The H19X‐encoded miR‐424(322)/503 cluster regulates multiple cellular functions. Here, it is reported for the first time that it is also a critical linchpin of fat mass expansion. Deletion of this ...miRNA cluster in mice results in obesity, while increasing the pool of early adipocyte progenitors and hypertrophied adipocytes. Complementary loss and gain of function experiments and RNA sequencing demonstrate that miR‐424(322)/503 regulates a conserved genetic program involved in the differentiation and commitment of white adipocytes. Mechanistically, it is demonstrated that miR‐424(322)/503 targets γ‐Synuclein (SNCG), a factor that mediates this program rearrangement by controlling metabolic functions in fat cells, allowing adipocyte differentiation and adipose tissue enlargement. Accordingly, diminished miR‐424(322) in mice and obese humans co‐segregate with increased SNCG in fat and peripheral blood as mutually exclusive features of obesity, being normalized upon weight loss. The data unveil a previously unknown regulatory mechanism of fat mass expansion tightly controlled by the miR‐424(322)/503 through SNCG.
Absence of H19X‐encoded miR‐424(322)/503 in mice results in altered progenitor/adipose stem cell homeostasis, adipose tissue expansion, and its expression is reduced in obese subjects. Mechanistically, epigenetically‐controlled miR‐424(322)/503 modulates adipocyte differentiation by regulating γ‐Synuclein (SNCG). Expression levels of miR‐424(322)/503 and tissular/soluble SNCG co‐segregate with obesity in humans and can be modulated by weight loss surgically induced by gastric bypass.
The ribosomal protein S6 kinase 1 (S6K1) is a relevant effector downstream of the mammalian target of rapamycin complex 1 (mTORC1), best known for its role in the control of lipid homeostasis. ...Consistent with this, mice lacking the
S6k1
gene have a defect in their ability to induce the commitment of fat precursor cells to the adipogenic lineage, which contributes to a significant reduction of fat mass. Here, we assess the therapeutic blockage of S6K1 in diet-induced obese mice challenged with LY2584702 tosylate, a specific oral S6K1 inhibitor initially developed for the treatment of solid tumors. We show that diminished S6K1 activity hampers fat mass expansion and ameliorates dyslipidemia and hepatic steatosis, while modifying transcriptome-wide gene expression programs relevant for adipose and liver function. Accordingly, decreased mTORC1 signaling in fat (but increased in the liver) segregated with defective epithelial-mesenchymal transition and the impaired expression of Cd36 (coding for a fatty acid translocase) and Lgals1 (Galectin 1) in both tissues. All these factors combined align with reduced adipocyte size and improved lipidomic signatures in the liver, while hepatic steatosis and hypertriglyceridemia were improved in treatments lasting either 3 months or 6 weeks.
Confinement during the COVID‐19 pandemic is expected to have a serious and complex impact on the mental health of patients with an eating disorder (ED) and of patients with obesity. The present ...manuscript has the following aims: (1) to analyse the psychometric properties of the COVID Isolation Eating Scale (CIES), (2) to explore changes that occurred due to confinement in eating symptomatology; and (3) to explore the general acceptation of the use of telemedicine during confinement. The sample comprised 121 participants (87 ED patients and 34 patients with obesity) recruited from six different centres. Confirmatory Factor Analyses (CFA) tested the rational‐theoretical structure of the CIES. Adequate goodness‐of‐fit was obtained for the confirmatory factor analysis, and Cronbach alpha values ranged from good to excellent. Regarding the effects of confinement, positive and negative impacts of the confinement depends of the eating disorder subtype. Patients with anorexia nervosa (AN) and with obesity endorsed a positive response to treatment during confinement, no significant changes were found in bulimia nervosa (BN) patients, whereas Other Specified Feeding or Eating Disorder (OSFED) patients endorsed an increase in eating symptomatology and in psychopathology. Furthermore, AN patients expressed the greatest dissatisfaction and accommodation difficulty with remote therapy when compared with the previously provided face‐to‐face therapy. The present study provides empirical evidence on the psychometric robustness of the CIES tool and shows that a negative confinement impact was associated with ED subtype, whereas OSFED patients showed the highest impairment in eating symptomatology and in psychopathology.
Adipose tissue of obese subjects is known to exhibit increased inflammatory activity linked to altered expression of factors involved in glucose and lipid metabolism. The surgical procedure ...constitutes an injury per se, evoking a systemic inflammatory response.
