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OBJECTIVE The impact of weight loss induced by bariatric surgery (BS) and nonsurgical approaches on cardiovascular risk factors (CVRFs) has not been fully elucidated. We assessed the effects of BS and a nonsurgical approach on carotid intima-media thickness (CIMT) and CVRFs in participants with class 3 obesity. METHODS A total of 87 participants with obesity (59 women; 46 [37-52] years old; BMI, 43 [40-47]) and 75 controls were recruited; 21 (25%) participants with obesity underwent BS. BMI, blood pressure, cholesterol, triglycerides, fasting plasma glucose, C-reactive protein, CIMT, and Framingham Risk Score were measured at baseline and at 3-year follow-up. Independent factors for reduction in CIMT were analyzed. The literature on the effects of BS and CIMT was reviewed. RESULTS After BS, BMI decreased from 45.45 to 27.28 (P

Subclinical hypothyroidism is known to be associated with increased serum cholesterol. Since thyroid-stimulating hormone (TSH) exerts an inductor effect on cholesterol biosynthesis, we aimed to investigate the relationship between TSH mRNA and cholesterol metabolism in human adipose tissue (AT). Cross-sectionally, AT TSH-β (TSHB) mRNA was evaluated in 4 independent cohorts in association with serum total and LDL cholesterol, and AT lipidomics. Longitudinally, the effects of statins and of diet and exercise on AT TSHB mRNA were also examined. The bidirectional relationship between cholesterol and TSHB were studied in isolated human adipocytes. TSHB mRNA was consistently detected in AT from euthyroid subjects, and positively associated with serum total- and LDL-cholesterol, and with AT-specific cholesterol metabolism-associated lipids [arachidonoyl cholesteryl ester, C8-dihydroceramide, N-stearoyl-d-sphingosine, and GlcCer(18:0, 24:1)]. Reduction of cholesterol with statins and with diet and exercise interventions led to decreased TSHB mRNA in human AT, whereas excess cholesterol up-regulated TSHB mRNA in human adipocytes. In addition, recombinant human TSH α/β administration resulted in increased HMGCR mRNA levels in human adipocytes. In mice, subcutaneous AT Tshb expression levels correlated directly with circulating cholesterol levels. In summary, current results provide novel evidence of TSHB as a paracrine factor that is modulated in parallel with cholesterol metabolism in human AT.—Moreno-Navarrete, J. M., Moreno, M., Ortega, F., Xifra, G., Hong, S., Asara, J. M., Serrano, J. C. E., Jové, M., Pissios, P., Blüher, M., Ricart, W., Portero-Otin, M., Fernández-Real, J. M. TSHB mRNA is linked to cholesterol metabolism in adipose tissue.

Scope: Changes in genetic variations affecting the taste receptor, type 2, member 38 (TAS2R38) may identify the interacting mechanism leading to obesity and potential associations with proteins partaking in innate immunity, such as surfactant protein D (SPD) and mannan-binding lectin (MBL). Methods and results: We evaluated haplotypes of the bitter-taste receptor TAS2R38 in an identification sample of 210 women in different weight conditions, including anorexia nervosa and obesity. The association with SPD and MBL was tested in an independent sample picturing general population (n = 534). The relationship with obesity was validated in an extended final sample of 1319 participants. In the sample comprised of women in extreme weight conditions, increased obesity was identified in AVI/AVI subjects (OR = 2.5 [1.06–6.11], p = 0.035). In the sample picturing general population, increased SPD and MBL concentrations were found in nonsmoking AVI carriers. In this cohort, smoking and obesity blunted associations between TAS2R38 haplotypes and SPD and MBL. In the extended sample, the association of AVI/AVI haplotypes with increased obesity was also identified (OR = 1.4 [0.99/1.85], p = 0.049), being more robust in subjects aged

In the version of this article originally published, the received date was missing. It should have been listed as 2 January 2018. The error has been corrected in the HTML and PDF versions of this article.

Hepatic steatosis is a multifactorial condition that is often observed in obese patients and is a prelude to non-alcoholic fatty liver disease. Here, we combine shotgun sequencing of fecal metagenomes with molecular phenomics (hepatic transcriptome and plasma and urine metabolomes) in two well-characterized cohorts of morbidly obese women recruited to the FLORINASH study. We reveal molecular networks linking the gut microbiome and the host phenome to hepatic steatosis. Patients with steatosis have low microbial gene richness and increased genetic potential for the processing of dietary lipids and endotoxin biosynthesis (notably from Proteobacteria), hepatic inflammation and dysregulation of aromatic and branched-chain amino acid metabolism. We demonstrated that fecal microbiota transplants and chronic treatment with phenylacetic acid, a microbial product of aromatic amino acid metabolism, successfully trigger steatosis and branched-chain amino acid metabolism. Molecular phenomic signatures were predictive (area under the curve = 87%) and consistent with the gut microbiome having an effect on the steatosis phenome (>75% shared variation) and, therefore, actionable via microbiome-based therapies. Metabolic activity of specific human gut microorganisms contributes to liver steatosis in obese women.

Background 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. Objective To evaluate changes in the expression of key-genes in adipose tissue after common surgical procedures performed in obese patients. Setting A tertiary hospital. Methods 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. Results The surgical procedure led to increased expression of interleukin 6, interleukin 8 ( P 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 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. Conclusions 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.

