Serum phospholipid fatty acid profile and dietary intake in an adult Mediterranean population with cystic fibrosis.

The relative importance of the usual diet in serum phospholipids in subjects with cystic fibrosis (CF) has been poorly studied. To compare the fatty acid profile in serum phospholipids from adult CF subjects with that of healthy subjects, and determine the role of the normal diet in this profile, we studied thirty-seven adult CF subjects with stable pulmonary disease and thirty-seven healthy controls matched for age, sex and nutritional status. A dietary questionnaire was obtained, anthropometric data were recorded, and the fatty acid profile measured by GLC. Compared with the controls, the percentages of myristic, palmitoleic and stearic acids and total MUFA were significantly higher in the CF group, and DHA, linoleic acid, total PUFA and n-6 fatty acids were significantly lower in the CF group. The CF subjects with worse pulmonary function and with pancreatic insufficiency had significantly lower levels of linoleic and n-6 fatty acids. The total energy intake was significantly higher in the CF subjects, although the energy distribution in the CF subjects and the controls was not different for the carbohydrates, lipids and proteins. No differences were detected in fat intake for MUFA (51 (SD 4) v. 52 (SD 4) %) or saturated fatty acids (33.5 (SD 5) v. 31.2 (SD 3.8) %), but the PUFA were slightly lower in the CF subjects (15.4 (SD 4.5) v. 17.4 (SD 4.2) %; P=0.02). The usual dietary intake of fatty acids by adult CF subjects does not appear to explain the difference in the fatty acid profile compared with controls. This suggests an abnormal fatty acid metabolism in CF subjects.

Common variants of the liver fatty acid binding protein gene influence the risk of type 2 diabetes and insulin resistance in Spanish population

SUMMARY The main objective was to evaluate the association between SNPs and haplotypes of the FABP1-4 genes and type 2 diabetes, as well as its interaction with fat intake, in one general Spanish population. The association was replicated in a second population in which HOMA index was also evaluated. METHODS 1217 unrelated individuals were selected from a population-based study [Hortega study: 605 women; mean age 54 y; 7.8% with type 2 diabetes]. The replication population included 805 subjects from Segovia, a neighboring region of Spain (446 females; mean age 52 y; 10.3% with type 2 diabetes). DM2 mellitus was defined in a similar way in both studies. Fifteen SNPs previously associated with metabolic traits or with potential influence in the gene expression within the FABP1-4 genes were genotyped with SNPlex and tested. Age, sex and BMI were used as covariates in the logistic regression model. RESULTS One polymorphism (rs2197076) and two haplotypes of the FABP-1 showed a strong association with the risk of DM2 in the original population. This association was further confirmed in the second population as well as in the pooled sample. None of the other analyzed variants in FABP2, FABP3 and FABP4 genes were associated. There was not a formal interaction between rs2197076 and fat intake. A significant association between the rs2197076 and the haplotypes of the FABP1 and HOMA-IR was also present in the replication population. CONCLUSIONS The study supports the role of common variants of the FABP-1 gene in the development of type 2 diabetes in Caucasians.

De novo lipogenesis in adipose tissue is associated with course of morbid obesity after bariatric surgery.

OBJECTIVE De novo lipogenesis is involved in fatty acid biosynthesis and could be involved in the regulation of the triglyceride storage capacity of adipose tissue. However, the association between lipogenic and lipolytic genes and the evolution of morbidly obese subjects after bariatric surgery remains unknown. In this prospective study we analyze the association between the improvement in the morbidly obese patients as a result of bariatric surgery and the basal expression of lipogenic and lipolytic genes. METHODS We study 23 non diabetic morbidly obese patients who were studied before and 7 months after bariatric surgery. Also, we analyze the relative basal mRNA expression levels of lipogenic and lipolytic genes in epiploic visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (SAT). RESULTS When the basal acetyl-CoA carboxylase 1 (ACC1), acetyl-CoA synthetase 2 (ACSS2) and ATP citrate lyase (ACL) expression in SAT was below percentile-50, there was a greater decrease in weight (P = 0.006, P = 0.034, P = 0.026), body mass index (P = 0.008, P = 0.033, P = 0.034) and hip circumference (P = 0.033, P = 0.021, P = 0.083) after bariatric surgery. In VAT, when the basal ACSS2 expression was below percentile-50, there was a greater decrease in hip circumference (P = 0.006). After adjusting for confounding variables in logistic regression models, only the morbidly obese patients with SAT or VAT ACSS2 expression ≥ P50 before bariatric surgery had a lower percentage hip circumference loss (fatty acid metabolism may have repercussions on the improvement of these patients.

