Heterogeneous miRNA-mRNA Regulatory Networks of Visceral and Subcutaneous Adipose Tissue in the Relationship Between Obesity and Renal Clear Cell Carcinoma.

Background: Clear cell renal cell carcinoma (ccRCC) is one of the most lethal urologic cancer. Associations of both visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) with ccRCC have been reported, and underlying mechanisms of VAT perhaps distinguished from SAT, considering their different structures and functions. We performed this study to disclose different miRNA-mRNA networks of obesity-related ccRCC in VAT and SAT using datasets from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA); and find out different RNAs correlated with the prognosis of ccRCC in VAT and SAT. Methods: We screened out different expressed (DE) mRNAs and miRNAs of obesity, in both VAT and SAT from GEO datasets, and constructed miRNA-mRNA networks of obesity-related ccRCC. To evaluate the sensitivity and specificity of RNAs in networks of obesity-related ccRCC in both VAT and SAT, Receiver Operating Characteristic (ROC) analyses were conducted using TCGA datasets. Spearman correlation analyses were then performed to find out RNA pairs with inverse correlations. We also performed Cox regression analyses to estimate the association of all DE RNAs of obesity with the overall survival. Results: 136 and 185 DE mRNAs of obesity in VAT and SAT were found out. Combined with selected DE miRNAs, miRNA-mRNA networks of obesity-related ccRCC were constructed. By performing ROC analyses, RNAs with same trend as shown in networks and statistically significant ORs were selected to be paired. Three pairs were finally remained in Spearman correlation analyses, including hsa-miR-182&ATP2B2, hsa-miR-532&CDH2 in VAT, and hsa-miR-425&TFAP2B in SAT. Multivariable Cox regression analyses showed that several RNAs with statistically significant adjusted HRs remained consistent trends as shown in DE analyses of obesity. Risk score analyses using selected RNAs showed that the overall survival time of patients in the low-risk group was significantly longer than that in the high-risk group regardless of risk score models. Conclusions: We found out different miRNA-mRNA regulatory networks of obesity-related ccRCC for both VAT and SAT; and several DE RNAs of obesity-related ccRCC were found to remain consistent performance in terms of ccRCC prognosis. Our findings could provide valuable evidence on the targeted therapy of obesity-related ccRCC.

White adipose tissue-infiltrated CD11b+ myeloid cells are a source of S100A4, a new potential marker of hepatic damage.

CONTEXT: The endocrine and immunological properties of subcutaneous vs visceral adipose tissue (sWAT and vWAT, respectively) have turned a milestone in the study of metabolic diseases. The cytokine S100A4 is increased in obesity and has a role in adipose tissue dysfunction. However, the cellular source and its potential role in hepatic damage in obesity has not been elucidated. OBJECTIVE: We aim to study the regulation of S100A4 in immune cells present in sWAT and vWAT, as well as its potential role as a circulating marker of hepatic inflammation and steatosis. DESIGN: A cohort of 60 patients with obesity and distinct metabolic status was analyzed. CD11b+ myeloid cells and T cells were isolated from sWAT and vWAT by magnetic-activating cell sorting, and RNA was obtained. S100A4 gene expression was measured, and correlation analysis with clinical data was performed. Liver biopsies were obtained from 20 patients, and S100A4 circulating levels were measured to check the link with hepatic inflammation and steatosis. RESULTS: S100A4 gene expression was strongly upregulated in sWAT- vs vWAT-infiltrated CD11b+ cells, but this modulation was not observed in T cells. S100A4 mRNA levels from sWAT (and not from vWAT) CD11b+ cells positively correlated with glycemia, triglycerides, TNF-α gene expression and proliferation markers. Finally, circulating S100A4 directly correlated with liver steatosis and hepatic inflammatory markers. CONCLUSION: Our data suggest that sWAT-infiltrated CD11b+ cells could be a major source of S100A4 in obesity. Moreover, our correlations identify circulating S100A4 as a potential novel biomarker of hepatic damage and steatosis.

Clinical significance of increased peripheral venous blood adipocyte-specific protein FABP4 after joint replacement.

