Oxylipin status, before and after LC n-3 PUFA supplementation, has little relationship with skeletal muscle biology in older adults at risk of sarcopenia.

INTRODUCTION: Oxylipins form endogenously via the oxygenation of long-chain polyunsaturated fatty acids (LC PUFA). Several oxylipins are highly bioactive molecules and are believed to be key mediators of LC PUFA metabolism in the body. However, little is known in relation to whether oxylipins mediate alterations in skeletal muscle mass and function. The objective of this study was to determine if a relationship exists between the oxylipin profile and skeletal muscle biology in healthy older adults at risk of sarcopenia and determine if this changes in response to LC n-3 PUFA supplementation. MATERIALS AND METHODS: This exploratory study investigated the baseline correlations between LC n-3, n-6 and n-9 PUFA-derived oxylipins and markers of muscle biology. For this, the concentration of 79 free (i.e., non-esterified) oxylipins was quantified in human plasma by liquid chromatography-mass spectrometry (LC-MS) and retrospectively correlated to phenotypic outcomes obtained pre-intervention from the NUTRIMAL study (n = 49). After examining the baseline relationship, the potential effect of supplementation (LC n-3 PUFA or an isoenergetic control made of high-oleic sunflower and corn oil) was evaluated by correlating the change in oxylipins concentration and the change in markers of skeletal muscle biology. The relationship between oxylipins pre- and post-intervention and their parent PUFA were also examined. RESULTS: At baseline, the hydroxy product of mead acid (n-9 PUFA), 5-HETrE, was negatively correlated to the phenotypic parameters appendicular lean mass index (ALMI) (p = 0.003, r=-0.41), skeletal muscle mass index (SMMI) (p = 0.001, r=-0.46), handgrip strength (HGS) (p<0.001, r = 0.48) and isometric knee extension (p<0.001, r=-0.48). Likewise, LC n-6 PUFA hydroxy­PUFA were negatively correlated to HGS (i.e., 12-HETrE, p = 0.002, r=-0.42, and 5- and 11-HETE, p = 0.006, r=-0.47 and p<0.001, r=-0.50 respectively), single leg stand time (i.e., 12-HETrE, p = 0.006, r=-0.39 and 16-HETE, p = 0.002, r=-0.43), and five-time-sit-to-stand test (FTST) performance (16-HETE, p = 0.006, r = 0.39), and positively correlated to gait speed (i.e., 12-HETrE, p = 0.007, r = 0.38 and 16-HETE, p = 0.006, r = 0.39). LC n-3 PUFA supplementation increased eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) derived oxylipins and reduced n-6 PUFA derived oxylipins. Parameters of skeletal muscle mass and strength were not significantly altered in either LC n-3 PUFA or placebo groups. Changes in plasma oxylipins concentrations were closely related to changes in their parent PUFA, assessed in the erythrocyte membrane, but were not associated with any changes in skeletal muscle parameters. DISCUSSION AND CONCLUSION: At baseline, the status n-9 (5-HETrE) and n-6 PUFA derivates [12-HETrE, and 5-, 11- and 16-HETE], but not n-3 PUFA derived oxylipins, were associated with poor skeletal muscle health parameters (i.e., mass and strength). However, these correlations were no longer present when correlating relative changes from pre to post timepoints. An independent cohort validation is needed to explore baseline correlations further. Further research is warranted to assess other biological mechanisms by which LC n-3 PUFA might affect muscle biology.

Inflammation and metabolism: the role of adiposity in sarcopenic obesity.