Plasma Elaidic Acid Level as Biomarker of Industrial Trans Fatty Acids and Risk of Weight Change: Report from the EPIC Study.

BACKGROUND Few epidemiological studies have examined the association between dietary trans fatty acids and weight gain, and the evidence remains inconsistent. The main objective of the study was to investigate the prospective association between biomarker of industrial trans fatty acids and change in weight within the large study European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. METHODS Baseline plasma fatty acid concentrations were determined in a representative EPIC sample from the 23 participating EPIC centers. A total of 1,945 individuals were followed for a median of 4.9 years to monitor weight change. The association between elaidic acid level and percent change of weight was investigated using a multinomial logistic regression model, adjusted by length of follow-up, age, energy, alcohol, smoking status, physical activity, and region. RESULTS In women, doubling elaidic acid was associated with a decreased risk of weight loss (odds ratio (OR) = 0.69, 95% confidence interval (CI) = 0.55-0.88, p = 0.002) and a trend was observed with an increased risk of weight gain during the 5-year follow-up (OR = 1.23, 95% CI = 0.97-1.56, p = 0.082) (p-trend<.0001). In men, a trend was observed for doubling elaidic acid level and risk of weight loss (OR = 0.82, 95% CI = 0.66-1.01, p = 0.062) while no significant association was found with risk of weight gain during the 5-year follow-up (OR = 1.08, 95% CI = 0.88-1.33, p = 0.454). No association was found for saturated and cis-monounsaturated fatty acids. CONCLUSIONS These data suggest that a high intake of industrial trans fatty acids may decrease the risk of weight loss, particularly in women. Prevention of obesity should consider limiting the consumption of highly processed foods, the main source of industrially-produced trans fatty acids.

Long-term effects of varying consumption of ω3 fatty acids in ear, nose and throat cancer patients: assessment 1 year after radiotherapy.

Abstract A prospective 1-year follow-up study in ear, nose, and throat (ENT) cancer patients was carried out one year after radiotherapy to assess the effect of varying consumption of ω3 fatty acid according to whether they consumed more or less than the 50th percentile of ω3 fatty acids. Clinical, analytical, inflammatory (CRP and IL-6), and oxidative variables (TAC, GPx, GST, and SOD) were evaluated. The study comprised 31 patients (87.1% men), with a mean age of 61.3 ± 9.1 years. Hematological variables showed significant differences in the patients with a lower consumption of ω3 fatty acids. A lower mortality and longer survival were found in the group with ω3 fatty acid consumption ≥50th percentile but the differences were not significant. No significant difference was reached in toxicity, inflammation, and oxidative stress markers. The group with ω3 fatty acid consumption <50th percentile significantly experienced more hematological and immune changes.

Influence of a fat overload on lipogenic regulators in metabolic syndrome patients

Several epidemiological studies have related an increase of lipids in the postprandial state to an individual risk for the development of CVD, possibly due to the increased plasma levels of TAG and fatty acids (FA) through enzymes of FA metabolism. The interaction between nutrition and the human genome determines gene expression and metabolic response. The aim of the present study was to evaluate the influence of a fat overload on the gene mRNA levels of lipogenic regulators in peripheral blood mononuclear cells (PBMC) from patients with the metabolic syndrome. The study included twenty-one patients with criteria for the metabolic syndrome who underwent a fat overload. Measurements were made before and after the fat overload of anthropometric and biochemical variables and also the gene mRNA levels of lipogenic factors. The main results were that the fat overload led to an increased mRNA levels of sterol regulatory element binding protein-1 (SREBP1), retinoid X receptor α (RXRα) and liver X receptor α (LXRα) in PBMC, and this increase was associated with the FA synthase (FASN) mRNA levels. We also found that TAG levels correlated with FASN mRNA levels. In addition, there was a positive correlation of SREBP1 with RXRα and of LXRα with the plasma lipoperoxide concentration. The fat overload led to an increase in regulators of lipogenesis in PBMC from patients with the metabolic syndrome.