A new method of diagnosing fat embolism (FE) at the molecular level was proposed, and the diagnostic value of adipocyte-specific protein fatty acid-binding protein 4 (Homo sapiens [human]) gene ID = 2167 (FABP4) for FE was preliminarily explored. Eight joint replacement patients, 5 internal medicine patients, and 6 healthy persons were recruited. Serum of internal medicine patients, healthy people, and patients before and 24 hours after joint replacement were taken as study samples. Subcutaneous adipose, intra-articular adipose and intramedullary yellow bone marrow of patients undergoing joint replacement were taken as study samples. The level of FABP4 in the above samples was detected by enzyme-linked immunoassay. Normal distribution was tested. Paired sample T test was used for self-control. Univariate analysis of variance was used for multigroup comparison.There was no significant difference in serum FABP4 level between healthy persons, medical patients, and preoperative patients. The FABP4 level in yellow bone marrow and subcutaneous adipose was significantly higher than that in serum of healthy people, medical patients, and preoperative patients. FABP4 level in the serum after joint replacement was significantly higher than that before joint replacement. FABP4 may be a specific indicator of FE diagnosis, but further studies are needed to confirm its clinical value.

Adipose tissue macrophage burden, systemic inflammation, and insulin resistance.

Adipose tissue inflammation, as defined by macrophage accumulation, is proposed to cause insulin resistance and systemic inflammation. Because the strength of this relationship for humans is unclear, we tested whether adipose tissue macrophage (ATM) burden is correlated with these health indicators. Using immunohistochemistry, we measured abdominal subcutaneous CD68+ (total ATM), CD14+ (proinflammatory/M1), and CD206+ (anti-inflammatory/M2) ATM in 97 volunteers (BMI 20-38 kg/m2, in addition to body composition, adipocyte size, homeostasis model assessment of insulin resistance, ADIPO-IR, adipose tissue insulin resistance measured by palmitate, plasma lipids, TNF, and IL-6 concentrations. There were several significant univariate correlations between metabolic parameters to IL-6 and ATM per 100 adipocytes, but not ATM per gram tissue; adipocyte size was a confounding variable. We used matching strategies and multivariate regression analyses to investigate the relationships between ATM and inflammatory/metabolic parameters independent of adipocyte size. Matching approaches revealed that the groups discordant for CD206 but concordant for adipocyte size had significantly different fasting insulin and IL-6 concentrations. However, groups discordant for adipocyte size but concordent for ATM differeded in that visceral fat, plasma triglyceride, glucose, and TNF concentrations were greater in those with large adipocytes. Multivariate regression analysis indicated that indexes of insulin resistance and fasting triglycerides were predicted by body composition; the predictive value of ATM per 100 adipocytes or per gram tissue was variable between males and females. We conclude that the relationship between ATM burden and metabolic/inflammatory variables is confounded by adipocyte size/body composition and that ATM do not predict insulin resistance, systemic inflammation, or dyslipidemia. ATM may primarily play a role in tissue remodeling rather than in metabolic pathology.

Androstenedione and testosterone but not progesterone are potential biomarkers of pregnancy in Humpback Whales (Megaptera novaeangliae) approaching parturition.

The blubber steroid hormone profiles of 52 female humpback whales migrating along the east coast of Australia were investigated for seasonal endocrine changes associated with reproduction. Individuals were randomly sampled during two stages of the annual migration: before reaching the breeding grounds (northward migration; June/July), and after departing from the breeding grounds (southward migration; September/October). Assignment of reproductive status of the sampled individuals was based on season, single-hormone ranks and multi-variate analysis of the hormonal profiles. High concentrations of progesterone (>19 ng/g, wet weight), recognised as an indicator of pregnancy in this species, were only detected in one sample. However, the androgens, testosterone and androstenedione were measured in unusually high concentrations (1.6-12 and 7.8-40 ng/g wet weight, respectively) in 36% of the females approaching the breeding grounds. The absence of a strong accompanying progesterone signal in these animals raises the possibility of progesterone withdrawal prior to parturition. As seen with other cetacean species, testosterone and androstenedione could be markers of near-term pregnancy in humpback whales. Confirmation of these androgens as alternate biomarkers of near-term pregnancy would carry implications for improved monitoring of the annual fecundity of humpback whales via non-lethal and minimally invasive methods.

Relationships between visceral/subcutaneous adipose tissue FABP4 expression and coronary atherosclerosis in patients with metabolic syndrome.