Objective: Circulating and adipose tissue markers of iron overload are increased in subjects with obesity. The aim is to study iron signals in adipose tissue. Methods: Adipose tissue R2* values and hepatic iron concentration (HIC) were evaluated using magnetic resonance imaging (MRI) in 23 middle-aged subjects with obesity and 20 subjects without obesity. Results: Subcutaneous (SAT) and visceral adipose tissue (VAT) R2* were increased in subjects with obesity (P = 0.004 and P = 0.008) and correlated significantly and positively with HIC in all subjects. Strikingly, most of the associations of liver iron with metabolic parameters were replicated with SAT and VAT R2*. BMI, waist circumference, fat mass, HOMA value, and C-reactive protein positively correlated with HIC and SAT and VAT R2*. BMI or percent fat mass (but not insulin resistance) contributed independently to 26.8-34.8% of the variance in sex- and age-adjusted SAT or VAT R2* (β > 0.40, P

Objective To investigate CISD1 mRNA and protein in human adipose tissue in association with obesity and adipogenesis. Methods Subcutaneous (SAT) and visceral (VAT) adipose tissue CISD1 gene expression (real-time PCR) and protein (Western blot) levels were investigated in human adipose tissue and during human adipocyte differentiation. Results SAT and VAT CISD1 mRNA and protein levels were significantly decreased in subjects with obesity and negatively correlated with BMI after controlling for age and sex. In participants with morbid obesity, VAT CISD1 gene expression was positively correlated with insulin sensitivity (r = 0.47, P = 0.01), and bariatric surgery-induced weight loss led to increased SAT CISD1 mRNA levels. In both VAT and SAT, CISD1 gene expression was significantly associated with SIRT1, ISCA2, and mitochondrial biogenesis-related (PPARGC1A, TFAM, and MT-CO3) and browning-related (PRDM16 and UCP1) gene expression. In addition, VAT CISD1 gene expression was significantly associated with adipogenic and iron metabolism-related genes. Importantly, these correlations were replicated in a second cohort. At the cellular level, CISD1 gene expression increased during human adipocyte differentiation in correlation with adipogenic genes (r > 0.60, P

Rodent models have found that osteocalcin crosses the blood-brain barrier and regulates behaviour. No data are available on osteocalcin's effects on brain microstructure and cognitive performance in humans. We evaluated the association between serum osteocalcin concentrations and (i) brain microstructural changes on magnetic resonance imaging (MRI) and (ii) neuropsychological performance.We studied 24 consecutive obese subjects (13 women; age, 49·8 ± 8·1 years; body mass index [BMI], 43·9 ± 4·54 kg/m(2) ) and 20 healthy volunteers (10 women; age, 48·8 ± 9·5 years; BMI, 24·3 ± 3·54 kg/m(2) ) in a cross-sectional study within the multicentre FLORINASH Project. FLAIR signal intensity and DTI-metrics (primary (λ1 ), secondary (λ2 ) and tertiary (λ3 ) eigenvalues; fractional anisotropy (FA); and mean diffusivity) in the caudate, hypothalamus, thalamus and putamen, and in subcortical white matter were assessed. Cognitive performance evaluated by neuropsychological test battery.Lower osteocalcin concentrations were associated with BMI, higher λ1, λ2 and λ3 values at the caudate and lower FLAIR signal intensity at the caudate and putamen. Obese patients with lower osteocalcin concentrations had higher FA at putamen and thalamus. Lower osteocalcin concentrations were associated with higher Iowa Gambling Task (IGT) scores. FLAIR signal intensity at the caudate601·832 yielded 85·7% sensitivity, 64·3% specificity, 70·6% negative predictive value and 81·8% positive predictive value for IGT score. Lower osteocalcin was an independent predictor of worse cognitive performance on multivariate analysis (F = 3·551, P = 0·01343; R(2) = 0·103). Bayesian information criterion demonstrated that osteocalcin had the predominant role in predicting IGT score.Lower serum osteocalcin concentrations are associated with brain microstructural changes and worse cognitive performance.

Context: Molecular mechanisms associated with physiological variations in adipose tissue (AT) are not fully recognized. The most recent reports highlight the critical relevance of microRNAs (miRNAs) found in AT. Objective: To identify changes in messenger RNA (mRNA) and miRNA expressions and their interaction in human AT before and after surgery-induced weight loss. Research Design and Setting: Genome-wide mRNA and miRNA expressions were assessed by microarrays in abdominal subcutaneous AT of 16 morbidly obese women before and 2 years after laparoscopic Roux-en-Y gastric bypass. The association of changes in miRNAs with their respective mRNA targets was studied. The results were replicated in publicly available microarray datasets. Validation was made by real-time polymerase chain reaction in additional fat samples from 26 age-matched lean women and in isolated human adipocytes. Results: A total of 5018 different mRNA probe sets and 15 miRNAs were differentially expressed after surgery-induced weight loss. The clustering of similar expression patterns for gene products with related functions revealed molecular footprints that elucidate significant changes in cell cycle, development, lipid metabolism, and the inflammatory response. The participation of inflammation was demonstrated by results assessed in isolated adipocytes. Interestingly, when transcriptomes were analyzed taking into account the presence of miRNA target sites, miRNA target mRNAs were upregulated in obese AT (P value = 2 × 10−181) and inflamed adipocytes (P value = 4 × 10−61), according to the number of target sites harbored by each transcript. Conclusions: Current findings suggest impaired miRNA target gene expression in obese AT in close association with inflammation, both improving after weight loss.

