metabolic liver disease, cardiovascular disease and chronic kidney disease, we aimed to evaluate the risk of developing albuminuria regarding the presence of epicardial adipose tissue and the steatotic liver disease status., Methods: A retrospective long-term longitudinal study including 181 patients was carried out. Epicardial adipose tissue and steatotic liver disease were assessed by computed tomography. The presence of albuminuria at follow-up was defined as the outcome., Results: After a median follow up of 11.2 years, steatotic liver disease (HR 3.15; 95% CI, 1.20-8.26; p = 0.02) and excess amount of epicardial adipose tissue (HR 6.12; 95% CI, 1.69-22.19; p = 0.006) were associated with an increased risk of albuminuria after adjustment for visceral adipose tissue, sex, age, weight status, type 2 diabetes, prediabetes, hypertriglyceridemia, hypercholesterolemia, arterial hypertension, and cardiovascular prevention treatment at baseline. The presence of both conditions was associated with a higher risk of developing albuminuria compared to having steatotic liver disease alone (HR 5.91; 95% CI 1.15-30.41, p = 0.033). Compared with the first tertile of visceral adipose tissue, the proportion of subjects with liver steatosis and abnormal epicardial adipose tissue was significantly higher in the second and third tertile. We found a significant correlation between epicardial fat and steatotic liver disease (rho = 0.43 [p < 0.001])., Conclusions: Identification and management/decrease of excess adiposity must be a target in the primary and secondary prevention of chronic kidney disease development and progression. Visceral adiposity assessment may be an adequate target in the daily clinical setting. Moreover, epicardial adipose tissue and steatotic liver disease assessment may aid in the primary prevention of renal dysfunction., (© 2024. The Author(s).)

Background and Aims: Small-dense-low-density-lipoprotein cholesterol (sdLDL-C) is proatherogenic and not commonly measured. The aims were to evaluate capillary blood and its stability for sdLDL-C measurement and measure sdLDL-C in patients with metabolic syndrome (MS)., Methods: 182 patients were studied (49 with MS). sdLDL-C was measured by electrophoresis (LipoPrint®), direct measurement (Roche Diagnostics) and Sampson equation. Intima-media thickness (IMT) and presence of atheroma was evaluated. sdLDL-C was compared in paired venous and capillary blood according to CLSI-EP09c (n = 40). sdLDL-C stability was studied after 24 h at room temperature (RT)., Results: sdLDL-C in capillary blood and venous blood showed agreement with the direct measurement (bias: 4.17 mg/dL, LOA 95 %:-5.66; 13.99) and estimation (bias:8.12 mg/dL, LOA 95 %:-8.59; 24.82). sdLDL-C is stable in capillary blood for 24 h at RT. The electrophoretic method yielded lower (p < 0.05) sdLDL-C than the equation or direct measurement. Patients with MS had (p < 0.05) higher sdLDL-C (%) than patients without MS. Patients with atheroma plaques had higher sdLDL-C (p < 0.05). Estimated sdLDL-C correlated with IMT (r = 0.259, p < 0.001)., Conclusions: Capillary blood is an alternative to venous blood for sdLDL-C measurement and is stable for 24 h after collection. Estimated and directly measured sdLDL-C associate with the MS being accessible tools for cardiovascular risk assessment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Atherosclerosis is the main etiology of cardiovascular diseases (CVD), associated to systemic inflammation. Matrix metalloproteinases (MMPs) are related to atherosclerosis progression through the SDF1/CXCR4 axis promoting macrophages recruitment within the vascular wall. The goal was to assess new circulatory inflammatory markers in relation to atherosclerosis., Methods: Measurement of SDF1, MMP12 and CRP in blood samples of 298 prospective patients with cardiovascular risk. To explore atherosclerosis progression, CXCR4/SDF1 axis and MMP12 expression were determined by RT-qPCR and by immunohistochemistry in the aorta of accelerated and delayed atherosclerosis mice models (Apoe-/- and Apoe-/-Mmp10-/-)., Results: SDF1, MMP12 and CRP were elevated in patients with clinical atherosclerosis, but after controlling by confounding factors, only SDF1 and CRP remained increased. Having high levels of both biomarkers showed 2.8-fold increased risk of presenting clinical atherosclerosis ( p = 0.022). Patients with elevated SDF1, MMP12 and CRP showed increased risk of death in follow-up (HR = 3.2, 95%CI: 1.5-7.0, p = 0.004). Gene and protein expression of CXCR4 and MMP12 were increased in aortas from Apoe-/- mice., Conclusions: The combination of high circulating SDF1, MMP12 and CRP identified patients with particular inflammatory cardiovascular risk and increased mortality. SDF1/CXCR4 axis and MMP12 involvement in atherosclerosis development suggests that they could be possible atherosclerotic targets.