BACKGROUND: Cytoplasmic fatty acid-binding proteins facilitate the transport of lipids to specific compartments in cells. Fatty acid-binding protein 4 (FABP4), also known as aP2 or A-FABP, plays a key role in the development of atherosclerosis, insulin resistance, obesity, and metabolic syndrome (MS). The FABP4 polymorphisms are associated with protein expression changes in vitro and metabolic and vascular alterations in vivo. The aim of this study was to investigate the association between FABP4 messenger ribonucleic acid (mRNA) expression levels in epicardial (EAT), pericardial (PAT), and subcutaneous adipose tissues (SAT), and the extent of coronary atherosclerosis in coronary artery disease (CAD) patients with MS. Furthermore, the relationship between the extent of coronary atherosclerosis and epicardial adipose tissue volume (EATV) and FABP4 gene variations was evaluated. PATIENTS AND METHODS: A total of 37 patients undergoing coronary artery bypass grafting because of CAD (MS CAD group) and 23 non-MS patients undergoing heart valve surgery (control group) were included. Coronary angiography was performed for all patients and the extent of coronary atherosclerosis was assessed using the Sullivan's scoring system. The mRNA expression levels of FABP4 gene in EAT, PAT, and SAT, and FABP4 polymorphisms were analyzed using the quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: An increased FABP4 expression was observed in EAT and PAT of MS CAD group compared to controls. In the MS CAD group, FABP4 mRNA expression levels in EAT was 2.8-fold higher compared to PAT. The expression of FABP4 in EAT was positively correlated with the extent of atherosclerosis and EATV in MS CAD group (r = 0.588, P= 0.001, r = 0.174, P = 0.001, respectively). There were no correlations between PAT and SAT versus the extent of atherosclerosis and EATV. The FABP4 EAT mRNA expression levels were found to significantly increase in mutant allele carriers of rs1054135, whereas they significantly decreased in mutant allele carriers of rs77878271 (T-87C) in MS CAD group (P < 0.05). The extent of atherosclerosis was also found to be significantly associated with rs1054135 (P < 0.05). A cut-off point of 57.5 cm3 EATV was used indicating the presence of CAD with a significant area under the curve of 0.783%, 98% sensitivity, and 100% specificity (95% CI 0.620-0.880; P < 0.05). CONCLUSIONS: Our study results suggest that FABP4 expression in EAT is strongly associated with the extent of atherosclerosis and EATV in MS CAD patients.

Plasma and tissue pharmacokinetics of fosfomycin in morbidly obese and non-obese surgical patients: a controlled clinical trial.

OBJECTIVES: To assess the pharmacokinetics and tissue penetration of fosfomycin in obese and non-obese surgical patients. METHODS: Fifteen obese patients undergoing bariatric surgery and 15 non-obese patients undergoing major intra-abdominal surgery received an intravenous single short infusion of 8 g of fosfomycin. Fosfomycin concentrations were determined by LC-MS/MS in plasma and microdialysate from subcutaneous tissue up to 8 h after dosing. The pharmacokinetic analysis was performed in plasma and interstitial fluid (ISF) by non-compartmental methods. RESULTS: Thirteen obese patients (BMI 38-50 kg/m2) and 14 non-obese patients (BMI 0-29 kg/m2) were evaluable. The pharmacokinetics of fosfomycin in obese versus non-obese patients were characterized by lower peak plasma concentrations (468 ±âŸ139 versus 594 ±âŸ149 mg/L, P = 0.040) and higher V (24.4 ±âŸ6.4 versus 19.0 ±âŸ3.1 L, P = 0.010). The differences in AUC∞ were not significant (1275 ±âŸ477 versus 1515 ±âŸ352 mg·h/L, P = 0.16). The peak concentrations in subcutaneous tissue were reached rapidly and declined in parallel with the plasma concentrations. The drug exposure in tissue was nearly halved in obese compared with non-obese patients (AUC∞ 1052 ±âŸ394 versus 1929 ±âŸ725 mg·h/L, P = 0.0010). The tissue/plasma ratio (AUCISF/AUCplasma) was 0.86 ±âŸ0.32 versus 1.27 ±âŸ0.34 (P = 0.0047). CONCLUSIONS: Whereas the pharmacokinetics of fosfomycin in plasma of surgical patients were only marginally different between obese and non-obese patients, the drug exposure in subcutaneous tissue was significantly lower in the obese patients.

Minor lipids profiling in subcutaneous and epicardial fat tissue using LC/MS with an optimized preanalytical phase.

