Mercé Hernández

New adipokines vaspin and omentin. Circulating levels and gene expression in adipose tissue from morbidly obese women

BackgroundVaspin and omentin are recently described molecules that belong to the adipokine family and seem to be related to metabolic risk factors. The objectives of this study were twofold: to evaluate vaspin and omentin circulating levels and mRNA expression in subcutaneous and visceral adipose tissues in non-diabetic morbidly obese women; and to assess the relationship of vaspin and omentin with anthropometric and metabolic parameters, and other adipo/cytokines.DesignWe analysed vaspin and omentin circulating levels in 71 women of European descent (40 morbidly obese [BMI ≥ 40 kg/m2] and 31 lean [BMI ≤ 25]). We assessed vaspin and omentin gene expression in paired samples of visceral and subcutaneous abdominal adipose tissue from 46 women: 40 morbidly obese and 6 lean. We determined serum vaspin and plasma omentin levels with an Enzyme-Linked Immunosorbent Assay and adipose tissue mRNA expression by real time RT-PCR.ResultsSerum vaspin levels in the morbidly obese were not significantly different from those in controls. They correlated inversely with levels of lipocalin 2 and interleukin 6. Vaspin mRNA expression was significantly higher in the morbidly obese, in both subcutaneous and visceral adipose tissue.Plasma omentin levels were significantly lower in the morbidly obese and they correlated inversely with glucidic metabolism parameters. Omentin circulating levels, then, correlated inversely with the metabolic syndrome (MS). Omentin expression in visceral adipose tissue was significantly lower in morbidly obese women than in controls.ConclusionsThe present study indicates that vaspin may have a compensatory role in the underlying inflammation of obesity. Decreased omentin circulating levels have a close association with MS in morbidly obese women.

TNFα expression of subcutaneous adipose tissue in obese and morbid obese females: relationship to adipocyte LPL activity and leptin synthesis

Introduction: Tumor necrosis factor (TNFα) has been invoked as an adipostat. Accordingly, the adipose tissue expression of TNFα has been shown to be proportional to the degree of adiposity. The regulatory role of TNFα in obesity may be controlled by several mechanisms. These include the inhibitory effect on LPL activity, the mediation on glucose homeostasis or the effect on leptin. To assess the role of TNFα in obesity we measured adipocyte TNFα expression in 96 females with a wide range of adiposity and with or without type 2 diabetes. We analysed the relationship between TNFα expression, adipocyte LPL activity, insulin resistance and leptin in this population.Results: The TNFα and leptin expression of the adipose tissue in obese and morbid obese patients were significantly higher than in controls. Obese and morbid obese patients had slightly higher levels of LPL activity, but these differences were not significant. We observed a significant relationship between adipose TNFα expression and body mass index (r=0.35, P<0.001). TNFα expression was negatively related to LPL activity (r=−0.28, P<0.05) and positively related to leptin expression (r=0.35, P<0.001).Conclusion: Our results indicate that obese women, even those with morbid obesity, over-express TNFα in subcutaneous adipose tissue in proportion to the magnitude of the fat depot and independently of the presence of type 2 diabetes. The TNFα system may be a homeostatic mechanism that prevents further fat deposition by regulating LPL activity and leptin production.

FABP 4 is associated with inflammatory markers and metabolic syndrome in morbidly obese women.

OBJECTIVE The adipocyte/macrophage fatty acid-binding protein 4 (FABP4) has been described as a biomarker for adiposity and metabolic syndrome (MS). The aims of this study were to assess the relationship between FABP4 and inflammatory cytokines related to obesity, and to evaluate FABP4 mRNA expression in visceral and subcutaneous adipose tissue in non-diabetic morbidly obese women versus healthy lean women. METHODS We analyzed circulating levels of FABP4 in 81 Spanish women: 38 lean (body mass index (BMI)<25 kg/m(2)) and 43 morbidly obese (BMI>40 kg/m(2)). We took 30 follow-up blood samples at 6 and 12 months after bariatric surgery. We assessed FABP4 gene expression in samples of subcutaneous abdominal and visceral adipose tissue. Adipose tissue mRNA expression was determined by real-time RT-PCR. RESULTS In morbidly obese women, plasma FABP4 levels were significantly higher than in non-obese patients. These levels positively correlated with BMI, homeostasis model assessment of insulin resistance (HOMA2-IR), and plasma glucose and insulin levels. Post-operative FABP4 levels decreased by a maximum of 30% after 12 months. We also found an inverse association between FABP4 and adiponectin levels, and positive correlations between FABP4 and circulating leptin, tumor necrosis factor (TNF) receptors, C-reactive protein (CRP) and interleukin 6 levels. Linear regression analysis revealed that FABP4 was more closely related to HOMA2-IR than adiponectin, CRP, TNF-RI, or leptin. Furthermore, high circulating FABP4 levels were associated with the presence of MS. FABP4 mRNA expression in visceral adipose tissue was related to its circulating levels in morbidly obese women. CONCLUSIONS Our results indicate that serum FABP4 is associated with inflammatory factors related to obesity and MS in non-diabetic morbidly obese women.