Background: Obesity is a major public health problem, which continues to be diagnosed and classified by BMI, excluding the most elemental concepts of the precision medicine approach. Obesity does not equally affect males and females, even with the same BMI. Microalbuminuria is a risk marker of cardiovascular disease closely related to obesity. The aim of this study was to evaluate the gender-dependent differences in the development of early obesity-related disease, focusing on pathologic microalbuminuria (PMA)., Material and Methods: We developed a single-centre cross-sectional study including 1068 consecutive adults from May 2016 to January 2018, divided into two groups: one including the first 787 patients attended, evaluated as a description population; the second group included 281 subjects analysed as an external validation population. Collected data included medical history, anthropometric measures, abdominal bioimpedance and routine laboratory tests., Results: First, we confirmed the lack of accuracy of classic obesity measures in predicting microalbuminuria. Second, we tested the utility of a tailored evaluation to predict PMA, with an area under the ROC curve of 0.78 for females and 0.82 for males. We also confirmed the different physiology of visceral adiposity for males when compared to females, in which small variations of fat mass entail major changes in the clinical repercussion. Third, we performed an external validation of our results, achieving a 77% accuracy rate., Conclusions: Our findings support that there is an individual threshold of fat amount necessary to develop obesity-dependent PMA and that gender plays a major role in the interplay between PMA and adiposity., (© 2020 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

In hypertensive patients with heart failure (HF) a serum biomarker combination of high carboxy-terminal propeptide of procollagen type-I (PICP) and low carboxy-terminal telopeptide of collagen type-I to matrix metalloproteinase-1 (CITP:MMP-1) ratio identifies a histomolecular phenotype of malignant myocardial fibrosis (mMF) associated with severe diastolic dysfunction (DD) and poor outcomes. As chronic kidney disease (CKD) facilitates MF and DD, we investigated the influence of CKD on the mMF biomarker combination in HF patients with preserved ejection fraction (HFpEF). Hypertensives ( n = 365), 232 non-HF and 133 HFpEF, were studied, and 35% non-HF and 46% HFpEF patients had CKD (estimated glomerular filtration rate < 60 mL/min/1.73 m 2 or urine albumin-to-creatinine ratio ≥ 30 mg/g). Specific immunoassays were performed to determine biomarkers. Medians were used to establish the high PICP and low CITP:MMP-1 combination. A comparison with non-HF showed that the biomarker combination presence was increased in HFpEF patients, being associated with CKD in all patients. CKD influenced the association of the biomarker combination and HFpEF ( p for interaction ≤ 0.019). The E:e' ratio was associated with the biomarker combination in CKD patients. Among CKD patients with HFpEF, those with the biomarker combination exhibited higher ( p = 0.016) E:e' ratio than those without the pattern. These findings suggest that CKD facilitates the development of biomarker-assessed mMF and DD in hypertensive HFpEF patients.