Sarcopenic obesity is characterised by the double burden of diminished skeletal muscle mass and the presence of excess adiposity. From a mechanistic perspective, both obesity and sarcopenia are associated with sub-acute, chronic pro-inflammatory states that impede metabolic processes, disrupting adipose and skeletal functionality, which may potentiate disease. Recent evidence suggests that there is an important cross-talk between metabolism and inflammation, which has shifted focus upon metabolic-inflammation as a key emerging biological interaction. Dietary intake, physical activity and nutritional status are important environmental factors that may modulate metabolic-inflammation. This paradigm will be discussed within the context of sarcopenic obesity risk. There is a paucity of data in relation to the nature and the extent to which nutritional status affects metabolic-inflammation in sarcopenic obesity. Research suggests that there may be scope for the modulation of sarcopenic obesity with alterations in diet. The potential impact of increasing protein consumption and reconfiguration of dietary fat composition in human dietary interventions are evaluated. This review will explore emerging data with respect to if and how different dietary components may modulate metabolic-inflammation, particularly with respect to adiposity, within the context of sarcopenic obesity.

Identification of a plasma signature of psychotic disorder in children and adolescents from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort.

The identification of an early biomarker of psychotic disorder is important as early treatment is associated with improved patient outcome. Metabolomic and lipidomic approaches in combination with multivariate statistical analysis were applied to identify plasma alterations in children (age 11) (38 cases vs 67 controls) and adolescents (age 18) (36 cases vs 117 controls) preceeding or coincident with the development of psychotic disorder (PD) at age 18 in the Avon Longitudinal Study of Parents and Children (ALSPAC). Overall, 179 lipids were identified at age 11, with 32 found to be significantly altered between the control and PD groups. Following correction for multiple comparisons, 8 of these lipids remained significant (lysophosphatidlycholines (LPCs) LPC(18:1), LPC(18:2), LPC(20:3); phosphatidlycholines (PCs) PC(32:2; PC(34:2), PC(36:4), PC(0-34-3) and sphingomyelin (SM) SM(d18:1/24:0)), all of which were elevated in the PD group. At age 18, 23 lipids were significantly different between the control and PD groups, although none remained significant following correction for multiple comparisons. In conclusion, the findings indicate that the lipidome is altered in the blood during childhood, long before the development of psychotic disorder. LPCs in particular are elevated in those who develop PD, indicating inflammatory abnormalities and altered phospholipid metabolism. These findings were not found at age 18, suggesting there may be ongoing alterations in the pathophysiological processes from prodrome to onset of PD.

Clustering high-dimensional mixed data to uncover sub-phenotypes: joint analysis of phenotypic and genotypic data.

The LIPGENE-SU.VI.MAX study, like many others, recorded high-dimensional continuous phenotypic data and categorical genotypic data. LIPGENE-SU.VI.MAX focuses on the need to account for both phenotypic and genetic factors when studying the metabolic syndrome (MetS), a complex disorder that can lead to higher risk of type 2 diabetes and cardiovascular disease. Interest lies in clustering the LIPGENE-SU.VI.MAX participants into homogeneous groups or sub-phenotypes, by jointly considering their phenotypic and genotypic data, and in determining which variables are discriminatory. A novel latent variable model that elegantly accommodates high dimensional, mixed data is developed to cluster LIPGENE-SU.VI.MAX participants using a Bayesian finite mixture model. A computationally efficient variable selection algorithm is incorporated, estimation is via a Gibbs sampling algorithm and an approximate BIC-MCMC criterion is developed to select the optimal model. Two clusters or sub-phenotypes ('healthy' and 'at risk') are uncovered. A small subset of variables is deemed discriminatory, which notably includes phenotypic and genotypic variables, highlighting the need to jointly consider both factors. Further, 7 years after the LIPGENE-SU.VI.MAX data were collected, participants underwent further analysis to diagnose presence or absence of the MetS. The two uncovered sub-phenotypes strongly correspond to the 7-year follow-up disease classification, highlighting the role of phenotypic and genotypic factors in the MetS and emphasising the potential utility of the clustering approach in early screening. Additionally, the ability of the proposed approach to define the uncertainty in sub-phenotype membership at the participant level is synonymous with the concepts of precision medicine and nutrition. Copyright © 2017 John Wiley & Sons, Ltd.

Dietary fat may modulate adipose tissue homeostasis through the processes of autophagy and apoptosis.