Effect of long-term administration of cross-sex hormone therapy on serum and urinary uric acid in transsexual persons.

BACKGROUND. Transsexual persons afford a very suitable model to study the effect of sex steroids on uric acid metabolism. DESIGN. This was a prospective study to evaluate the uric acid levels and fractional excretion of uric acid (FEUA) in a cohort of 69 healthy transsexual persons, 22 male-to-female transsexuals (MFTs) and 47 female-to-male transsexuals (FMTs).The subjects were studied at baseline and 1 and 2 yr after starting cross-sex hormone treatment. RESULTS. The baseline levels of uric acid were higher in the MFT group.Compared with baseline, uric acid levels had fallen significantly after 1 yr of hormone therapy in the MFT group and had risen significantly in the FMT group. The baseline FEUA was greater in the FMT group. After 2 yr of cross-sex hormone therapy, the FEUA had increased in MFTs (P = 0.001) and fallen in FMTs (P = 0.004).In MFTs, the levels of uric acid at 2 yr were lower in those who had received higher doses of estrogens (P = 0.03),and the FEUA was higher (P = 0.04).The FEUA at 2 yr was associated with both the estrogen dose (P = 0.02) and the serum levels of estradiol-17beta (P =0.03).In MFTs, a correlation was found after 2 yr of therapy between the homeostasis model assessment of insulin resistance and the serum uric acid (r = 0.59; P = 0.01). CONCLUSIONS. Serum levels of uric acid and the FEUA are altered in transsexuals as a result of cross-sex hormone therapy.The results concerning the MFT group support the hypothesis that the lower levels of uric acid in women are due to estrogen-induced increases in FEUA.

Inverse relation between levels of anti-oxidized-LDL antibodies and eicosapentanoic acid (EPA).

Oxidative modification of LDL is thought to play an important role in the development of atherosclerosis. Susceptibility of LDL to peroxidation may partly depend on the compositional characteristics of the antioxidant and fatty acid content. The aim of this study was to examine the association between levels of antibodies to oxidized LDL and the various serum fatty acids in women. A total of 465 women aged 18-65 years were selected randomly from the adult population census of Pizarra, a town in southern Spain. Measurement of anti-oxidized-LDL was done by ELISA and the fatty acid composition of serum phospholipids was determined by GC. The levels of anti-oxidized-LDL antibodies were significantly related with age (r - 0.341, P < 0.001), BMI (r - 0.239, P < 0.001), waist:hip ratio (r - 0.285, P < 0.001), glucose (r - 0.208, P < 0.001), cholesterol (r - 0.243, P < 0.001), LDL-cholesterol (r - 0.185, P = 0.002), EPA (r - 0.159, P = 0.003), DHA (r - 0.121, P = 0.026), and the sum of the serum phospholipid n-3 PUFA (r - 0.141, P = 0.009). Multiple regression analysis showed that the variables that explained the behaviour of the levels of anti-oxidized-LDL antibodies were age (P < 0.001) and the serum phospholipid EPA (P < 0.001). This study showed that the fatty acid composition of serum phospholipids, and especially the percentage of EPA, was inversely related with the levels of anti-oxidized-LDL antibodies.

Adipose tissue gene expression of factors related to lipid processing in obesity.

BACKGROUND Adipose tissue lipid storage and processing capacity can be a key factor for obesity-related metabolic disorders such as insulin resistance and diabetes. Lipid uptake is the first step to adipose tissue lipid storage. The aim of this study was to analyze the gene expression of factors involved in lipid uptake and processing in subcutaneous (SAT) and visceral (VAT) adipose tissue according to body mass index (BMI) and the degree of insulin resistance (IR). METHODS AND PRINCIPAL FINDINGS VLDL receptor (VLDLR), lipoprotein lipase (LPL), acylation stimulating protein (ASP), LDL receptor-related protein 1 (LRP1) and fatty acid binding protein 4 (FABP4) gene expression was measured in VAT and SAT from 28 morbidly obese patients with Type 2 Diabetes Mellitus (T2DM) or high IR, 10 morbidly obese patients with low IR, 10 obese patients with low IR and 12 lean healthy controls. LPL, FABP4, LRP1 and ASP expression in VAT was higher in lean controls. In SAT, LPL and FABP4 expression were also higher in lean controls. BMI, plasma insulin levels and HOMA-IR correlated negatively with LPL expression in both VAT and SAT as well as with FABP4 expression in VAT. FABP4 gene expression in SAT correlated inversely with BMI and HOMA-IR. However, multiple regression analysis showed that BMI was the main variable contributing to LPL and FABP4 gene expression in both VAT and SAT. CONCLUSIONS Morbidly obese patients have a lower gene expression of factors related with lipid uptake and processing in comparison with healthy lean persons.