Context: Bone loss is accelerated in the late perimenopause and early menopause. The date of the final menstrual period cannot be stated until 1 year after it has ended, and at that time, most of the rapid bone loss phase will have elapsed. Therefore, early detection of bone loss is crucial., Objectives: To evaluate the utility of bone turnover markers (BTM) to identify the women who are more likely to lose more bone mass during the transition to menopause and quantify the loss of bone quality measured by trabecular bone score (TBS)., Design, Patients and Setting: Sixty-four healthy premenopausal women, mean age between 44 and 57 years old, were enrolled and followed up for 5 years. Clinical features, lifestyle, bone densitometry, TBS and BTM (CTX, P1NP and osteocalcin) were measured at baseline and follow-up., Results: All women had densitometrically normal bone at the time of enrolment. After 5 years, 48.4% had normal bone mineral density, 45.8% low bone mass and 6.3% osteoporosis. Women with osteopenia/osteoporosis at follow-up had higher CTX and P1NP at enrolment compared with women with densitometrically normal bone. The areas under the curve for the prediction of low bone mass or osteoporosis were 0.69 (P = 0.011) for P1NP, 0.69 for CTX (P = 0.013) and 0.77 (P 0.001) for OC. A significant correlation was found between P1NP increase after 5 years and the decrease in lumbar bone density (r = -0.383, P = 0.002). At baseline, 7 (10.9%) women had deteriorated microarchitecture (TBS < 1.3). Three of these women developed osteoporosis and four osteopenia at follow-up., Conclusions: Women with higher P1NP and CTX and lower TBS at baseline had lower BMD in the transition to menopause suggesting these novel tools could have potential use in identifying women at high risk of rapidly decreasing bone mass., (© 2019 John Wiley & Sons Ltd.)

Introduction: Monocytes play an important role in atherosclerotic progression having both pro and anti-inflammatory effects depending on different circulating monocyte subpopulations. The objective of this study is to characterize these subpopulations and their association with cardiovascular risk factors., Methods: Transversal study including 102 selected patients, mean age: 65 years-old (range 41-86), 69% males. A set of specific antibodies against classical monocytes (Mon1, CD14+CD16- CD300e+HLADR+), intermediate (Mon2, CD14+CD16+CD300e+HLADR+) and non-classical (Mon3, CD14-CD16+CD300e+HLADR+) was assayed. Three groups of patients were included: 17 asymptomatic with more than one cardiovascular risk factor (group 1), 56 subjects asymptomatic but with vascular pathology assessed by ultrasound or microalbuminuria (group 2) and 19 patients with a previous atherothrombotic event (group 3). The cardiovascular risk was determined by Framingham and REGICOR scores., Results: An association between study groups and the percentage of Mon1 and Mon2 was observed (ANOVA, p<.05), being independent of age and sex for Mon2. Likewise Mon1 and Mon2 subpopulations were associated with cardiovascular adverse events (β=0.86, p=.02 y β=0.1 p=.002, respectively), independently of age and sex in the case of Mon2. Moreover the percentage of Mon3 was associated with the presence of several cardiovascular risk factors (β=0.21, p=.04) in the univariate analysis. In addition, there was a correlation between the levels of Mon1 and Mon2 and leukocytes (r=0.7, p<.001 and r=0.26, p=.01, respectively)., Conclusions: The analysis of monocyte subpopulations may be clinically useful to stratify the inflammatory profile related to the different cardiovascular risk groups., (Copyright © 2019 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.)

Obesity favors the development of cardiometabolic alterations such as type 2 diabetes (T2D) and the metabolic syndrome (MS). Obesity and the MS are distinguished by an increase in circulating leptin concentrations, in parallel to a drop in the levels of adiponectin. Consequently, the Adpn/Lep ratio has been suggested as a maker of dysfunctional adipose tissue. We aimed to investigate in humans ( n = 292) the reliability of the Adpn/Lep ratio as a biomarker of adipose tissue dysfunction. We considered that an Adpn/Lep ratio of ≥1.0 can be considered normal, a ratio of ≥0.5 <1.0 suggests moderate-medium increased risk, and a ratio of <0.5 indicates a severe increase in cardiometabolic risk. Using these cut-offs, 5%, 54% and 48% of the lean, normoglycemic and without-MS subjects, respectively, fall within the group with an Adpn/Lep ratio below 0.5; while 89%, 86% and 90% of the obese, with T2D and with MS patients fall within the same group ( p < 0.001). A significant negative correlation ( r = -0.21, p = 0.005) between the Adpn/Lep ratio and serum amyloid A (SAA) concentrations, a marker of adipose tissue dysfunction, was found. We concluded that the Adpn/Lep ratio is a good indicator of a dysfunctional adipose tissue that may be a useful estimator of obesity- and MS-associated cardiometabolic risk, allowing the identification of a higher number of subjects at risk.

