VENDRELL, JOAN, MONTSERRAT BROCH, NURIA VILARRASA, ANA MOLINA, JOSE MANUEL GÓ MEZ, CRISTINA GUTIÉ RREZ, IMMACULADA SIMÓ N, JOAN SOLER, AND CRISTÓ BAL RICHART. Resistin, adiponectin, ghrelin, leptin, and proinflammatory cytokines: relationships in obesity. Obes Res. 2004;12:962-971. Objective: To evaluate interactions among leptin, adiponectin, resistin, ghrelin, and proinflammatory cytokines [tumor necrosis factor receptors (TNFRs), interleukin-6 (IL-6)] in nonmorbid and morbid obesity. Research Methods and Procedures: We measured these hormones by immunoenzyme or radiometric assays in 117 nonmorbid and 57 morbidly obese patients, and in a subgroup of 34 morbidly obese patients before and 6 months after gastric bypass surgery. Insulin resistance by homeostasis model assessment, lipid profile, and anthropometrical measurements were also performed in all patients. Results: Average plasma lipids in morbidly obese patients were elevated. IL-6, leptin, adiponectin, and resistin were increased and ghrelin was decreased in morbidly obese compared with nonmorbidly obese subjects. After adjusting for age, gender, and BMI in nonmorbidly obese, adiponectin was positively associated with HDLc and gender and negatively with weight (␤ ϭ Ϫ0.38, p Ͻ 0.001). Leptin and resistin correlated positively with soluble tumor necrosis factor receptor (sTNFR) 1 (␤ ϭ 0.24, p ϭ 0.01 and ␤ ϭ 0.28, p ϭ 0.007). In the morbidly obese patients, resistin and ghrelin were positively associated with sTNFR2 (␤ ϭ 0.39, p ϭ 0.008 and ␤ ϭ 0.39, p ϭ 0.01). In the surgically treated morbidly obese group, body weight decreased significantly and was best predicted by resistin concentrations before surgery (␤ ϭ 0.45, p ϭ 0.024). Plasma lipids, insulin resistance, leptin, sTNFR1, and IL-6 decreased and adiponectin and ghrelin increased significantly. Insulin resistance improved after weight loss and correlated with high adiponectin levels. Discussion: TNF␣ receptors were involved in the regulatory endocrine system of body adiposity independently of leptin and resistin axis in nonmorbidly obese patients. Our results suggest coordinated roles of adiponectin, resistin, and ghrelin in the modulation of the obesity proinflammatory environment and that resistin levels before surgery treatment are predictive of the extent of weight loss after bypass surgery.

Polymorphism at the ADH2 and ADH3 loci of alcohol dehydrogenase (ADH) has been shown to have an effect on the predisposition to alcoholism in Asian individuals. However, the results are not conclusive for white individuals. We have analyzed the ADH genotype of 876 white individuals from Spain (n ‫؍‬ 251), France (n ‫؍‬ 160), Germany (n ‫؍‬ 184), Sweden (n ‫؍‬ 88), and Poland (n ‫؍‬ 193). Peripheral blood samples from healthy controls and groups of patients with viral cirrhosis and alcohol-induced cirrhosis, as well as alcoholics with no liver disease, were collected on filter paper. Genotyping of the ADH2 and ADH3 loci was performed using polymerase chain reactionrestriction fragment length polymorphism methods on white cell DNA. In healthy controls, ADH2*2 frequencies ranged from 0% (France) to 5.4% (Spain), whereas ADH3*1 frequencies ranged from 47.6% (Germany) to 62.5% (Sweden). Statistically significant differences were not found, however, between controls from different countries, nor between patients with alcoholism and/or liver disease. When all individuals were grouped in nonalcoholics (n ‫؍‬ 451) and alcoholics (n ‫؍‬ 425), ADH2*2 frequency was higher in nonalcoholics (3.8%) than in alcoholics (1.3%) (P ‫؍‬ .0016), whereas the ADH3 alleles did not show differences. Linkage disequilibrium was found between ADH2 and ADH3, resulting in an association of the alleles ADH2*2 and ADH3*1, both coding for the most active enzymatic forms. In conclusion, the ADH2*2 allele decreases the risk for alcoholism, whereas the ADH2*2 and ADH3*1 alleles are found to be associated in the European population. (HEPATOLOGY 2000;31:984-989.)Ingested alcohol is mostly metabolized in the liver by the successive action of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Both enzymes exhibit genetic polymorphisms that influence the rate of conversion of ethanol to acetaldehyde, and of acetaldehyde to acetate. It has been consistently reported that ALDH2 is the most important alcohol-metabolizing gene affecting predisposition to alcoholism in Asian populations. The prevalence of the ALDH2*2 allele, which codes for a physiologically inactive mitochondrial ALDH form, is lower in alcoholics than in nonalcoholics. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] However, this allele has not been found in white individuals. 21 Regarding ADH, polymorphism is detected at the ADH2 and ADH3 loci. Alleles of ADH2 found in whites and Asians are ADH2*1 and ADH2*2, which encode for the low activity (␤1) and high activity (␤2) subunits, respectively. The kcat values for the resulting dimeric isozymes are very different: 9.2 min Ϫ1 for ␤1␤1 and 400 min Ϫ1 for ␤2␤2. 22 The ADH2*2 frequency is much higher in Asians (60%-80%) than in whites (0%-10%). 21 ADH3 alleles are ADH3*1 and ADH3*2, which produce the ␥1 and ␥2 subunits. The ␥1␥1 isozyme (kcat ϭ 87 min Ϫ1 ) is moderately more active than the ␥2␥2 isozyme (kcat ϭ 35 min Ϫ1 ). 22 ADH3*1 frequency is about 50% to 60% in whites and higher than 90% in Asians. 3,23 ...