Scope Very few studies have evaluated serum hepcidin in patients with type 2 diabetes and they have reported conflicting results. In addition, the effect of antidiabetic drugs on circulating hepcidin has not been explored so far. The aims of the study were to evaluate hepcidin concentrations and hepcidin/ferritin ratio in type 2 diabetes subjects and healthy non-diabetic controls and to evaluate the effect of metformin on hepcidin concentrations. Methods and results Study 1: Cross-sectional multivariate study of 239 non-diabetic individuals and 65 people with type 2 diabetes. The multivariate analysis included covariates of chronic inflammation, BMI, pharmacological treatment, menopausal status and insulin resistance. Study 2: Randomized, double-blinded, placebo-controlled 4-month trial metformin compared to placebo among 36 type 2 diabetic patients. In both groups diet was controlled by maintaining a hypocaloric intake across the trial. Hepcidin levels were significantly lower in patients with type 2 diabetes than in non-diabetic individuals either in crude or adjusted regression models (P

cope Angiopoietin-like protein 4 (ANGPTL-4) regulates plasma lipoprotein levels but its relevance in human obesity and type 2 diabetes is largely unknown. We aimed to investigate the regulation of circulating ANGPTL-4 levels in obesity, type 2 diabetes and after changes in body weight. Methods and results Circulating ANGPTL-4 levels were measured in two different cohorts. First, in a cross-sectional study, we evaluated ANGPTL-4 levels in lean and obese patients with normoglycemia or with altered glucose tolerance (n = 282). Second, in a longitudinal intervention study, 51 obese participants were evaluated. A hypocaloric diet was prescribed, with follow up two years later. ANGPTL-4 levels were significantly increased in obese patients with altered glucose tolerance compared to lean participants. Moreover, ANGPTL-4 was positively correlated with BMI, waist circumference, fat mass, HbA1c, HOMA-IR, fasting triglycerides and with inflammatory markers. Participants gaining weight after the follow up showed increased ANGPTL-4 levels in parallel to increased BMI, fat mass and fasting glucose, while ANGPTL-4 levels were reduced in participants losing weight. Conclusion Our data support a relevant role of ANGPTL-4 in human obesity and its involvement in long-term body weight changes. This article is protected by copyright. All rights reserved

The mycobiotic component of the microbiota comprises an integral, yet under-researched, part of the gastrointestinal tract. Here, we present a preliminary study of the possible contribution of gut mycobiota to sub-clinical atherosclerosis in a well-characterised group of obese and non-obese subjects in association with the Framingham Risk Score (FRS) and carotid intima-media thickness (cIMT). From all taxa identified, the relative abundance of the phylum Zygomycota, comprising the family Mucoraceae and genus Mucor, was negatively associated with cIMT and this association remained significant after controlling for false discovery rate. Obese subjects with detectable Mucor spp. had a similar cardiovascular risk profile as non-obese subjects. Interestingly, the relative abundance of Mucor racemosus was negatively associated both with FRS and cIMT. Partial least square discriminant analyses modelling, evaluating the potential relevance of gut mycobiota in patients stratified by mean values of cIMT, showed that even a 1 component model had a high accuracy (0.789), with a high R2 value (0.51). Variable importance in projection scores showed that M. racemosus abundance had the same impact in the model as waist-to-hip ratio, high-density lipoprotein-cholesterol, fasting triglycerides or fasting glucose, suggesting that M. racemosus relative abundance in the gut may be a relevant biomarker for cardiovascular risk.

Summary Background & aims Increased iron stores significantly influence the clinical course of several chronic metabolic diseases. Recent studies have shown that iron overload decreases osteocalcin. We aimed to explore the relationship among osteocalcin, iron stores and insulin sensitivity. Methods Extensive clinical and laboratory measurements, including serum ferritin, cross-linked C-telopeptide of type I collagen (CTX) and osteocalcin (OC) concentrations, were analyzed in 250 adult consecutive Caucasian men. Insulin sensitivity was evaluated through frequently sampled intravenous glucose tolerance tests with minimal model analysis. Results Circulating serum ferritin were negatively associated with serum OC and CTX (p = 0.004 and p = 0.045 respectively). In all subjects as a whole, BMI and ferritin contributed to explain 5.2% of OC variance after controlling for age and smoking status. However, the association between OC and insulin sensitivity remained significant only in lean subjects (BMI Conclusions The association of circulating osteocalcin with parameters of insulin sensitivity and iron stores were dependent on obesity status. Increased iron stores could contribute to the detrimental metabolic effects of overweight and obesity on bone.

Background:Circulating thyroid hormones have been described to be intrinsically associated with insulin sensitivity in healthy subjects. μ-Crystallin is a nicotinamide adenine dinucleotide phosphate-dependent thyroid hormone-binding protein that has been shown to bind T3 in the cytoplasm. We aimed to study μ-Crystallin expression in adipose tissue and in muscle in association with insulin action and thyroid function.Methods:μ-Crystallin gene expression was studied in 81 visceral and 75 sc adipose tissue samples and in 26 muscle samples from a cohort of subjects with a wide spectrum of adiposity (cohort 1). μ-Crystallin was also evaluated in 30 morbidly obese subjects in whom insulin action was evaluated using euglycemic clamp (cohort 2) and in 22 sc adipose tissue samples obtained before and after bariatric surgery-induced weight loss (cohort 3). μ-Crystallin was also evaluated during differentiation of human adipocytes. μ-Crystallin was overexpressed in human sc adipocytes using lentiviruses.Results:μ-Crystallin gene expression was 2.6- to 3-fold higher in sc vs visceral adipose tissue in direct association with the expression of thyroid hormone receptor α 1 in cohort 1 and cohort 2. Visceral, but not sc, adipose tissue μ-Crystallin was positively associated with the serum T3/T4 ratio in cohort 1 and with insulin sensitivity in cohort 2. In fact, μ-Crystallin gene expression was significantly decreased in visceral adipose tissue (−43%) and in muscle (−26%) in subjects with impaired fasting glucose and type 2 diabetes. Weight loss did not result in significant sc adipose tissue μ-Crystallin changes. μ-Crystallin overexpression led to increased insulin-induced Ser473Akt phosphorylation in sc adipocytes. During differentiation of adipocytes, μ-Crystallin gene expression decreased in both visceral (P = .006) and sc (P = .003) adipocytes from obese subjects.Conclusion:Visceral, but not sc, adipose tissue μ-Crystallin is an adipose tissue factor linked to parameters of thyroid hormone action (T3/T4 ratio) and might mediate the interaction of thyroid function and insulin sensitivity.