Analysis of bioactive lipids in adipose tissue could lead to better understanding of the pathogenesis of obesity and its complications. However, current MS methods are limited by a high content of triacylglycerols (TAGs), which markedly surpasses the amount of other lipids and suppresses their ionization. The aim of our study was thus to optimize the preanalytical phase of lipid analysis in adipose tissue, focusing in particular on less-abundant lipids. Next, the optimized method was used to describe the differences between epicardial and subcutaneous adipose tissues obtained from patients undergoing cardiac surgery. Lipids were extracted using a modified Folch method with subsequent detachment of TAGs by thin layer chromatography (TLC). The extracts with/without TAGs were analyzed by tandem LC/MS. The repeatability of the presented method expressed by the median of the coefficients of variation was 12/5% for analysis with/without TAGs separation, respectively. The difference in the relative abundance of TAGs gained with/without TLC was, on average, 19% and did not reach significance (p value > 0.05) for any identified TAG. The novel preanalytical step allowed us to detect 37 lipids, which could not have been detected without TAG separation, because their signal to noise ratio is <5 in current methods of untargeted lipidomics. These lipids belong predominately to ceramides, glycerophosphatidylserines, glycerophosphatidylinsitols, sphingomyelins, glycerophosphatidylcholines, glycerophosphatidylethanolamines, diacylglycerols. The two adipose tissue depots differed mainly in the following lipid classes: glycerophosphatidylcholines, glycerophosphatidylinositols, glycerophosphatidylethanolamine, and sphingomyelins. Moreover, other major lipids showed distinctly different distributions between the two adipose tissues. Among these, the changes in TAGs were the most striking, which correspond to previously published data describing the differences between omental and subcutaneous adipose tissue. Implementation of the TLC step for the elimination of TAGs was crucial for enhancing the MS detection limit of minor lipids in adipose tissue. The differences between the overall lipid profiles of subcutaneous and epicardial tissue reflect their different functions arising from their location.

Cefuroxime plasma and tissue concentrations in patients undergoing elective cardiac surgery: Continuous vs bolus application. A pilot study.

AIMS: Surgical site infections contribute to morbidity and mortality after surgery. The authors hypothesized that higher antibiotic tissue concentrations can be reached for a prolonged time span by continuous administration of prophylactic cefuroxime compared to bolus administration. METHODS: Twelve patients undergoing elective cardiac surgery were investigated. Group A received 1.5 g cefuroxime as bolus infusions before surgery, and 12 and 24 hours thereafter. In group B, a continuous infusion of 3.0 g cefuroxime was started after a bolus of 1.5 g. Cefuroxim levels were determined in blood and tissue (microdialysis). T-test, Wilcoxon signed rank test and χ2 test were used for statistical analysis. RESULTS: The area under the curve (AUC) of plasma cefuroxime concentrations was greater in group B (399 [333-518]) as compared to group A (257 [177-297] h mg L-1 , [median and interquartile range], P = .026). Furthermore, a significantly longer percentage of time > minimal inhibitory concentrations of 2 mg L-1 (100% vs 50%), 4 mg L-1 (100% vs 42%), 8 mg L-1 (100% vs 17%) and 16 mg L-1 (83% vs 8%) was found for free plasma cefuroxime in group B. In group B, area under the curve in subcutaneous tissue (78 [61-113] h mg L-1 ) and median peak concentration (33 [26-38] mg L-1 ) were markedly higher compared to group A (P = 0.041 and P = .026, respectively). CONCLUSIONS: Higher cefuroxime concentrations were measured in plasma and subcutaneously over a prolonged period of time when cefuroxime was administered continuously. The clinical implication of this finding still has to be elucidated.

Marine n-3 Polyunsaturated Fatty Acids and the Risk of Ischemic Stroke.