PURPOSE: Obesity increases the risk of cardiovascular disease, type 2 diabetes mellitus and cancer development. Autophagy and apoptosis are critical processes for development and homeostasis in multicellular organisms and have been linked to a variety of disorders. We aimed to investigate whether the quantity and quality of dietary fat can influence these processes in the adipose tissue of obese people. METHODS: A randomized, controlled trial within the LIPGENE study assigned 39 obese people with metabolic syndrome to 1 of 4 diets: (a) a high-saturated fatty acid diet, (b) a high-monounsaturated fatty acid (HMUFA) diet, and (c, d) two low-fat, high-complex carbohydrate diets supplemented with long-chain n-3 polyunsaturated fatty acids (LFHCC n-3) or placebo (LFHCC), for 12 weeks each. RESULTS: We found an increase in the expression of autophagy-related BECN1 and ATG7 genes after the long-term consumption of the HMUFA diet (p = 0.001 and p = 0.004, respectively) and an increase in the expression of the apoptosis-related CASP3 gene after the long-term consumption of the LFHCC and LFHCC n-3 diets (p = 0.001 and p = 0.029, respectively). CASP3 and CASP7 gene expression changes correlated with HOMA index. CONCLUSION: Our results suggest that the processes of autophagy and apoptosis in adipose tissue may be modified by diet and that the consumption of a diet rich in monounsaturated fat may contribute to adipose tissue homeostasis by increasing autophagy. They also reinforce the notion that apoptosis in adipose tissue is linked to insulin resistance. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00429195.

Dietary isoflavone intake is associated with evoked responses to inflammatory cardiometabolic stimuli and improved glucose homeostasis in healthy volunteers.

BACKGROUND AND AIMS: Consumption of foods that modulate inflammatory stress in genetically-prone individuals may influence development of cardiometabolic diseases. Isoflavones in soy-derived foods function as phytoestrogens, have antioxidant and anti-inflammatory activity, inhibit protein-tyrosine kinase activity, and may be atheroprotective. We examined the relationship between soy food consumption and inflammatory responses to endotoxemia, postprandial responses to oral lipid tolerance test (OLTT), and insulin sensitivity from frequently sampled intravenous tolerance tests (FSIGTT). METHODS AND RESULTS: We administered low-dose endotoxin (LPS 1 ng/kg) to induce transient endotoxemia in young, healthy volunteers (N = 215) of African (AA), and European (EA) ancestry as part of the GENE Study. We further supported these findings in two independent samples: the MECHE Study and NHANES. Soy food consumption was a significant predictor of peak cytokine response following LPS. Individuals with moderate-high (>1.48 mg/day, N = 65) vs. low-no (<1.48 mg/day, N = 150) isoflavone consumption had significantly higher tumor necrosis factor alpha (TNFα) post-LPS (AUC, P = 0.009). Further, high-isoflavone consumers were protected against inflammation-induced decline in insulin sensitivity (SI) in GENE. We observed significant differences by soy consumption in the interferon gamma (IFNγ) response to OLTT, and the insulin response to OGTT in MECHE, as well as significantly lower fasting insulin, and 2-hour glucose post-OGTT in EA NHANES subjects. CONCLUSION: We demonstrate that soy consumption may influence inflammatory and metabolic responses. In research of nutritional exposures, measuring evoked phenotypes may be more informative than describing resting characteristics. The GENE Study was registered under NCT00953667 and the MECHE Study under NCT01172951, both at clinicaltrials.gov.

Habitual dietary intake impacts on the lipidomic profile.