OBJECTIVE Circulating markers of iron overload are associated with insulin resistance. Less is known about the impact of iron overload on adipose tissue (AT). We hypothesized that gene expression markers of iron metabolism in AT could be associated with insulin action. RESEARCH DESIGN AND METHODS The AT expression of ferroportin (SLC40A1), transferrin (TF), TF receptor (TFRC), ferritin (FT) heavy polypeptide 1 (FTH1), and FT light polypeptide (FTL) was analyzed cross-sectionally in three independent cohorts and also after weight loss–induced changes in insulin sensitivity (clamp M value) in an independent fourth cohort. RESULTS In human AT, TF mRNA and protein levels were decreased with obesity and insulin resistance in the three cohorts and were positively associated with adipogenic mRNAs and insulin action. Otherwise, FTL mRNA and protein and SLC40A1 transcripts were positively associated with BMI and negatively linked to adipogenic genes and insulin action. Bariatric surgery–induced weight loss led to increased TF and decreased TFRC, FTH1, FTL, and SLC40A1 in subcutaneous AT in parallel to improved insulin action. CONCLUSIONS These results suggest that iron overload impacts on AT in association with insulin resistance.

OBJECTIVE The linkage among the tissue iron stores, insulin resistance (IR), and cognition remains unclear in the obese population. We aimed to identify the factors that contribute to increased hepatic iron concentration (HIC) and brain iron overload (BIO), as evaluated by MRI, and to evaluate their impact on cognitive performance in obese and nonobese subjects. RESEARCH DESIGN AND METHODS We prospectively recruited 23 middle-aged obese subjects without diabetes (13 women; age 50.4 ± 7.7 years; BMI 43.7 ± 4.48 kg/m2) and 20 healthy nonobese volunteers (10 women; age 48.8 ± 9.5 years; BMI 24.3 ± 3.54 kg/m2) in whom iron load was assessed in white and gray matter and the liver by MRI. IR was measured from HOMA-IR and an oral glucose tolerance test. A battery of neuropsychological tests was used to evaluate the cognitive performance. Multivariate regression analysis was used to identify the independent associations of BIO and cognitive performance. RESULTS A significant increase in iron load was detected at the caudate nucleus (P < 0.001), lenticular nucleus (P = 0.004), hypothalamus (P = 0.002), hippocampus (P < 0.001), and liver (P < 0.001) in obese subjects. There was a positive correlation between HIC and BIO at caudate (r = 0.517, P < 0.001), hypothalamus (r = 0.396, P = 0.009), and hippocampus (r = 0.347, P < 0.023). The area under the curve of insulin was independently associated with BIO at the caudate (P = 0.001), hippocampus (P = 0.028), and HIC (P = 0.025). BIOs at the caudate (P = 0.028), hypothalamus (P = 0.006), and lenticular nucleus (P = 0.012) were independently associated with worse cognitive performance. CONCLUSIONS Obesity and IR may contribute to increased HIC and BIO being associated with worse cognitive performance. BIO could be a potentially useful MRI biomarker for IR and obesity-associated cognitive dysfunction.

Metformin is widely used in the treatment of type 2 diabetes (T2D), but its mechanism of action is poorly defined. Recent evidence implicates the gut microbiota as a site of metformin action. In a double-blind study, we randomized individuals with treatment-naive T2D to placebo or metformin for 4 months and showed that metformin had strong effects on the gut microbiome. These results were verified in a subset of the placebo group that switched to metformin 6 months after the start of the trial. Transfer of fecal samples (obtained before and 4 months after treatment) from metformin-treated donors to germ-free mice showed that glucose tolerance was improved in mice that received metformin-altered microbiota. By directly investigating metformin–microbiota interactions in a gut simulator, we showed that metformin affected pathways with common biological functions in species from two different phyla, and many of the metformin-regulated genes in these species encoded metalloproteins or metal transporters. Our findings provide support for the notion that altered gut microbiota mediates some of metformin's antidiabetic effects.

Recently, serum lipopolysaccharide-binding protein (LBP) has been closely associated with coronary artery disease. Here, we aimed to investigate the possible relationship between serum LBP and markers of atherosclerosis.Serum LBP and carotid intima media thickness (C-IMT) were measured in 332 subjects (101 men and 231 women) who were recruited from an ongoing multicenter project.Serum LBP was significantly associated with obesity [BMI, fat mass and waist circumference (r 0.38, p 0.0001)], HOMA (r = 0.36, p 0.0001) and high sensitivity CRP (hsCRP) (r = 0.50, p 0.0001). Circulating LBP was also positively associated with C-IMT (r = 0.27, p 0.0001). Circulating LBP (β = 0.16; p = 0.001) contributed independently to C-IMT variance, after controlling for the effects of age, gender, BMI and hsCRP. Of note, circulating LBP was found to be increased in the population with carotid plaque (n = 50; 32.7 ± 12.5 vs 28.7 ± 10.7; p = 0.021).The consistent association between serum LBP and the carotid intima media thickness, a widely used atherosclerosis marker, reveals serum LBP as a putative factor related to atherosclerosis.