Recent studies have shown that the tumor necrosis factor (TNF) system is implicated in the insulin resistance of human obesity. Plasma concentrations of the soluble fraction of the TNF receptors 1 and 2 (sTNFR1 and sTNFR2) are thought to reflect the degree of activation of the TNF system. The purpose of this study was to explore whether this activation, as measured by the levels of circulating sTNFR1 and sTNFR2, is associated with insulin resistance. A total of 19 men (mean age 36.2 +/- 1.9; BMI 28.8 +/- 1.2, range 22.2-35.7) and 17 premenopausal women (age 34.9 +/- 1.4; BMI 28.1 +/- 0.8, range 19-37.9) were studied. Men showed higher levels of plasma sTNFR1 and sTNFR2 than women. However, obese men showed increased levels of sTNFR2 but similar levels of sTNFR1 in comparison with obese women. In fact, sTNFR2 levels correlated with BMI (r = 0.50, P = 0.002), fat-free mass (FFM) (r = 0.61, P < 0.0001), and waist-to-hip ratio (WHR) (r = 0.39, P = 0.02), but not with fat mass or percent fat mass. sTNFR2 levels correlated with basal glucose levels (r = 0.45, P = 0.007), area under the curve (AUC) for glucose during an oral glucose tolerance test (r = 0.42, P = 0.013), and with the quotient AUC glucose/log AUC insulin (r = 0.41, P = 0.015). sTNFR2 also correlated negatively with insulin sensitivity (S(I)), evaluated using the frequently sampled intravenous glucose tolerance test with minimal model analysis (r = -0.38, P = 0.02). Plasma sTNFR1 levels were not associated with any of these variables. Because WHR influenced both S(I) and sTNFR2 levels, we constructed a multiple linear regression to predict S(I), with WHR and sTNFR2 as independent variables. In this model, both WHR (P = 0.0078) and sTNFR2 levels (P = 0.025) contributed to 47% of the variance in S(I). In parallel with higher FFM, lean and obese men showed a lower S(I) (2.9 +/- 0.9 vs. 5.2 +/- 1.3 min(-1) x mU x l(-1), P = 0.001; and 1.15 +/- 1.1 vs. 1.8 +/- 0.8 min(-1) x mU x l(-1), P = 0.035, respectively) and higher sTNFR2 levels in comparison with lean and obese women, respectively. After controlling for FFM, the correlation between S(I) and sTNFR2 levels disappeared, indicating that FFM was significantly influencing these associations. In summary, plasma sTNFR2 levels, but not sTNFR1, were proportional to BMI, WHR, FFM (a well-known confounder in the evaluation of insulin sensitivity), basal and postload glucose levels, and insulin resistance. These findings support TNF-alpha as a system regulating insulin action in human obesity.