Reliable dietary assessments are essential when attempting to understand the complex links between diet and health. Traditional methods for collecting dietary exposure can be unreliable, therefore there is an increasing interest in identifying biomarkers to provide a more accurate measurement. Metabolomics is a technology that offers great promise in this area. The aim of this study was to use a multivariate statistical strategy to link lipidomic patterns with dietary data in an attempt to identify dietary biomarkers. We assessed the relationship between lipidomic profiles and dietary data in volunteers (n=34) from the Metabolic Challenge Study (MECHE). Principal component analysis (PCA), linear regression and receiver operating characteristic (ROC) analysis were used to (1) reduce the lipidomic data into lipid patterns (LPs), (2) investigate relationships between these patterns and dietary data and (3) identify biomarkers of dietary intake. Our study identified a total of 6 novel LPs. LP1 was highly predictive of dietary fat intake (area under the curve AUC=0.82). A random forest (RF) classification model used to discriminate between low and high consumers resulted with an error rate of >10%, with a panel of six metabolites identified as the most predictive. LP4 was highly predictive of alcohol intake (AUC=0.81) with lysophosphatidylcholine alkyl C18:0 (LPCeC18:0) identified as a potential biomarker of alcohol consumption. LP6 had a reasonably good ability to predict dietary fish intake (AUC=0.76), with lysophosphatidylethanolamine acyl C18:2 (LPEaC18:2) phoshatidylethanolamine diaclyl C38:4 (PEaaC38:4) identified as potential biomarkers. The identification of these LPs and specific biomarkers will help in better classifying a persons dietary intake and in turn will improve the assessment of the relationship between diet and disease. Linking these LPs and specific biomarkers with health parameters will be an important future step.

Leucocytosis in women with polycystic ovary syndrome (PCOS) is incompletely explained by obesity and insulin resistance.

OBJECTIVES: Low-grade chronic inflammation predicts cardiovascular outcomes and is observed in women with polycystic ovary syndrome (PCOS). Whether this is entirely a cause or consequence of insulin resistance (IR) is unknown. METHODS: Seventy pairs of women with and without PCOS, matched for age, body mass index (BMI) and IR (HOMA, QUICKI and Avignon index), were generated from a larger cohort of 103 women with and 104 BMI-matched women without PCOS. Women with PCOS were studied in the follicular phase of the menstrual cycle. White cell count (WCC), high-sensitivity CRP (hsCRP) and a series of 12 cytokines and growth factors were measured. These inflammatory markers were also compared between women with PCOS and 10 normal women studied in the follicular, peri-ovulatory and luteal stages. RESULTS: When all subjects were compared, WCC (6.75 × 10(9) vs 5.60 × 10(9 ) g/l, P < 0.005), hsCRP (4.04 vs 2.90 mg/l, P < 0.05) and IL-6 (1.11 vs 0.72 pg/ml, P < 0.05) were greater in women with PCOS. Pair-matching for IR eliminated between-group differences in hsCRP and cytokines but did not alter the difference in WCC (6.60 × 10(9) vs 5.60 × 10(9 ) g/l, P < 0.005). WCC was greater in PCOS compared to normal women at all stages of the menstrual cycle. CONCLUSIONS: Low-grade inflammation occurs in PCOS. Increased hsCRP and cytokines are associated with IR, but increased WCC is observed even when IR is accounted for. The explanation for this and its clinical significance is unknown.

A gene variation (rs12691) in the CCAT/enhancer binding protein α modulates glucose metabolism in metabolic syndrome.

BACKGROUND AND AIMS: CCAAT/enhancer-binding protein alpha (CEBPA) is a transcription factor involved in adipogenesis and energy homeostasis. Caloric restriction reduces CEBPA protein expression in patients with metabolic syndrome (MetS). A previous report linked rs12691 SNP in CEBPA to altered concentration of fasting triglycerides. Our objective was to assess the effects of rs12691 in glucose metabolism in Metabolic Syndrome (MetS) patients. METHODS AND RESULTS: Glucose metabolism was assessed by static (glucose, insulin, adiponectin, leptin and resistin plasma concentrations) and dynamic (disposition index, insulin sensitivity index, HOMA-IR and acute insulin response to glucose) indices, performed at baseline and after 12 weeks of 4 dietary interventions (high saturated fatty acid (SFA), high monounsaturated fatty acid (MUFA), low-fat and low-fat-high-n3 polyunsaturated fatty acid (PUFA)) in 486 subjects with MetS. Carriers of the minor A allele of rs12691 had altered disposition index (p = 0.0003), lower acute insulin response (p = 0.005) and a lower insulin sensitivity index (p = 0.025) indicating a lower insulin sensitivity and a lower insulin secretion, at baseline and at the end of the diets. Furthermore, A allele carriers displayed lower HDL concentration. CONCLUSION: The presence of the A allele of rs12691 influences glucose metabolism of MetS patients.