FABP4 Dynamics in Obesity: Discrepancies in Adipose Tissue and Liver Expression Regarding Circulating Plasma Levels.

BACKGROUND FABP4 is predominantly expressed in adipose tissue, and its circulating levels are linked with obesity and a poor atherogenic profile. OBJECTIVE In patients with a wide BMI range, we analyze FABP4 expression in adipose and hepatic tissues in the settings of obesity and insulin resistance. Associations between FABP4 expression in adipose tissue and the FABP4 plasma level as well as the main adipogenic and lipolytic genes expressed in adipose tissue were also analyzed. METHODS The expression of several lipogenic, lipolytic, PPAR family and FABP family genes was analyzed by real time PCR. FABP4 protein expression in total adipose tissues and its fractions were determined by western blot. RESULTS In obesity FABP4 expression was down-regulated (at both mRNA and protein levels), with its levels mainly predicted by ATGL and inversely by the HOMA-IR index. The BMI appeared as the only determinant of the FABP4 variation in both adipose tissue depots. FABP4 plasma levels showed a significant progressive increase according to BMI but no association was detected between FABP4 circulating levels and SAT or VAT FABP4 gene expression. The gene expression of FABP1, FABP4 and FABP5 in hepatic tissue was significantly higher in tissue from the obese IR patients compared to the non-IR group. CONCLUSION The inverse pattern in FABP4 expression between adipose and hepatic tissue observed in morbid obese patients, regarding the IR context, suggests that both tissues may act in a balanced manner. These differences may help us to understand the discrepancies between circulating plasma levels and adipose tissue expression in obesity.

Inverse relation between FASN expression in human adipose tissue and the insulin resistance level.

BACKGROUND Adipose tissue is a key regulator of energy balance playing an active role in lipid storage and may be a dynamic buffer to control fatty acid flux. Just like PPARgamma, fatty acid synthesis enzymes such as FASN have been implicated in almost all aspects of human metabolic alterations such as obesity, insulin resistance or dyslipemia. The aim of this work is to investigate how FASN and PPARgamma expression in human adipose tissue is related to carbohydrate metabolism dysfunction and obesity. METHODS The study included eighty-seven patients which were classified according to their BMI and to their glycaemia levels in order to study FASN and PPARgamma gene expression levels, anthropometric and biochemical variables. RESULTS The main result of this work is the close relation between FASN expression level and the factors that lead to hyperglycemic state (increased values of glucose levels, HOMA-IR, HbA1c, BMI and triglycerides). The correlation of the enzyme with these parameters is inversely proportional. On the other hand, PPARgamma is not related to carbohydrate metabolism. CONCLUSIONS We can demonstrate that FASN expression is a good candidate to study the pathophysiology of type II diabetes and obesity in humans.

Leucine supplementation protects from insulin resistance by regulating adiposity levels.