Type 2 diabetes and the insulin resistance syndrome have been hypothesized to constitute manifestations of an ongoing acute-phase response. We aimed to study an interleukin-6 (IL-6) gene polymorphism in relation to insulin sensitivity (I L-6 is the main cytokine involved in an acute-phase response). Subjects homozygous for the C allele at position -174 of the IL-6 gene (SfaNI genotype), associated to lower plasma IL-6 levels, showed significantly lower integrated area under the curve of serum glucose concentrations (AUC glucose ) after an oral glucose tolerance test, lower blood glycosylated hemoglobin, lower fasting insulin levels, lower total and differential white blood cell count (a putative marker of peripheral IL-6 action), and an increased insulin sensitivity index than carriers of the G allele, despite similar age and body composition. A gene dosage effect was especially remarkable for AUC g l u c o s e (6.4 vs. 9.3 vs. 9 . 7 mmol/l in C/C, C/G, and G/G individuals, respectively). The serum concentration of fully glycosylated cortisol binding globulin (another marker of IL-6 action), suggested by concanavalin A adsorption, was lower in C/C subjects than in G/G individuals (32.6 ± 2.9 vs. 37.6 ± 4.6 mg/l, P = 0.03). In summary, a polymorphism of the I L-6 gene influences the relationship among insulin sensitivity, postload glucose levels, and peripheral white blood cell count. Diabetes 49:517-520, 2000 I t has been hypothesized that type 2 diabetes and the insulin resistance syndrome are partly a manifestation of an ongoing acute-phase response (1,2). This hypothesis is based on the findings of increased blood concentrations of markers of the acute-phase response, including C-reactive protein, serum amyloid-A, -1 acid glycoprotein, sialic acid, and cortisol (1-4).Interleukin (IL)-6 is a pleiotropic cytokine involved in the regulation of the acute-phase reaction, immune responses, and hematopoiesis. Plasma IL-6 levels are elevated in type 2 diabetic patients, particularly in those with features of the insulin resistance syndrome (1,2). Although the concentrations of multiple components of the acute-phase response increase together, not all of them increase uniformly in all patients. These variations indicate that the components of the acute-phase response are individually regulated, and this may be explained in part by differences in the pattern of production of specific cytokines (5). Recently, it has been reported that a polymorphism in the 5 flanking region of the I L-6 gene alters the transcriptional response to stimuli such as endotoxin and IL-1 (6).In addition to its role in acute-phase response, IL-6 has been recently shown to be released by adipose tissue, and this release is greater in obese subjects, especially in those with a higher waist-to-hip ratio (7). Furthermore, IL-6 increases p o s t p r a n d i a l l y, in parallel to glucose and insulin levels, in the interstitial fluid of subcutaneous adipose tissue (8). This increase suggests that IL-6 might modulate adipose glucose metabolism in the...

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.

OBJECTIVE -Fatty acids (FAs) have been involved in the development of chronic inflammatory conditions such as insulin resistance and obesity. However, the relation among insulin resistance, obesity, inflammatory activity (circulating interleukin [IL]-6) and dietary FAs has been scarcely studied in otherwise healthy subjects.RESEARCH DESIGN AND METHODS -We aimed to study these interactions in 123 overweight (BMI 26.9 Ϯ 2.4 kg/m 2 [means Ϯ SD]) subjects and 109 lean (BMI 21.7 Ϯ 1.7 kg/m 2 , P Ͻ 0.000001) subjects. IL-6 was measured by immunoassay and FA by gas liquid cromatography.RESULTS -The percentage of saturated FAs (r ϭ 0.30, P ϭ 0.01) and -6 FAs (r ϭ Ϫ0.32, P ϭ 0.001) were significantly associated with circulating IL-6, whereas the percentage of -3 FAs correlated negatively with C-reactive protein in overweight subjects (P ϭ 0.04). Saturated-to--3 and saturated-to--6 FA ratios were significantly and positively associated with C-reactive protein (P Ͻ 0.0001) and IL-6 (P Ͻ 0.001), respectively. In contrast, none of these associations reached statistical significance in lean subjects. Those subjects in the most insulin-sensitive quintile (homeostasis model assessment value) showed a significantly higher percentage of linoleic acid (C18:2 6) (P ϭ 0.03) and a significantly lower level of araquidic (C20:0) (P ϭ 0.04), behenic (C22:0) (P ϭ 0.009), lignoceric (C24:0) (P ϭ 0.02), and nervonic (C24:1 9) (P ϭ 0.001) FAs than the remaining subjects. In parallel, the most insulin-sensitive subjects showed significantly decreased C-reactive protein (P ϭ 0.03). Serum C-reactive protein was significantly associated with percent linoleic acid and eicosapentaenoic acid in nonsmoking men (P ϭ 0.03 and P ϭ 0.04, respectively) and with docosahexaenoic acid in nonsmoking women (r ϭ Ϫ0.46, P Ͻ 0.0001). We constructed a multivariant regression analysis to predict circulating IL-6. Age, BMI, waist-to-hip ratio (WHR), smoking status, and the relation of saturated to -6 or saturated to -3 FAs were considered as independent variables separately in men and women. In overweight men, the ratio of saturated to -3 FAs (P ϭ 0.01), but not age, sex, BMI, WHR, or smoking status, independently contributed to 17% of IL-6 variance. In lean men, smoking status (P ϭ 0.02), but not the remaining variables, contributed to 8% of IL-6 variance.CONCLUSIONS -Dietary FAs (as inferred from plasma FA concentration) seem to be linked to inflammatory activity in overweight subjects and in subjects with insulin resistance. Being overweight modulates the relation of FAs to inflammatory markers. Diabetes Care 26:1362-1368, 2003I nsulin resistance is increasingly viewed as a chronic inflammatory disease (1). Different cytokines and chemical messengers constitute the main regulators of this inflammatory process, achieving biological effects individually as well as in association with each other. Interleukin (IL)-6 is a proinflammatory cytokine produced by many different cell types, including immune cells and adipose tissue (2,3). The major effects of IL-6 take pl...