Inhibition of hepatic cell nuclear DNA fragmentation by zinc in carbon tetrachloride-treated rats.

BACKGROUND/AIMS The aims of this study were to ascertain: 1) whether hepatic cell DNA fragmentation is increased in rats with early stages of liver disease induced by carbon tetrachloride; 2) whether the inhibition of DNA cleavage is involved in the hepatoprotective effects of zinc; and 3) if relationships exist between DNA fragmentation and the onset of fibrosis in this experimental model. METHODS Twenty-one treated rats and 23 controls were divided into two groups to receive either a standard diet or one supplemented with zinc. All the animals were sacrificed 1 week later for histological and biochemical assessments, which included a DNA fragmentation index, hepatic zinc and metallothionein concentrations, fibrosis measured by hepatic hydroxyproline concentration and plasma alanine aminotransferase activity. RESULTS Hepatic cell DNA fragmentation was increased in rats with early hepatic fibrosis and the increase was independent of hepatocytolysis, as measured by alanine aminotransferase activity. Oral zinc administration inhibited hepatic cell DNA fragmentation in the treated rats and was proportional to the hepatic concentration of the metal. The mechanism of the zinc-mediated decrease in DNA cleavage was related to an increase in the hepatic metallothionein concentration. Hepatic cell DNA fragmentation was related to hydroxyproline concentration. CONCLUSIONS Our results suggest that apoptosis may be involved in the early transformations occurring in the liver and which can lead to the initiation of cirrhosis. As such, the potential therapeutic use of zinc supplementation would warrant further investigation.

Upregulation of lipocalin 2 in adipose tissues of severely obese women: positive relationship with proinflammatory cytokines.

Because the role of lipocalin 2 (LCN2) in morbid obesity is still not well defined, the aim of this study was to evaluate the circulating levels and the expression of LCN2 in visceral (VAT) and subcutaneous adipose tissue (SAT) in severely obese (SO) women. We also analyzed its relationship with inflammatory cytokines in the same subjects. The study comprised 90 white women, 39 of whom were lean controls (BMI ≤25 kg/m2) and 51 SO (BMI ≥40 kg/m2). Both circulating and adipose tissue levels of LCN2 were quantified by enzyme‐linked immunosorbent assays. LCN2 mRNA levels from VAT and SAT were assessed by real‐time reverse transcriptase‐PCR (n = 60). LCN2 serum levels were significantly higher in the SO women than in the lean controls (P = 0.042), and were found to be strongly correlated with tumor necrosis factor receptor I (TNFR1) circulating levels. In the SO cohort, LCN2 serum levels were also associated with higher BMI values, but not with the homeostasis model assessments of insulin resistance (HOMA2‐IR). LCN2 mRNA expression was markedly higher in SO women than in lean women in both VAT (P = 0.043) and SAT (P = 0.031). In SAT, LCN2 was negatively correlated with adiponectin and adiponectin receptor‐2 expression, and positively with interleukin‐6 (IL‐6) expression. A strong positive correlation was also found between LCN2 expression and the mean diameter of adipocytes in VAT. Our results revealed that the circulating level of LCN2 is associated with obesity and BMI. LCN2 mRNA is over‐expressed in adipose tissue from SO subjects. Finally, the expression of LCN2 is strongly related to an expression profile of proinflammatory cytokines but not to insulin resistance in nondiabetic SO women.

Immunohistochemical analysis of paraoxonases‐1 and 3 in human atheromatous plaques

Eur J Clin Invest 2011; 41 (3): 308–314

Retinol binding protein-4 circulating levels were higher in nonalcoholic fatty liver disease vs. histologically normal liver from morbidly obese women.