The human intestine is home to a diverse range of bacterial and fungal species, forming an ecological community that contributes to normal physiology and disease susceptibility. Here, the fungal microbiota (mycobiome) in obese and non-obese subjects was characterized using Internal Transcribed Spacer (ITS)-based sequencing. The results demonstrate that obese patients could be discriminated by their specific fungal composition, which also distinguished metabolically "healthy" from "unhealthy" obesity. Clusters according to genus abundance co-segregated with body fatness, fasting triglycerides and HDL-cholesterol. A preliminary link to metabolites such as hexadecanedioic acid, caproic acid and N-acetyl-L-glutamic acid was also found. Mucor racemosus and M. fuscus were the species more represented in non-obese subjects compared to obese counterparts. Interestingly, the decreased relative abundance of the Mucor genus in obese subjects was reversible upon weight loss. Collectively, these findings suggest that manipulation of gut mycobiome communities might be a novel target in the treatment of obesity.

Anaesthetic gases and disinfectants are a primary source of air contamination in hospitals. A highly sensitive sorbent-trap methodology has been used to analyse exhaled breath samples with detection limits in the pptv range, which allows volatile organic compounds (VOCs) to be detected at significantly lower levels (5?6 orders of magnitude below) than the recommended exposure limits by different organizations. Two common VOCs used in hospital environments, isopropyl alcohol (IPA) and sevoflurane, have been evaluated. Forced-expiratory breath samples were obtained from 100 volunteers (24 hospital staff, 45 hospital visitors and 31 external controls). Significant differences for IPA were found between samples from volunteers who had not been in contact with hospital environments (mean value of 8.032 ppbv) and people staying (20.981 ppbv, p??=??0.0002) or working (19.457 ppbv, p??=??0.000?09) in such an environment. Sevoflurane, an anaesthetic gas routinely used as an inhaled anaesthetic, was detected in all samples from volunteers in the hospital environment but not in volunteers who had not been in recent contact with a hospital environment. The levels of sevoflurane were significantly higher (p??=??0.000?24) among staff members (0.522 ppbv) than among visitors to the hospital (0.196 ppbv). We conclude that highly sensitive methods are required to detect anaesthetic gas contamination in hospital environments.

Different genetic and imaging iron markers are known to be increased in the liver, adipose tissue, and brain of obese subjects.We aimed to investigate these markers in human skeletal muscle. DESIGN, SETTING, PATIENTS, AND OUTCOME MEASURES: Markers of iron accumulation were measured in three different territories: Iron gene markers (TFRC1, TF, SLC11A2, FTL, FTH1, and SLC40A1) were studied in abdominal rectus abdominis (Cohort 1, n = 26) and quadriceps (Cohort 2, n = 13) muscle using real-time PCR, whereas paravertebral muscle R2* signal (as surrogate of iron content) (Cohort 3, n = 43) was evaluated by means of magnetic resonance imaging.In a subgroup of 14 obese participants from Cohort 3, a diet-induced weight loss was performed.Rectus abdominis muscle age-adjusted gene expression of SLC40A1 (ferroportin) (r = 0.47; P = .04), SLC11A2 (r = 0.50; P = .03) and CYBA (r = 0.62; P = .006) increased with body fatness. In obese participants from Cohort 1, muscle CYBA gene expression was positively correlated with serum ferritin. This association was replicated in quadriceps from obese participants (Cohort 2). Paravertebral muscle R2* was positively associated with body mass index, waist circumference, and fat mass (measured by dual-energy x-ray absorptiometry) in parallel with hepatic iron content, serum ferritin, and hepcidin. In multivariate regression analyses, obesity parameters (P.0001) and hsCRP concentration (P.05) contributed independently to the variance of sex-, serum hepcidin- and age-adjusted muscle R2*. Of note, weight loss intervention resulted in decreased muscle R2* (P = .02) in correlation with the change of serum ferritin (r = 0.69; P = .01).These findings emphasize a significant iron accumulation in human skeletal muscle in association with obesity. The mechanisms implicated in these observations should be studied further.

Human gut microbiota consists of trillions of microorganisms and thousands of bacterial phylotypes that are deeply involved in a different function of host metabolism. The collective genomes of our gut microbes (microbiome) may contain >150 times more genes than our own genome. Eighty to ninety percent of the bacterial phylotypes are members of two phyla: the Bacteroidetes (Gram-negative) and the Firmicutes (Gram-positive), followed by Actinobacteria (Gram-positive) and Proteobacteria . Recent studies have described dietary intervention impact on gut microbial gene richness. Initial studies on gut microbial composition and function were limited by the difficulty to culture all intestinal microbes. The introduction of bacterial genome sequencing and “metagenomic” analysis has contributed to increased knowledge about uncultivable microbes, gut microbial functions, its cross-talk with the host, and the potential pathogenic role related to host's diseases.

Serum hepcidin concentration is known to increase in parallel to circulating markers of iron stores. We aimed to investigate whether this is reflected at the tissue level in subjects with obesity.Serum hepcidin and ferritin levels (ELISA) and hepatic iron content (using magnetic resonance imaging) were analyzed longitudinally in 44 participants (19 without obesity and 25 with obesity). In a subgroup of 16 participants with obesity, a weight loss intervention was performed.Serum hepcidin, ferritin and hepatic iron content (HIC) were significantly increased in participants with obesity. Age- and gender-adjusted serum hepcidin was positively correlated with BMI, hsCRP, ferritin and HIC. In addition, age- and gender-adjusted serum hepcidin was positively correlated with ferritin and HIC in both non-obese and obese participants. In multivariate regression analysis, hepatic iron content (p 0.01) and serum ferritin (p 0.001) contributed independently to circulating hepcidin concentration variation after controlling for age, gender, BMI and hsCRP. Diet intervention-induced weight loss led to decreased serum hepcidin (p = 0.01), serum ferritin concentration (p = 0.01) and HIC (p = 0.002). Of note, the percent change of serum hepcidin strongly correlated with the percent change of serum ferritin (r = 0.69, p = 0.01) and HIC (r = 0.61, p = 0.03) even after controlling for age and gender.Serum hepcidin is a reliable marker of the hepatic iron content in subjects with obesity.