Expression of perilipins in human skeletal muscle in vitro and in vivo in relation to diet, exercise and energy balance.

The perilipin proteins enclose intracellular lipid droplets. We describe the mRNA expression of the five perilipins in human skeletal muscle in relation to fatty acid supply, exercise and energy balance. We observed that all perilipins were expressed in skeletal muscle biopsies with the highest mRNA levels of perilipin 2, 4 and 5. Cultured myotubes predominantly expressed perilipin 2 and 3. In vitro, incubation of myotubes with fatty acids enhanced mRNA expression of perilipin 1, 2 and 4. In vivo, low fat diet increased mRNA levels of perilipin 3 and 4. Endurance training, but not strength training, enhanced the expression of perilipin 2 and 3. Perilipin 1 mRNA correlated positively with body fat mass, whereas none of the perilipins were associated with insulin sensitivity. In conclusion, all perilipins mRNAs were expressed in human skeletal muscle. Diet as well as endurance exercise modulated the expression of perilipins.

Pleiotropic effects of TCF7L2 gene variants and its modulation in the metabolic syndrome: from the LIPGENE study.

AIMS/HYPOTHESIS: Variants of the TCF7L2 gene predict the development of type 2 diabetes mellitus (T2DM). We investigated the associations between gene variants of TCF7L2 and clinical features of the metabolic syndrome (MetS) (an entity often preceding T2DM), and their interaction with non-genetic factors, including plasma saturated fatty acids (SFA) concentration and insulin resistance (IR). METHODS: Fasting lipid profiles, insulin sensitivity, insulin secretion, anthropometrics, blood pressure and 10 gene variations of the TCF7L2 gene were determined in 450 subjects with MetS. RESULTS: Several single nucleotide polymorphisms (SNP) showed phenotypic associations independent of SFA or IR. Carriers of the rare T allele of rs7903146, and of three other SNPs in linkage disequilibrium with rs7903146, had lower blood pressure and insulin secretion. High IR and the presence of the T-allele of rs7903146 acted synergistically to define those with reduced insulin secretion. Carriers of the minor allele of rs290481 exhibited an altered lipid profile, with increased plasma levels of apolipoprotein B, non-esterified fatty acids, cholesterol and apolipoprotein B in triglyceride rich lipoproteins, and LDL cholesterol. Carriers of the minor allele of rs11196224 that had higher plasma SFA levels showed elevated procoagulant/proinflammatory biomarkers, impaired insulin secretion and increased IR, whereas carriers of the minor allele of rs17685538 with high plasma SFA levels exhibited higher blood pressure. CONCLUSIONS/INTERPRETATION: SNP in the TCF7L2 gene are associated with differences in insulin secretion, blood pressure, blood lipids and coagulation in MetS patients, and may be modulated by SFA in plasma or IR.

Effects of dietary fat modification on insulin sensitivity and on other risk factors of the metabolic syndrome--LIPGENE: a European randomized dietary intervention study.