Background and Purpose- We hypothesized that total marine n-3 polyunsaturated fatty acids (PUFA), in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the diet and in adipose tissue (biomarkers of long-term intake and endogenous exposure) were inversely associated with the risk of ischemic stroke and its subtypes. Methods- The Diet, Cancer and Health cohort consisted of 57 053 participants aged 50 to 65 years at enrolment. All participants filled in a food frequency questionnaire and had an adipose tissue biopsy taken at baseline. Information on ischemic stroke during follow-up was obtained from The Danish National Patient Register, and all cases were validated. Cases and a random sample of 3203 subjects from the whole cohort had their fatty acid composition of adipose tissue determined by gas chromatography. Results- During 13.5 years of follow-up 1879 participants developed an ischemic stroke. Adipose tissue content of EPA was inversely associated with total ischemic stroke (hazard ratio [HR], 0.74; 95% CI, 0.62-0.88) when comparing the highest with the lowest quartile. Also, lower rates of large artery atherosclerosis were seen with higher intakes of total marine n-3 PUFA (HR, 0.69; 95% CI, 0.50-0.95), EPA (HR, 0.66; 95% CI, 0.48-0.91) and DHA (HR, 0.72; 95% CI, 0.53-0.99), and higher adipose tissue content of EPA (HR, 0.52; 95% CI, 0.36-0.76). Higher rates of cardioembolism were seen with higher intakes of total marine n-3 PUFA (HR, 2.50; 95% CI, 1.38-4.53) and DHA (HR, 2.12; 95% CI, 1.21-3.69) as well as with higher adipose tissue content of total marine n-3 PUFA (HR, 2.63; 95% CI, 1.33-5.19) and DHA (HR, 2.00; 95% CI, 1.04-3.84). The EPA content in adipose tissue was inversely associated with small-vessel occlusion (HR, 0.69; 95% CI, 0.55-0.88). Conclusions- EPA was associated with lower risks of most types of ischemic stroke, apart from cardioembolism, while inconsistent findings were observed for total marine n-3 PUFA and DHA.

Fatty Acid Composition in Various Types of Cardiac Adipose Tissues and Its Relation to the Fatty Acid Content of Atrial Tissue.

Diet, with its content of various types of fatty acids (FAs), is of great importance for cellular function. Adipose tissue (AT) serves as a storage for dietary FAs, but after appropriate activation it may also offer important biological properties, e.g., by releasing adipokines and cytokines to the surrounding milieu. Such effects may depend on the diet and type of FA involved. Similarly, the composition of FAs in the heart is also likely to be important for cardiac function. We investigated samples of epicardial adipose tissue (EAT), pericardial adipose tissue (PAT), subcutaneous adipose tissue (SCAT), and tissue from the right atrial appendage to compare the FA compositions in patients undergoing elective cardiac surgery. Minor differences among AT compartments were found, while the comparison of atrial tissue and EAT showed major differences in saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), and n-3 and n-6 polyunsaturated fatty acids (PUFAs). These findings may be of importance for understanding biological availability, dietary effects, and the effects of FAs on the heart.

Linoleic Acid in Adipose Tissue and Development of Ischemic Stroke: A Danish Case-Cohort Study.

BACKGROUND: We investigated the association between the content of linoleic acid in adipose tissue, a biomarker of long-term intake of linoleic acid, and the risk of ischemic stroke and its subtypes. METHODS AND RESULTS: The Danish cohort study Diet, Cancer and Health included 57 053 patients aged 50 to 65 years at enrollment. All participants had an adipose tissue biopsy performed at enrollment, while information on ischemic stroke during follow-up was obtained from the Danish National Patient Register. Stroke diagnoses were all validated and classified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. Cases and a randomly drawn subcohort of 3500 patients had their fatty acid composition in adipose tissue determined by gas chromatography. Hazard ratios with 95% confidence intervals were calculated using weighted Cox proportional hazard regression. During 13.5 years of follow-up, 1879 ischemic stroke cases were identified, for which 1755 adipose biopsies were available, while adipose biopsies were available for 3203 participants in the subcohort. When comparing the highest and the lowest quartiles of adipose tissue content of linoleic acid there was a negative association with the rate of total ischemic stroke (hazard ratio, 0.78; 95% confidence interval, 0.65-0.93) and large artery atherosclerosis (hazard ratio, 0.61; 95% confidence interval, 0.43-0.88), while there was an indication of a negative association with small-vessel occlusion (hazard ratio, 0.87; 95% confidence interval, 0.69-1.11). There was no clear association with the rate of cardioembolism. CONCLUSIONS: The content of linoleic acid in adipose tissue was inversely associated with the risk of total ischemic stroke and stroke caused by large artery atherosclerosis.

The effect of grapeseed oil on performance, rumen fermentation, antioxidant status and subcutaneous adipose fatty acid profile in lambs.