To evaluate changes in the expression of key-genes in adipose tissue after common surgical procedures performed in obese patients.
A tertiary hospital.
Paired subcutaneous (SAT) and visceral (VAT) adipose tissue samples were collected at the beginning and the end of surgery in 33 obese patients that underwent laparoscopic Roux-en-Y gastric bypass (RYGB, n = 17) or laparoscopic vertical sleeve gastrectomy (SG, n = 16). The expression of genes involved in inflammation, glucose and lipid metabolism was assessed.
The surgical procedure led to increased expression of interleukin 6, interleukin 8 (P<.0001 in both depots), tumor necrosis factor α (P = .001 in SAT), and lipopolysaccharide binding protein (P = .0004 in VAT). Surgery also induced concomitant decreased expression of GLUT4, IRS1 (P = .046 in VAT), and adiponectin, whereas the messenger RNA of lipogenic genes fatty acid synthase (P = .024); sterol regulatory element binding transcription factor 1 (P = .011) and aquaporin 9 (P<.0001) in SAT; and PPARγ (P = .018) and solute carrier family 27 (fatty acid transporter), member 2 (P = .028) in VAT increased in parallel to inflammation. Changes in gene expression during surgery were enhanced in patients following RYGB, when compared with SG.
Bariatric surgery acutely changes the expression of inflammatory and lipogenic genes in adipose tissue. This information should be considered cautiously when designing studies to assess adipose tissue gene expression in morbidly obese patients. The same timing of sampling is mandatory.
The aim of the study was to evaluate human plasma circulating levels of adipocyte fatty acid‐binding protein (A‐FABP) and its relationship with proinflammatory adipocytokines and insulin resistance ...in a severely obese cohort, before and 1 year after a surgical gastric bypass. Plasmatic levels of A‐FABP were measured in 77 morbid‐obese women before and 1 year after bariatric surgery. Anthropometrical parameters and body composition by bioelectrical impedance analysis were determined. Circulating levels of soluble tumor necrosis factor receptor 2 (sTNFR2), Interleukin 18 (IL‐18), adiponectin, and high‐sensitive C‐reactive protein (hsCRP) were also analyzed. Insulin resistance by homeostasis model assessment of insulin resistance (HOMA‐IR) index was calculated. After massive weight loss, A‐FABP plasmatic levels decreased significantly 7.6 (8.9) vs. 4.3 (5.1); P < 0,001 but no association with circulating adipokines or proinflammatory cytokines, both at the beginning and at the end of follow‐up, was observed. A decrease in sTNFR2, IL‐18, hsCRP, and an increase in adiponectin levels (P < 0.001 in all cases) were observed after the gastric bypass. HOMA‐IR index improved 1 year after surgery and after multiple regression analysis remained associated with A‐FABP after controlling for confounding variables (β = 0.322, P = 0.014; R2 for the model 0.281). In morbid‐obese women, plasma A‐FABP concentrations were dramatically reduced after gastric bypass surgery. After weight loss this protein contributed to HOMA‐IR index independently of proinflammatory/antinflammatory cytokine profile. Further studies are warranted to elucidate the role of A‐FABP in the pathogenesis of insulin resistance in morbid obesity.
Context: Caveolins are 21-24 kDa integral membrane proteins that serve as scaffolds to recruit numerous signaling molecules. Specific subclasses of caveolae carry out specific functions in cell ...metabolism. In particular, triglycerides are synthesized at the site of fatty acid entry in one of these caveolae classes. Objective and Methods: We studied the expression of caveolin-1 (CAV-1) gene in association with metabolic variables in 90 visceral and 55 subcutaneous adipose tissue samples from subjects with a wide range of fat mass, in the stromovascular fraction (SVC) and isolated adipocytes, and during differentiation of human adipocytes. Results: CAV-1 gene expression was significantly decreased in visceral adipose tissue (v-CAV-1) of obese subjects. v-CAV-1 was positively associated with several lipogenic genes such as acetyl-coA carboxylase (ACACA, r=0.34, p=0.004) and spot-14 (r=0.33, p=0.004). In non-obese subjects v-CAV-1 also correlated with fatty acid synthase (FAS, r=0.60, p<0.0001). Subcutaneous (sc) adipose tissue (Sc-CAV-1) gene expression was not associated with these lipogenic factors when obese and non-obese subjects were studied together. In obese subjects, however, sc-CAV-1 was associated with FAS (r=0.36, p=0.02), SREBP-1c (r=0.58, p<0.0001), ACACA (r=0.33, p=0.03), spot-14 (r=0.36, p=0.02), PPAR- co-activator-1 (PGC-1, r=0.88, n=19). In these obese subjects, Sc-CAV-1 was also associated with fasting triglycerides (r=-0.50, p<0.0001). CAV-1 expression in mature adipocytes was significantly higher than in stromal vascular cells. CAV-1 gene expression in adipocytes from subcutaneous adipose tissue (but not in adipocytes from visceral adipose tissue) was significatively associated with fasting triglycerides. CAV-1 gene expression did not change significantly during differentiation of human preadipocytes from lean or obese subjects despite significant increase of FAS gene expression. Conclusion: Decreased CAV-1 gene expression was simultaneously linked to increased triglycerides and decreased lipogenic gene expression among obese subjects, paralleling the observations of hypertriglyceridemia in CAV-1 knockout mice. However, the regulation of CAV-1 gene expression seems independent of the adipogenic program.