JOSÉ-MANUEL FERNÁNDEZ-REAL, MD, PHD 3,4OBJECTIVE -Recent investigations disclosed an upregulation of retinol-binding protein-4 (RBP4) in the adipose tissue of several insulin-resistant mouse models and increased serum RBP4 concentration in subjects with obesity and type 2 diabetes in association with insulin resistance. There is some experimental evidence that RBP4 also could been linked to insulin secretion. RESEARCH DESIGN AND METHODS-We aimed to evaluate insulin secretion, insulin sensitivity, insulin disposition index (minimal model analysis), and circulating RBP4 (enzyme-linked immunosorbent assay) in nondiabetic men with a wide range of obesity (n ϭ 107).RESULTS -Serum RBP4 concentration was nonsignificantly different among lean, overweight, and obese subjects. Circulating RBP4 was not associated with age, BMI, waist-to-hip ratio, or metabolic parameters, including insulin sensitivity (r ϭ Ϫ0.03, P ϭ 0.6). On the contrary, circulating RBP4 was negatively associated with insulin secretion, especially in obese subjects (r ϭ Ϫ0.48, P ϭ 0.007), in whom RBP4 also was linked to insulin disposition index (r ϭ Ϫ0.44, P ϭ 0.01). On multiple regression analyses to predict insulin secretion (acute insulin response [AIR g ]), insulin sensitivity was the only factor that contributed to 17% of AIR g variance in nonobese subjects. In obese subjects, however, RBP4 emerged as an independent factor that contributed independently to AIR g variance (23%).CONCLUSIONS -Our results suggest that oversecretion of RBP4 may negatively affect ␤-cell function directly or by preventing the binding of transthyretin to its receptor. These mechanisms could be behind the association between increased circulating RBP4 and type 2 diabetes. RBP4 could be one signal from insulin-resistant tissues that impacts on ␤-cell secretion. Diabetes Care 30:1802-1806, 2007S erum retinol-binding protein-4 (RBP4) recently has been found to be increased in insulin-resistant subjects (1). Graham et al. (1) reported increased serum RBP4 concentration in subjects with obesity or type 2 diabetes compared with lean subjects. Insulin resistance was positively associated with serum RBP4 concentration and invoked to be causally related with type 2 diabetes. In fact, RBP4 is upregulated in the adipose tissue of several insulin-resistant mouse models (1,2). Transgenic expression or injections of RBP4 caused insulin resistance in mice, whereas experimentally decreased RBP4 levels ameliorated insulin resistance in diet-induced obesity. RBP4 augmented hepatic gluconeogenesis and attenuated insulin signaling in skeletal muscle (2). RBP4 was established as a rodent adipokine several years ago (3,4) and confirmed recently (5).Recent findings in humans suggest that the increase in systemic RBP4 concentrations in insulin-resistant subjects or subjects with type 2 diabetes is not explained by increased RBP4 production in adipose tissue (5). In this study, the authors did not see a relationship between adipose tissue RBP4 expression and serum RBP4 levels in postmenopausal wome...

Better adherence to IDSA guidelines would help to improve survival among patients with severe CAP. Pseudomonas coverage should be considered for patients with chronic obstructive pulmonary disease, malignancy, or recent antibiotic exposure.