This experiment was carried out to examine the effect of grapeseed oil (GSO) on performance, rumen fermentation, antioxidant status and subcutaneous adipose fatty acid (FA) profile in lambs. Eighteen Baluchi lambs, 196 ± 14 days of age and 39.8 ± 1.7 kg body weight, were randomly assigned to three experimental diets: (i) diet without GSO (control), (ii) diet containing 2% of GSO (GSO2) and (iii) diet containing 4% of GSO (GSO4) for 42 days. Results showed that the experimental diets had no significant effect on dry matter intake and performance (p > 0.05). The supplemented diets with GSO had no effect on pH and NH3 -N of rumen fluid (p > 0.05), but GSO4 increased (p = 0.003) the concentration of propionic acid and reduced (p = 0.002) the concentration of acetate acid compared to the control. Inclusion 4% of GSO to the diet increased total antioxidant activity and decreased malondialdehyde in serum and muscle (p < 0.001). The level of blood glutathione peroxidase in diets containing GSO was higher than control diet (p = 0.02), but diets had no effect on superoxide dismutase in blood and muscle tissues (p > 0.05). The concentration of vaccenic acid, rumenic acid and linoleic acid and thus polyunsaturated fatty acid in subcutaneous fat was affected by experimental diets (p < 0.001), as control had the lowest amount of these FAs and GSO4 had the highest amount of them. Therefore, it can be concluded that the use of GSO up to 4% improves the antioxidant status and adipose fatty acid profile in lambs without effects on performance.

Bone and subcutaneous adipose tissue pharmacokinetics of vancomycin in total knee replacement patients.

Background and purpose - The incidence of orthopedic methicillin-resistant Staphylococcus aureus (MRSA) infections is increasing. Vancomycin may therefore play an increasingly important role in orthopedic perioperative antimicrobial prophylaxis. Studies investigating perioperative bone and soft tissue concentrations of vancomycin are sparse and challenged by a lack of appropriate methods. We assessed single-dose plasma, subcutaneous adipose tissue (SCT) and bone concentrations of vancomycin using microdialysis in male patients undergoing total knee replacement. Methods - 1,000 mg of vancomycin was administered postoperatively intravenously over 100 minutes to 10 male patients undergoing primary total knee replacement. Vancomycin concentrations in plasma, SCT, cancellous, and cortical bone were measured over the following 8 hours. Microdialysis was applied for sampling in solid tissues. Results - For all solid tissues, tissue penetration of vancomycin was significantly impaired. The time to a mean clinically relevant minimal inhibitory concentration (MIC) of 2 mg/L was 3, 36, 27, and 110 min for plasma, SCT, cancellous, and cortical bone, respectively. As opposed to the other compartments, a mean MIC of 4 mg/L could not be reached in cortical bone. The area under the concentration-time curve from 0 to the last measured value and peak drug concentrations (Cmax) for SCT, cancellous, and cortical bone was lower than that of free plasma. The time to Cmax was higher for all tissues compared with free plasma. Interpretation - Postoperative penetration of vancomycin to bone and SCT was impaired and delayed in male patients undergoing total knee replacement surgery. Adequate perioperative vancomycin concentrations may not be reached using standard prophylactic dosage.

Adipose Tissue Macrophages in Rheumatoid Arthritis: Prevalence, Disease-Related Indicators, and Associations With Cardiometabolic Risk Factors.

OBJECTIVE: Adipose tissue macrophages (ATMs) are a potent source of inflammatory cytokines, with profound effects on adipose tissue function, yet their potential role in rheumatoid arthritis (RA) pathobiology is largely unstudied. METHODS: Periumbilical subcutaneous adipose tissue was obtained from 36 RA patients and 22 non-RA controls frequency matched on demographics and body mass index. Samples were stained for the macrophage marker CD68, and the average proportions of ATMs, crown-like structures (periadipocyte aggregates of 3 or more ATMs), and fibrosis were compared between groups. RESULTS: The adjusted proportion of ATMs among all nucleated cells was 76% higher in RA than in non-RA samples (37.7 versus 21.3%, respectively; P < 0.001), and the adjusted average number of crown-like structures was more than 1.5-fold higher in the RA group than in controls (0.58 versus 0.23 crown-like structure/high-power field, respectively; P = 0.001). ATMs were significantly more abundant in early RA and in those with anti-cyclic citrullinated peptide seropositivity. Users of methotrexate, leflunomide, and tumor necrosis factor inhibitors had a significantly lower proportion of ATMs compared with nonusers. Crown-like structures were significantly higher in patients with rheumatoid factor seropositivity and in those with C-reactive protein levels ≥10 mg/liter, and significantly lower among those treated with statins. Linear ATMs were significantly associated with whole-body insulin resistance, but not with serum lipids. CONCLUSIONS: ATMs and crown-like structures were more abundant in RA patients and were associated with systemic inflammation, autoimmunity, and whole-body insulin resistance, suggesting possible contributions to the RA disease process. Lower levels of ATMs and crown-like structures associated with specific RA treatments suggest that adipose tissue inflammation may be ameliorated by immunomodulation.