BACKGROUND: Excessive energy intake and obesity lead to the metabolic syndrome (MetS). Dietary saturated fatty acids (SFAs) may be particularly detrimental on insulin sensitivity (SI) and on other components of the MetS. OBJECTIVE: This study determined the relative efficacy of reducing dietary SFA, by isoenergetic alteration of the quality and quantity of dietary fat, on risk factors associated with MetS. DESIGN: A free-living, single-blinded dietary intervention study. SUBJECTS AND METHODS: MetS subjects (n = 417) from eight European countries completed the randomized dietary intervention study with four isoenergetic diets distinct in fat quantity and quality: high-SFA; high-monounsaturated fatty acids and two low-fat, high-complex carbohydrate (LFHCC) diets, supplemented with long chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs) (1.2 g per day) or placebo for 12 weeks. SI estimated from an intravenous glucose tolerance test (IVGTT) was the primary outcome measure. Lipid and inflammatory markers associated with MetS were also determined. RESULTS: In weight-stable subjects, reducing dietary SFA intake had no effect on SI, total and low-density lipoprotein cholesterol concentration, inflammation or blood pressure in the entire cohort. The LFHCC n-3 PUFA diet reduced plasma triacylglycerol (TAG) and non-esterified fatty acid concentrations (P < 0.01), particularly in men. CONCLUSION: There was no effect of reducing SFA on SI in weight-stable obese MetS subjects. LC n-3 PUFA supplementation, in association with a low-fat diet, improved TAG-related MetS risk profiles.

Increased levels of microparticles originating from endothelial cells, platelets and erythrocytes in subjects with metabolic syndrome: relationship with oxidative stress.

BACKGROUND AND AIMS: The Metabolic Syndrome (MetS) is associated with increased cardiovascular risk. Circulating microparticles (MP) are involved in the pathogenesis of atherothrombotic disorders and are raised in individual with CVD. We measured their level and cellular origin in subjects with MetS and analyzed their associations with 1/anthropometric and biological parameters of MetS, 2/inflammation and oxidative stress markers. METHODS AND RESULTS: Eighty-eight subjects with the MetS according to the NCEP-ATPIII definition were enrolled in a bicentric study and compared to 27 healthy controls. AnnexinV-positive MP (TMP), MP derived from platelets (PMP), erythrocytes (ErMP), endothelial cells (EMP), leukocytes (LMP) and granulocytes (PNMP) were determined by flow cytometry. MetS subjects had significantly higher counts/µl of TMP (730.6±49.7 vs 352.8±35.6), PMP (416.0±43.8 vs 250.5±23.5), ErMP (243.8±22.1 vs 73.6±19.6) and EMP (7.8±0.8 vs 4.0±1.0) compared with controls. LMP and PNMP were not statistically different between groups. Multivariate analysis demonstrated that each criterion for the MetS influenced the number of TMP. Waist girth was a significant determinant of PMP and EMP level and blood pressure was correlated with EMP level. Glycemia positively correlated with PMP level whereas dyslipidemia influenced EMP and ErMP levels. Interestingly, the oxidative stress markers, plasma glutathione peroxydase and urinary 8-iso-prostaglandin F(2) α, independently influenced TMP and PMP levels whereas inflammatory markers did not, irrespective of MP type. CONCLUSION: Increased levels of TMP, PMP, ErMP and EMP are associated with individual metabolic abnormalities of MetS and oxidative stress. Whether MP assessment may represent a marker for risk stratification or a target for pharmacological intervention deserves further investigation.

Lipoprotein subclass patterns in women with polycystic ovary syndrome (PCOS) compared with equally insulin-resistant women without PCOS.