We aimed to investigate the potential mechanisms involved in the compromised adipogenesis of visceral (VAT) vs subcutaneous adipose tissue (SAT) using comparative metabolomics. Based on the differentially identified metabolites, we focused on the relationship between the active form of vitamin B6 (pyridoxal 5-phosphate [PLP]), known to be generated through pyridoxal kinase (PDXK), and adipogenesis. Non-targeted metabolomics analyses were performed in paired VAT and SAT (n = 14, discovery cohort). PDXK gene expression was evaluated in two validation cohorts of paired SAT and VAT samples in relation to obesity status and insulin sensitivity, and mechanistically after weight loss in vivo and in 3T3-L1 cells in vitro. Comparative metabolomics showed that PLP was significantly decreased in VAT vs SAT. Concordantly, PDXK mRNA levels were significantly decreased in VAT vs SAT, specifically in adipocytes. The decrease was specially marked in obese individuals. PDXK mRNA levels showed a strong association with adipogenic, lipid-droplet-related and lipogenic genes. At a functional level, systemic insulin sensitivity positively associated with PDXK expression, and surgically-induced weight loss (improving insulin sensitivity) led to increased SAT PDXK mRNA levels in parallel with adipogenic genes. In human pre-adipocytes, PDXK mRNA levels increased during adipocyte differentiation and after administration of peroxisome proliferator-activated receptor-γ agonists, and decreased under inflammatory stimuli. Mechanistic studies in 3T3-L1 cells showed that PLP administration resulted in increased adipogenic mRNA markers during early adipogenesis, whereas the PLP antagonist 4-deoxypyridoxine exerted opposite effects. Overall, these results support the notion that in situ production of PLP is required for physiological adipogenesis.

Obesity is an important determinant of increased cardiovascular risk. Increased fat mass has been assumed to constitute the main prominent contributor to changes in carotid intima-media thickness (c-IMT).In 421 consecutive subjects (301 women), c-IMT was evaluated ultrasonographically in 6 independent territories and body composition was assessed by dual-energy X-ray absorptiometry.c-IMT was positively associated with lean body mass in both men (r = 0.328, p = 0.0001) and women (r = 0.268 p = 0.0001) and increased across lean mass quartiles (p = 0.0001 for linear-trend ANOVA). Stepwise linear regression analysis showed that age and lean mass (but not fat mass or traditional cardiovascular risk factors) contributed to 46.2% of c-IMT variance in men (p = 0.0001). Even within obese men, lean mass was an independent contributor to c-IMT variance. Among women, age, lean mass and ultrasensitive CRP levels contributed independently to 47.7% of c-IMT variance (p 0.0001).Lean mass, and not fat mass, might contribute to increase c-IMT in obese patients independently of classical atherosclerotic risk factors. These data reinforce the concept that the increase in metabolically fat-free mass that accompanies the body weight enlargement is closely related to the raise in blood pressure.

The human intestine is home to a diverse range of bacterial and fungal species, forming an ecological community that contributes to normal physiology and disease susceptibility. Here, the fungal microbiota (mycobiome) in obese and non-obese subjects was characterized using Internal Transcribed Spacer (ITS)-based sequencing. The results demonstrate that obese patients could be discriminated by their specific fungal composition, which also distinguished metabolically “healthy” from “unhealthy” obesity. Clusters according to genus abundance co-segregated with body fatness, fasting triglycerides and HDL-cholesterol. A preliminary link to metabolites such as hexadecanedioic acid, caproic acid and N-acetyl-L-glutamic acid was also found. Mucor racemosus and M. fuscus were the species more represented in non-obese subjects compared to obese counterparts. Interestingly, the decreased relative abundance of the Mucor genus in obese subjects was reversible upon weight loss. Collectively, these findings suggest that manipulation of gut mycobiome communities might be a novel target in the treatment of obesity.

Osteoporosis represents the most prevalent metabolic disorder in elderly people. Calcium and vitamin D have been and are still considered the main important nutrient for preventing bone loss with aging. Nevertheless, other nutrients are emerging to improve bone strength. Olive oil is an example. Recent in vitro studies have shown that oleuropein, the main phenolic compound in virgin olive oil, reduced the expression of peroxisomal proliferator-activated receptor-γ, inhibiting adipocyte differentiation and enhancing differentiation of mesenchymal stem cells into osteoblasts. In addition, oleuropein administration led to increase the gene expression of osteoblastogenesis markers. In concordance with these in vitro experiments, a prospective effect of olive oil and oleuropein has been also observed in animal models and in humans. This limited evidences led us to suggest that olive oil consumption might exert a positive role in bone health, mainly in osteoporosis prevention.