Do polychlorinated biphenyls cause cancer? A systematic review and meta-analysis of epidemiological studies on risk of cutaneous melanoma and non-Hodgkin lymphoma.

In 2015 a IARC Working Group upgraded the classification of PCBs to Group 1 "Carcinogenic to humans", also on the basis of evidence from epidemiological studies showing an excess risk for melanoma. Increased risks for non-Hodgkin lymphoma (NHL) and breast cancer were also reported though the evidence was limited. However, some recent reviews of studies on PCB exposure and risk of cancer provided discrepant findings. Therefore, we re-evaluated the association between exposure to PCBs and risk of melanoma and NHL by a systematic review and meta-analysis. We retrieved 11 independent cohort studies on occupationally exposed workers. About half of them showed increased standardized mortality or incidence ratios (SMRs or SIRs) for melanoma and none for NHL. The pooled SMRs were 1.32 (95% CI: 1.05-1.64) for melanoma and 0.94 (0.73-1.23) for NHL. Among population-based cohort and case-control studies with individual measures of PCB exposure, one only study was carried out on PCB exposure and melanoma, showing an odds ratio (OR) of 6.0 (2.0-18.2) for the highest compared to lowest quartile of PCB distribution. 13 cohort and case-control studies evaluated the association between NHL and PCB concentration in blood or subcutaneous fat, with summary OR = 1.5 (1.1-1.7) for the highest vs lowest quantile of PCB distribution. However, two cohort studies on people intoxicated by rice oil containing PCBs found no excess of deaths for skin cancer and inconsistent results for NHL. In conclusion, these findings do not provide a strong evidence that PCB exposure can increase the risk of melanoma and NHL in humans.

Changes in the MicroRNA Profile Observed in the Subcutaneous Adipose Tissue of Obese Patients after Laparoscopic Adjustable Gastric Banding.

Background. Laparoscopic adjustable gastric banding (LAGB) results in significant lasting weight loss and improved metabolism in obese patients. To evaluate whether epigenetic factors could concur to these benefits, we investigated the subcutaneous adipose tissue (SAT) microRNA (miRNA) profile before (T0) and three years (T1) after LAGB in three morbidly obese women. Case Reports. SAT miRNA profiling, evaluated by TaqMan Array, showed four downexpressed (miR-519d, miR-299-5p, miR-212, and miR-671-3p) and two upexpressed (miR-370 and miR-487a) miRNAs at T1 versus T0. Bioinformatics predicted that these miRNAs regulate genes belonging to pathways associated with the cytoskeleton, inflammation, and metabolism. Western blot analysis showed that PPAR-alpha, which is the target gene of miR-519d, increased after LAGB, thereby suggesting an improvement in SAT lipid metabolism. Accordingly, the number and diameter of adipocytes were significantly higher and lower, respectively, at T1 versus T0. Bioinformatics predicted that the decreased levels of miR-212, miR-299-5p, and miR-671-3p at T1 concur in reducing SAT inflammation. Conclusion. We show that the miRNA profile changes after LAGB. This finding, although obtained in only three cases, suggests that this epigenetic mechanism, by regulating the expression of genes involved in inflammation and lipid metabolism, could concur to improve SAT functionality in postoperative obese patients.

Adipokine Levels Versus Hepatic Histopathology in Bariatric Surgery Patients.

BACKGROUND: Obesity is a worldwide prevalent disease and is an underlying factor of non-alcoholic fatty liver disease (NAFLD). It has been understood as a chronic inflammatory state, being associated with the production of adipokines. The aim of this study was to analyze the levels of adipokines in the serum, visceral, and subcutaneous fat and to compare them with hepatic histopathology in morbidly obese patients. METHODS: This is a cross-sectional observational study, which analyzed the findings of liver biopsy in patients undergoing bariatric surgery and who had performed analysis of adipokines mRNA expression (adiponectin-ADIPOQ, leptin-LEP, and resistin-RETN) in subcutaneous and visceral adipose tissue and circulating adipokines in serum. Liver biopsies performed were evaluated according to Kleiner criteria. RESULTS: The study analyzed 25 patients undergoing bariatric surgery. The sample was composed exclusively of women. There was a predominance of NAFLD, with 21 patients (84%) with intrahepatic fat accumulation. Twelve patients presented non-alcoholic steatohepatitis (NASH). Glycated hemoglobin levels (HbA1c) were elevated in NASH patients. ADIPOQ levels were directly correlated with high-density lipoprotein (HDL) cholesterol levels and inversely correlated with triglycerides and total cholesterol. LEP levels showed an inverse relationship with the degree of steatosis, and RETN levels showed an inverse relationship with fibrosis stages. CONCLUSION: Serum LEP levels were reduced in the presence of increased levels of intrahepatic fat, and serum levels of RETN were diminished in the presence of NASH. HbA1c levels were higher in the presence of NASH, indirectly reflecting insulin resistance. Moreover, ADIPOQ levels were related to blood lipid profile.