Exposure biomarkers are required in tobacco use studies to accurately assess smoking status since self-reporting usually results in misclassification estimates. This study uses breath analysis and ...assesses some volatile organic compounds (VOCs) as potential biomarkers of tobacco smoke exposure.
Forced-expiratory breath samples were obtained from 377 volunteers (174 smokers and 203 nonsmokers). Exhaled breath levels of different VOCs previously related to tobacco smoke were evaluated. The toluene-to-benzene ratio was evaluated as this ratio has been found to be different in atmospheric samples and tobacco smoke emissions. Finally, breath analyses from 64 patients attending a clinical practice were evaluated and the results were compared to their self-reporting status.
Univariate analysis shows that all compounds evaluated gave significant differences (p < .001). Receiver operating characteristic (ROC) curves suggest that xylenes and toluene are not able to accurately determine smoking status, and benzene and the T/B ratio present potential utility in certain conditions. The highest discriminant capacity was obtained for 2,5-dimethylfuran (AUC = 0.982, 95% confidence interval CI: 0.969-0.995), with a cut-off value of 0.016 ppbv (sensibility = 0.965, specificity = 0.896). Drinking coffee was the only confounding parameter that can give low breath levels for this compound. The evaluation of the results obtained from the patients attending a clinical practice showed that 8% of people who claim to be nonsmokers hid their real smoking status.
The results obtained confirm that the determination of 2,5-dimethylfuran in breath samples is a good and simpler alternative to conventional blood or urine tests for assessing smoking status.
Analysis of 2,5-dimethylfuran in breath samples results in a simple and fast method for the determination of the smoking status of a person. This methodology presents multiple advantages as it is neither invasive nor embarrassing for patients attending clinical practices. Moreover, analysis of biomarkers in breath samples is simpler and faster than using conventional methods based on urine or blood analysis.
Infections and new onset diabetes mellitus after transplantation (NODAT) are frequent complications after renal transplantation and may be related to innate immunity alterations. We evaluate the ...relationship among serum mannose-binding lectin (MBL), chronic inflammation, NODAT, and infection.
Between March 2005 and October 2006, consecutive nondiabetic renal transplant recipients were recruited. MBL, soluble tumor necrosis factor receptor 2, and neutrophil gelatinase-associated lipocalin were determined before transplant and at 1 and 3 months. An oral glucose tolerance test was performed at 3 months.
A total of 125 patients were recruited, and 111 patients had a functioning graft at 3 months. MBL levels remained unchanged after transplantation. Subjects with low MBL (lower tertile) had higher pretransplant soluble tumor necrosis factor receptor 2 (40+/-13 ng/mL vs. 35+/-11 ng/mL; P=0.05) and neutrophil gelatinase-associated lipocalin (638+/-114 ng/mL vs. 553+/-185 ng/mL; P=0.03), an increased incidence of bacterial/fungal infection (P=0.021), and an increased prevalence of NODAT at 3 months (44.4% vs. 22.6%; P=0.01). Multivariate analysis confirmed that MBL was a risk factor for NODAT (relative risk: 3.04, 95% confidence interval: 1.18-7.81; P=0.021) adjusting for age, pretransplant impaired fasting glucose, and body mass index.
Low pretransplant MBL is associated with chronic inflammation, NODAT, and infection.
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