SummaryObjective Whether nonalcoholic fatty liver disease (NAFLD) can predict atherosclerosis in obese patients remains unclear. The aim of our study was to investigate the usefulness of NAFLD and other cardiometabolic parameters in predicting subclinical atherosclerosis in obese patients. Design, Patients and Measurements We studied 314 consecutive obese subjects (223 women; mean age, 45·04 ± 9·34 years; body mass index 44·3 ± 5 kg/m2) and 47 healthy lean individuals. Hepatic steatosis and atherosclerosis [carotid intima-media thickness (cIMT) >0·8 mm and/or presence of plaques] were evaluated ultrasonographically. Liver biopsies were obtained in 51 patients. Results In obese patients, mean c-IMT was greater in those with NAFLD (P

Context: Growing evidence implicates hypothalamic inflammation in the pathogenesis of dietinduced obesity and cognitive dysfunction in rodent models. Few studies have addressed the association between obesity and hypothalamic damage in humans and its relevance. Objective: To determine markers of obesity-associated hypothalamic damage on diffusion tensor imaging (DTI) and to determine whether DTI-metrics are associated with performance on cognitive testing. Design and Participants: This cross-sectional study analyzed DTI-metrics (primary (λ1), secondary (λ2), and tertiary (λ3) eigenvalues; fractional anisotropy (FA); and mean diffusivity (MD)) in the hypothalamus of 24 consecutive middle-aged obese subjects (13 women; 49.8 ± 8.1 years; body mass index [BMI] 43.9 ± 0.92 Kg/m2) and 20 healthy volunteers (10 women; 48.8 ± 9.5 years; BMI 24.3 ± 0.79 Kg/m2). Outcome: measures: Hypothalamic damage assessed by DTI-metrics and cognitive performance evaluated by neuropsychological test-battery. Results: λ1 values in the hypothalamus were significantly lower in obese subjects (P

In the present study, we aimed to evaluate the possible role of PRDM16 in human adipocytes and in whole adipose tissue according to obesity and insulin sensitivity. PRDM16 knockdown (KD) had a dual behavior. While KD in preadipocytes led to enhanced gene expression markers of adipocyte differentiation, PRDM16 KD in fully differentiated adipocytes resulted in decreased adipogenic gene expression and insulin action. In line with KD in adipocytes, PRDM16 was positively associated with the expression of several genes involved in adipogenesis, insulin signaling, mitochondrial function and brown adipocyte-related markers in whole adipose tissue from two independent cohorts. PRDM16 was decreased in obese subjects in relation with the decrease of insulin sensitivity [HOM(AIR) (cohort 1) and M clamp value (cohort 2)]. Rosiglitazone (5 µmol/l) and metformin (5 mmol/l) led to increased PRDM16 mRNA and protein levels in isolated human adipocytes and in whole adipose tissue. In conclusion, PRDM16 might contribute to maintain adipose tissue "white fat" gene expression profile and systemic metabolic homeostasis.

OBJECTIVE This study sought to identify the profile of circulating microRNAs (miRNAs) in type 2 diabetes (T2D) and its response to changes in insulin sensitivity. RESEARCH DESIGN AND METHODS The circulating miRNA profile was assessed in a pilot study of 12 men: 6 with normal glucose tolerance (NGT) and 6 T2D patients. The association of 10 circulating miRNAs with T2D was cross-sectionally validated in an extended sample of 45 NGT vs. 48 T2D subjects (65 nonobese and 28 obese men) and longitudinally in 35 T2D patients who were recruited in a randomized, double-blinded, and placebo-controlled 3-month trial of metformin treatment. Circulating miRNAs were also measured in seven healthy volunteers before and after a 6-h hyperinsulinemic-euglycemic clamp and insulin plus intralipid/heparin infusion. RESULTS Cross-sectional studies disclosed a marked increase of miR-140-5p, miR-142-3p, and miR-222 and decreased miR-423-5p, miR-125b, miR-192, miR-195, miR-130b, miR-532-5p, and miR-126 in T2D patients. Multiple linear regression analyses revealed that miR-140-5p and miR-423-5p contributed independently to explain 49.5% (P < 0.0001) of fasting glucose variance after controlling for confounders. A discriminant function of four miRNAs (miR-140-5p, miR-423-5p, miR-195, and miR-126) was specific for T2D with an accuracy of 89.2% (P < 0.0001). Metformin (but not placebo) led to significant changes in circulating miR-192 (49.5%; P = 0.022), miR-140-5p (−15.8%; P = 0.004), and miR-222 (−47.2%; P = 0.03), in parallel to decreased fasting glucose and HbA1c. Furthermore, while insulin infusion during clamp decreased miR-222 (−62%; P = 0.002), the intralipid/heparin mixture increased circulating miR-222 (163%; P = 0.015) and miR-140-5p (67.5%; P = 0.05). CONCLUSIONS This study depicts the close association between variations in circulating miRNAs and T2D and their potential relevance in insulin sensitivity.

The Trp64Arg β3-adrenergic receptor gene polymorphism is associated with endothelium-dependent vasodilatation

et al., Transgenic overexpression of adipose tissue (AT) transducin-like enhancer of split 3 (TLE3) mimicked peroxisome proliferator-activated receptor gamma (PPARγ) agonists, improving insulin resistance in mice. This study aimed to investigate TLE3 gene expression (qRT-PCR) and protein (Western blot) in subjects with a wide spectrum of obesity and insulin sensitivity and in an independent cohort of obese subjects following surgery-induced weight loss. TLE3 was analyzed in human adipocytes and after treatment with rosiglitazone. Given the findings in humans, TLE3 was also investigated in mice after a high-fat diet (HFD) and in PPARγ knockout mice. Subcutaneous (SC) AT TLE3 was increased in subjects with type 2 diabetes (T2D). In fact, SC TLE3 was associated with increased fasting glucose (r = 0.25, p = 0.015) and S6K1 activity (r = 0.671, p = 0.003), and with decreased Glut4 (r = −0.426, p = 0.006) and IRS-1 expression (−31 %, p = 0.007) and activation (P-IRS-1/IRS-1, −17 %, p = 0.024). TLE3 was preferentially expressed in mature adipocytes and increased during in vitro differentiation in parallel to PPARγ. Weight loss led to improved insulin sensitivity, increased AT PPARγ and decreased TLE3 (−24 %, p = 0.0002), while rosiglitazone administration downregulated TLE3 gene expression in fully differentiated adipocytes (−45 %, p, This study was supported by the Spanish Ministry of Science and Innovation (FIS 2011– 00214) and CIBER de la Fisiopatología de la Obesidad y la Nutrición (CIBERobn). The CIBER de la Fisiopatología de la Obesidad y Nutrición (CIBERobn) is an initiative from the Instituto de Salud Carlos III (ISCIII)