Background: Smoking is a recognized risk factor for osteoporosis. Trabecular bone score (TBS) is a novel texture parameter to evaluate bone microarchitecture. TBS and their main determinants are unknown in active and former smokers., Objective: To assess TBS in a population of active or former smokers with and without Chronic Obstructive Pulmonary Disease (COPD) and to determine its predictive factors., Methods: Active and former smokers from a pulmonary clinic were invited to participate. Clinical features were recorded and bone turnover markers (BTMs) measured. Lung function, low dose chest Computed Tomography scans (LDCT), dual energy absorptiometry (DXA) scans were performed and TBS measured. Logistic regression analysis explored the relationship between measured parameters and TBS., Results: One hundred and forty five patients were included in the analysis, 97 (67.8%) with COPD. TBS was lower in COPD patients (median 1.323; IQR: 0.13 vs 1.48; IQR: 0.16, p = 0.003). Regression analysis showed that a higher body mass index (BMI), younger age, less number of exacerbations and a higher forced expiratory volume-one second (FEV1%) was associated with better TBS (β = 0.005, 95% CI:0.000-0.011, p = 0.032; β = -0.003, 95% CI:-0.007(-)-0.000, p = 0.008; β = -0.019, 95% CI:-0.034(-)-0.004, p = 0.015; β = 0.001, 95% CI:0.000-0.002, p = 0.012 respectively). The same factors with similar results were found in COPD patients., Conclusions: A significant proportion of active and former smokers with and without COPD have an affected TBS. BMI, age, number of exacerbations and the degree of airway obstruction predicts TBS values in smokers with and without COPD. This important information should be considered when evaluating smokers at risk of osteoporosis., Competing Interests: The authors have declared that no competing interests exist.

Context: Human obesity is associated with increased circulating TNF-α, a proinflammatory cytokine that induces hepatocyte cell death., Objective: The potential beneficial effects of acylated and desacyl ghrelin in the progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis in obesity via the inhibition of TNF-α-induced hepatocyte apoptosis, autophagic cell death, and pyroptosis were investigated., Design, Settings, and Participants: Plasma ghrelin isoforms and TNF-α were measured in 158 participants, and hepatocyte cell death was evaluated in liver biopsies from 76 patients with morbid obesity undergoing bariatric surgery with available liver echography and pathology analysis. The effect of acylated and desacyl ghrelin on basal and TNF-α-induced cell death was determined in vitro in human HepG2 hepatocytes., Results: Circulating TNF-α and the acylated/desacyl ghrelin ratio were increased, whereas desacyl ghrelin levels were decreased in patients with obesity and NAFLD. Six months after bariatric surgery, decreased acylated/desacyl ghrelin levels, and improved hepatic function were found. Patients with obesity and type 2 diabetes showed increased hepatic ghrelin O-acyltransferase transcripts as well as an increased hepatic apoptosis, pyroptosis, and compromised autophagy. In HepG2 hepatocytes, acylated and desacyl ghrelin treatment reduced TNF-α-induced apoptosis, evidenced by lower caspase-8 and caspase-3 cleavage, as well as TUNEL-positive cells and pyroptosis, revealed by decreased caspase-1 activation and lower high-mobility group box 1 expression. Moreover, acylated ghrelin suppressed TNF-α-activated hepatocyte autophagy, as evidenced by a decreased LC3B-II/I ratio and increased p62 accumulation via AMPK/mTOR., Conclusions: Ghrelin constitutes a protective factor against hepatocyte cell death. The increased acylated/desacyl ghrelin ratio in patients with obesity and NAFLD might constitute a compensatory mechanism to overcome TNF-α-induced hepatocyte apoptosis, autophagy, and pyroptosis.