The Facial Adipose Tissue: A Revision.

Recent advantages in the anatomical understanding of the face have turned the focus toward the subcutaneous and deep facial fat compartments. During facial aging, these fat-filled compartments undergo substantial changes along with other structures in the face. Soft tissue filler and fat grafting are valid methods to fight the signs of facial aging, but little is known about their precise effect on the facial fat. This narrative review summarizes the current knowledge about the facial fat compartments in terms of anatomical location, histologic appearance, immune-histochemical characteristics, cellular interactions, and therapeutic options. Three different types of facial adipose tissue can be identified, which are located either superficially (dermal white adipose tissue) or deep (subcutaneous white adipose tissue): fibrous (perioral locations), structural (major parts of the midface), and deposit (buccal fat pad and deep temporal fat pad). These various fat types differ in the size of the adipocytes and the collagenous composition of their extracellular matrix and thus in their mechanical properties. Minimal invasive (e.g., soft tissue fillers or fat grafting) and surgical interventions aiming to restore the youthful face have to account for the different fat properties in various facial areas. However, little is known about the macro- and microscopic characteristics of the facial fat tissue in different compartments and future studies are needed to reveal new insights to better understand the process of aging and how to fight its signs best.

Loss of visceral adipose tissue precedes subcutaneous adipose tissue and associates with n-6 fatty acid content.

BACKGROUND & AIM: During cancer development, fat loss occurs in most cancer patients. Characterization of the behavior of fat loss from visceral (VAT) and subcutaneous adipose tissue (SAT) depots has not been established. The first objective of this study was to assess the intensity and time course of changes in VAT and SAT depots of advanced cancer patients in the year preceding death. Secondly, this study explored the differences in adipokine content and fatty acid composition between VAT and SAT depots and in relation to changes in fat mass. METHODS: Longitudinal quantitative analyses of computed tomography images was conducted to define changes in adipose tissue cross sectional areas in fat depots in advanced colorectal and cholangiocarcinoma cancer patients (n = 46) at mean time points corresponding to 9, 6, 3 and 1 month before death. Proportions of adipose tissue fatty acid and adipokine content were characterized in a second cohort of advanced colorectal cancer patients (n = 16). RESULTS: On average, loss of total adipose tissue (TAT) happens at all time intervals but there is an elevation in the intensity of loss close to death. Nine months from death, 42% of patients were losing fat (Mean TAT cross sectional area change = -0.2 ± 13 cm2) whereas within one month from death, fat wasting was observed in 78% of patients (-60.1 ± 9.2 cm2, P = 0.001). However, loss of TAT did not reflect changes in VAT and SAT in the same direction or intensity. Intensity of VAT loss remains constant throughout the disease progression whereas SAT is more likely to be gained further way from death. Nine month prior to death, mean change in cross sectional area of VAT was -7.9 ± 6.8 cm2 whereas, mean change in CSA of SAT was 7.4 ± 7.7 cm2 (p = 0.03). One month before death, mean VAT and SAT absolute changes were -24.5 ± 4.9 cm2 and -34.5 ± 5.2 cm2, respectively (p = 0.05). Moreover, fat losing patients had higher proportions of polyunsaturated fatty acids, especially n-6 fatty acids, in VAT compared to patients who were gaining fat (mean = 15.4% in losing group vs. 13.4% in gaining group; p = 0.03). VAT contained more monocyte chemoattractant protein-1 than SAT, whereas leptin levels were higher in SAT. CONCLUSIONS: Further from death, VAT and SAT behave differently whereas close to death, accelerated loss occurs in both depots. These differences are further characterized by differences in fatty acid composition and adipokine levels.