We aimed to analyze the retinol binding protein‐4 (RBP4) messenger RNA (mRNA) expression profiles in adipose tissues and liver of morbidly obese (MO) women with or without nonalcoholic fatty liver disease (NAFLD), and to study the relationships with other pro‐ and anti‐inflammatory adipokines in vivo and in vitro.

Mapping of the circulating metabolome reveals α-ketoglutarate as a predictor of morbid obesity-associated non-alcoholic fatty liver disease.

Background:Obesity severely affects human health, and the accompanying non-alcoholic fatty liver disease (NAFLD) is associated with high morbidity and mortality. Rapid and non-invasive methods to detect this condition may substantially improve clinical care.Methods:We used liquid and gas chromatography–quadruple time-of-flight–mass spectrometry (LC/GC-QTOF-MS) analysis in a non-targeted metabolomics approach on the plasma from morbidly obese patients undergoing bariatric surgery to gain a comprehensive measure of metabolite levels. On the basis of these findings, we developed a method (GC-QTOF-MS) for the accurate quantification of plasma α-ketoglutarate to explore its potential as a novel biomarker for the detection of NAFLD.Results:Plasma biochemical differences were observed between patients with and without NAFLD indicating that the accumulation of lipids in hepatocytes decreased β-oxidation energy production, reduced liver function and altered glucose metabolism. The results obtained from the plasma analysis suggest pathophysiological insights that link lipid and glucose disturbances with α-ketoglutarate. Plasma α-ketoglutarate levels are significantly increased in obese patients compared with lean controls. Among obese patients, the measurement of this metabolite differentiates between those with or without NAFLD. Data from the liver were consistent with data from plasma. Clinical utility was assessed, and the results revealed that plasma α-ketoglutarate is a fair-to-good biomarker in patients (n=230). Other common laboratory liver tests used in routine application did not favourably compare.Conclusion:Plasma α-ketoglutarate is superior to common liver function tests in obese patients as a surrogate biomarker of NAFLD. The measurement of this biomarker may potentiate the search for a therapeutic approach, may decrease the need for liver biopsy and may be useful in the assessment of disease progression.

Plasma visfatin levels and gene expression in morbidly obese women with associated fatty liver disease.

OBJECTIVES The few studies on the physiopathological role of visfatin in morbid obesity and the related metabolic diseases have led us to examine visfatin levels and its liver gene expression in morbidly obese women with non-alcoholic fatty liver disease (NAFLD). DESIGN AND METHODS We examined the circulating levels of visfatin by ELISA in serum samples from 95 morbidly obese women (MO) (BMI>40 kg/m(2)) who underwent bariatric surgery and 38 normal weight control women (BMI<25 kg/m(2)). We analysed visfatin liver and adipose tissue mRNA expression by RT-PCR. We evaluated the circulating levels and gene expression of adiponectin, resistin, RBP4, TNFα, IL6 and CRP. RESULTS Serum visfatin was significantly higher in MO compared with controls, and also in MO with NAFLD was significantly higher than MO with normal liver. We found that NAFLD diabetic patients presented similar serum visfatin levels than non-diabetic. Serum visfatin correlated with IL6 (r=0.496; p<0.001) and CRP levels (r=0.241; p=0.049). Liver visfatin expression was significantly higher in MO compared to controls and was also significantly higher in MO with NAFLD than in MO with normal liver. Visfatin liver expression correlated positively with resistin (r=0.436, p=0.018) and TNFα expression (r=0.328, p=0.028). Visfatin expression in adipose tissues was similar among the MO groups analysed. CONCLUSION Serum visfatin and its liver expression are higher in MO women with NAFLD, irrespective of the presence of diabetes. Serum visfatin and its liver expression correlate positively with pro-inflammatory factors. These findings suggest that visfatin may be a molecule related with fat inflammation in morbid obesity and fatty liver disease.

Increased levels and adipose tissue expression of visfatin in morbidly obese women: the relationship with pro‐inflammatory cytokines

Objective  The controversial results on the physiopathological role of visfatin led us to examine both circulating visfatin levels and gene expression in visceral (VAT) and subcutaneous fat (SAT) in a homogeneous group of morbidly obese women.