BACKGROUND Leucine supplementation might have therapeutic potential in preventing diet-induced obesity and improving insulin sensitivity. However, the underlying mechanisms are at present unclear. Additionally, it is unclear whether leucine supplementation might be equally efficacious once obesity has developed. METHODOLOGY/PRINCIPAL FINDINGS Male C57BL/6J mice were fed chow or a high-fat diet (HFD), supplemented or not with leucine for 17 weeks. Another group of HFD-fed mice (HFD-pairfat group) was food restricted in order to reach an adiposity level comparable to that of HFD-Leu mice. Finally, a third group of mice was exposed to HFD for 12 weeks before being chronically supplemented with leucine. Leucine supplementation in HFD-fed mice decreased body weight and fat mass by increasing energy expenditure, fatty acid oxidation and locomotor activity in vivo. The decreased adiposity in HFD-Leu mice was associated with increased expression of uncoupling protein 3 (UCP-3) in the brown adipose tissue, better insulin sensitivity, increased intestinal gluconeogenesis and preservation of islets of Langerhans histomorphology and function. HFD-pairfat mice had a comparable improvement in insulin sensitivity, without changes in islets physiology or intestinal gluconeogenesis. Remarkably, both HFD-Leu and HFD-pairfat mice had decreased hepatic lipid content, which likely helped improve insulin sensitivity. In contrast, when leucine was supplemented to already obese animals, no changes in body weight, body composition or glucose metabolism were observed. CONCLUSIONS/SIGNIFICANCE These findings suggest that leucine improves insulin sensitivity in HFD-fed mice by primarily decreasing adiposity, rather than directly acting on peripheral target organs. However, beneficial effects of leucine on intestinal gluconeogenesis and islets of Langerhans's physiology might help prevent type 2 diabetes development. Differently, metabolic benefit of leucine supplementation is lacking in already obese animals, a phenomenon possibly related to the extent of the obesity before starting the supplementation.

Oleoylethanolamide enhances β-adrenergic-mediated thermogenesis and white-to-brown adipocyte phenotype in epididymal white adipose tissue in rat.

β-adrenergic receptor activation promotes brown adipose tissue (BAT) β-oxidation and thermogenesis by burning fatty acids during uncoupling respiration. Oleoylethanolamide (OEA) can inhibit feeding and stimulate lipolysis by activating peroxisome proliferator-activating receptor-α (PPARα) in white adipose tissue (WAT). Here we explore whether PPARα activation potentiates the effect of β3-adrenergic stimulation on energy balance mediated by the respective agonists OEA and CL316243. The effect of this pharmacological association on feeding, thermogenesis, β-oxidation, and lipid and cholesterol metabolism in epididymal (e)WAT was monitored. CL316243 (1 mg/kg) and OEA (5 mg/kg) co-administration over 6 days enhanced the reduction of both food intake and body weight gain, increased the energy expenditure and reduced the respiratory quotient (VCO2/VO2). This negative energy balance agreed with decreased fat mass and increased BAT weight and temperature, as well as with lowered plasma levels of triglycerides, cholesterol, nonessential fatty acids (NEFAs), and the adipokines leptin and TNF-α. Regarding eWAT, CL316243 and OEA treatment elevated levels of the thermogenic factors PPARα and UCP1, reduced p38-MAPK phosphorylation, and promoted brown-like features in the white adipocytes: the mitochondrial (Cox4i1, Cox4i2) and BAT (Fgf21, Prdm16) genes were overexpressed in eWAT. The enhancement of the fatty-acid β-oxidation factors Cpt1b and Acox1 in eWAT was accompanied by an upregulation of de novo lipogenesis and reduced expression of the unsaturated-fatty-acid-synthesis enzyme gene, Scd1. We propose that the combination of β-adrenergic and PPARα receptor agonists promotes therapeutic adipocyte remodelling in eWAT, and therefore has a potential clinical utility in the treatment of obesity.

Metabolomic profiles of hepatocellular carcinoma in a European prospective cohort.

BACKGROUND Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer, is difficult to diagnose and has limited treatment options with a low survival rate. Aside from a few key risk factors, such as hepatitis, high alcohol consumption, smoking, obesity, and diabetes, there is incomplete etiologic understanding of the disease and little progress in identification of early risk biomarkers. METHODS To address these aspects, an untargeted nuclear magnetic resonance metabolomic approach was applied to pre-diagnostic serum samples obtained from first incident, primary HCC cases (n = 114) and matched controls (n = 222) identified from amongst the participants of a large European prospective cohort. RESULTS A metabolic pattern associated with HCC risk comprised of perturbations in fatty acid oxidation and amino acid, lipid, and carbohydrate metabolism was observed. Sixteen metabolites of either endogenous or exogenous origin were found to be significantly associated with HCC risk. The influence of hepatitis infection and potential liver damage was assessed, and further analyses were made to distinguish patterns of early or later diagnosis. CONCLUSION Our results show clear metabolic alterations from early stages of HCC development with application for better etiologic understanding, prevention, and early detection of this increasingly common cancer.