Background & Aims: Visceral adipose tissue (VAT) has been shown to be profoundly responsible of most of the obesity-associated metabolic derangements. The measurement of VAT usually implies the use of imaging techniques such as magnetic resonance imaging or computed tomography (CT). Our aim was to evaluate the accuracy of the determination of VAT by means of abdominal bioimpedance (BIA) with the ViScan device in comparison with CT and its clinical usefulness in the management of obesity., Methods: We studied a sample of 140 subjects (73 males/67 females) with BMI ranging from 17.7 to 50.4 kg/m 2 to evaluate the accuracy of the ViScan in comparison to CT to determine VAT. To further analyze ViScan's clinical usefulness we studied a separate cohort (n = 2849) analyzing cardiometabolic risk factors. Furthermore, we studied the ability of the ViScan to detect changes in VAT after weight gain (n = 107) or weight loss (n = 335). The study was performed from October 2009 through June 2015., Results: ViScan determines VAT with a good accuracy in individuals with a CT-VAT up to 200 cm 2 , and then with lower precision with increasing body mass, exhibiting a moderate-high correlation with CT-VAT (r = 0.75, P < 0.001). Importantly, VAT determination with the ViScan exhibits better correlations with several cardiometabolic risk factors such as glucose, triglycerides, HDL-cholesterol and markers of fatty liver than anthropometric measurements such as BMI or waist circumference. ViScan is able to detect VAT variations after body weight changes., Conclusions: Since the possibility of measuring VAT by imaging techniques is not always available, abdominal BIA represents a good alternative to estimate VAT, allowing the identification of patients with increased VAT-related cardiometabolic risk and a better management of obese patients., Trial Registration: ClinicalTrials.gov NCT01055626 and NCT01572090., (Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Chronic Obstructive Pulmonary Disease (COPD) is an independent risk factor for cardiovascular (CV) disease, one of the most frequent causes of death in COPD patients. The goal of the present study was to evaluate the prognostic value of non-invasive CV risk markers in COPD patients., Methods: CV risk was prospectively evaluated in 287 COPD patients using non-invasive markers including the Framingham score, the Systematic Coronary Risk Evaluation (SCORE) charts, coronary arterial calcium (CAC), epicardial adipose tissue (EAT), as well as clinical, biochemical and physiological variables. The predictive power of each parameter was explored using CV events as the main outcome., Results: During a median follow up of 65 months (ICR: 36-100), 44 CV events were recorded, 12 acute myocardial infarctions (27.3%), 10 ischemic heart disease/angina (22.7%), 12 peripheral artery disease events requiring surgery (27.3%) and 10 strokes (22.7%). A total of 35 CV deaths occurred during that period. Univariable analysis determined that age, hypertension, CRP, total Cholesterol, LDL-Cholesterol, Framingham score and CAC were independently associated with CV events. Multivariable analysis identified CAC as the best predictor of CV events (HR; 95%CI: 1.32; 1.19-1.46, p < 001)., Conclusions: In COPD patients attending pulmonary clinics, CAC was the best independent non-invasive predictor of CV events. This tool may help evaluate the risk for a CV event in patients with COPD. Larger studies should reproduce and validate these findings.

The aim of the present work was to study whether the leptin-adiponectin axis may have a pathophysiological role in the increased systemic inflammation and oxidative stress observed in patients with the metabolic syndrome (MS). Leptin, adiponectin, and markers of inflammation and oxidative stress were measured in a sample of 140 Caucasian subjects (74 males/66 females), aged 28-82 years, 60 with and 80 without the MS. Total concentrations of adiponectin as well as its multimeric forms HMW, MMW and LMW were significantly lower in individuals with the MS. The ratio adiponectin/leptin, a marker of dysfunctional adipose tissue, was dramatically decreased in the MS group. Systemic oxidative stress, as evidenced by levels of thiobarbituric acid reactive substances (TBARS), as well as markers of inflammation such as serum amyloid A (SAA), C-reactive protein (CRP) and osteopontin were significantly increased in subjects with the MS. Total adiponectin concentrations were negatively correlated with levels of TBARS and CRP levels. Furthermore, the ratio adiponectin/leptin was negatively correlated with SAA concentrations as well as with CRP levels. We concluded that a dysfunctional adipose tissue as suggested by a low adiponectin/leptin ratio may contribute to the increased oxidative stress and inflammation, hallmarks of the MS.