Summary Background: Thyroid hormone resistance (RTH) is a rare cause of thyroid dysfunction. High TSH levels, as described in RTH syndrome, are known to be associated with an increased risk of developing thyroid nodules with subsequent growth and malignancy. Patient findings: In 2006, a 29-year-old Caucasian man presented with a palpable mass in the neck. Increased free thyroxine and triiodothyronine levels were found in the context of unsuppressed TSH levels, despite no signs or symptoms of hyperthyroidism. Ultrasonography revealed a multinodular and enlarged goitre, and fine-needle aspiration cytology revealed suspicious features of malignancy. After excluding pituitary tumour and levothyroxine (l-T4) treatment, the patient was diagnosed with generalized RTH. Screening for all the known mutations in thyroid hormone receptor-β (TR β (THRB)) was negative. Thyroidectomy disclosed five Hürthle adenomas and three hyperplasic nodules. Euthyroidism was achieved after surgery with 6.1 μg/kg per day of l-T4. Conclusion: RTH may be a risk factor that predisposes to the development of multiple Hürthle cell adenomas. To our knowledge, this is the first case of multiple Hürthle cell adenomas in a patient with RTH. Learning points High TSH levels, as described in RTH syndrome, are known to be associated with an increased risk of developing thyroid nodules, with subsequent growth and malignancy. The exact role of TR β mutants in thyroid carcinogenesis is still undefined. We report the first case of multiple Hürthle cell adenomas associated with RTH.

Fibroblast growth factor 23 (FGF-23) is known to be produced by the bone and linked to metabolic risk. We aimed to explore circulating FGF-23 in association with fatness and insulin sensitivity, atherosclerosis and bone mineral density (BMD). Circulating intact FGF-23 (iFGF-23) and C-terminal (CtFGF-23) concentrations (ELISA) were measured in 133 middle aged men from the general population in association with insulin sensitivity (Cohort 1); and in association with fat mass and bone mineral density (DEXA) and atherosclerosis (intima media thickness, IMT) in 78 subjects (52 women) with a wide range of adiposity (Cohort 2). Circulating iFGF-23 was also measured before and after weight loss. In all subjects as a whole, serum intact and C-terminal concentrations were linearly and positively associated with BMI. In cohort 1, both serum iFGF-23 and CtFGF-23 concentrations increased with insulin resistance. Serum creatinine contributed to iFGF-23 variance, while serum ferritin and insulin sensitivity (but not BMI, age or serum creatinine) contributed to 17% of CtFGF-23 variance. In cohort 2, CtFGF-23 levels were higher in women vs. men, and increased with BMI, fat mass, fasting and post-load serum glucose, insulin, HOMA-IR and PTH, being negatively associated with circulating vitamin D and ferritin levels. The associations of CtFGF-23 with bone density in the radius, lumbar spine and carotid IMT were no longer significant after controlling for BMI. Weight loss led to decreased iFGF-23 concentrations. In summary, the associations of circulating FGF-23 concentration with parameters of glucose metabolism, bone density and atherosclerosis are dependent on iron and obesity status-associated insulin resistance.

Circulating lipopolysaccharide-binding protein (LBP) is an acute-phase reactant known to be increased in obesity. We hypothesised that LBP is produced by adipose tissue (AT) in association with obesity. LBP mRNA and LBP protein levels were analysed in AT from three cross-sectional (n = 210, n = 144 and n = 28) and three longitudinal (n = 8, n = 25, n = 20) human cohorts; in AT from genetically manipulated mice; in isolated adipocytes; and in human and murine cell lines. The effects of a high-fat diet and exposure to lipopolysaccharide (LPS) and peroxisome proliferator-activated receptor (PPAR)gamma agonist were explored. Functional in vitro and ex vivo experiments were also performed. LBP synthesis and release was demonstrated to increase with adipocyte differentiation in human and mouse AT, isolated adipocytes and human and mouse cell lines (Simpson-Golabi-Behmel syndrome [SGBS], human multipotent adipose-derived stem [hMAD] and 3T3-L1 cells). AT LBP expression was robustly associated with inflammatory markers and increased with metabolic deterioration and insulin resistance in two independent cross-sectional human cohorts. AT LBP also increased longitudinally with weight gain and excessive fat accretion in both humans and mice, and decreased with weight loss (in two other independent cohorts), in humans with acquired lipodystrophy, and after ex vivo exposure to PPAR gamma agonist. Inflammatory agents such as LPS and TNF-alpha led to increased AT LBP expression in vivo in mice and in vitro, while this effect was prevented in Cd14-knockout mice. Functionally, LBP knockdown using short hairpin (sh)RNA or anti-LBP antibody led to increases in markers of adipogenesis and decreased adipocyte inflammation in human adipocytes. Collectively, these findings suggest that LBP might have an essential role in inflammation- and obesity-associated AT dysfunction.