OBJECTIVES: Women with polycystic ovary syndrome (PCOS) are more insulin resistant and display an atherogenic lipid profile compared with normal women of similar body mass index (BMI). Insulin resistance (IR) at least partially underlies the dyslipidemia of PCOS, but it is unclear whether PCOS status per se confers additional risk. RESEARCH DESIGN AND METHODS: Using a case-control design, we compared plasma lipids and lipoprotein subclasses (using polyacrylamide gel tube electrophoresis) in 70 women with PCOS (National Institutes of Health criteria) and 70 normal women pair matched for age, BMI, and IR (homeostasis model assessment-IR, quantitative insulin sensitivity check index, and the Avignon Index). Subjects were identified as having a (less atherogenic) type A pattern consisting predominantly of large low-density lipoprotein (LDL) subfractions or a (more atherogenic) non-A pattern consisting predominantly of small-dense LDL subfractions. RESULTS: Total, high-density lipoprotein, or LDL cholesterol, or triacylglycerol did not differ between the groups, but very low-density lipoprotein levels (P<0.05) were greater in women with PCOS, whereas a non-A LDL profile was seen in 12.9% compared with 2.9% of controls (P<0.05, chi2). Multiple regression analysis revealed homeostasis model assessment-IR and waist circumference to be independent predictors of very low-density lipoprotein together explaining 40.2% of the overall variance. Logistic regression revealed PCOS status to be the only independent determinant of a non-A LDL pattern (odds ratio 5.48 (95% confidence interval 1.082-27.77; P<0.05). CONCLUSIONS: Compared with women matched for BMI and IR, women with PCOS have potentially important differences in lipid profile with greater very low-density lipoprotein levels and increased rates of a more atherogenic non-A LDL pattern.

Conjugated linoleic acid and inflammatory cell signalling.

Conjugated linoleic acids (CLA) are a family of polyunsaturated fatty acids (PUFA), some isomers occurring naturally in beef and dairy products and others being formed as a result of bihydrogenation of vegetable oils to form margarine. Synthetic and natural sources of CLA may have beneficial effects in a range of inflammatory conditions including colitis, atherosclerosis, metabolic syndrome and rheumatoid arthritis. Most of the biological effects have been attributed to the cis9, trans11- (c9, t11-) and the trans10, cis12- (t10, c12-) isomers. Evidence suggests that c9, t11-CLA is responsible for the anti-inflammatory effect attributed to CLA while t10, t12-CLA appears to be responsible for anti-adipogenic effects. This review will focus on the effects of CLA on the inflammatory components associated with insulin resistance, atherosclerosis and Th1 mediated inflammatory disease, at a cellular, systemic and clinical level. Whist CLA may ameliorate certain aspects of the inflammatory response, particularly within cellular and animal models, the relevance of this has yet to be clarified within the context of human health.

Effects of dietary fat modification on skeletal muscle fatty acid handling in the metabolic syndrome.

OBJECTIVE: In the metabolic syndrome (MetS), increased fat storage in 'nonadipose' tissues such as skeletal muscle may be related to insulin resistance ('lipid overflow' hypothesis). The objective of this study was to examine the effects of dietary fat modification on the capacity of skeletal muscle to handle dietary and endogenous fatty acids (FAs). SUBJECTS AND METHODS: In total, 29 men with the MetS were randomly assigned to one of four diets for 12 weeks: a high-fat saturated fat diet (HSFA, n=6), a high-fat monounsaturated fat diet (HMUFA, n=7) and two low-fat high-complex carbohydrate diets supplemented with (LFHCCn-3, n=8) or without (LFHCC, n=8) 1.24 g per day docosahexaenoic and eicosapentaenoic acid. Fasting and postprandial skeletal muscle FA handling was examined by measuring arteriovenous concentration differences across the forearm muscle. [(2)H(2)]-palmitate was infused intravenously to label endogenous triacylglycerol (TAG) and free fatty acids in the circulation and subjects received a high-fat mixed meal (2.6 MJ, 61 energy% fat) containing [U-(13)C]-palmitate to label chylomicron-TAG. RESULTS: Postprandial circulating TAG concentrations were significantly lower after dietary intervention in the LFHCCn-3 group compared to the HSFA group (DeltaiAUC -139+/-67 vs 167+/-70 micromol l(-1) min(-1), P=0.009), together with decreased concentrations of [U-(13)C]-labeled TAG, representing dietary FA. Fasting TAG clearance across forearm muscle was decreased on the HSFA diet, whereas no differences were observed in postprandial forearm muscle FA handling between diets. CONCLUSION: Chronic manipulation of dietary fat quantity and quality did not affect forearm muscle FA handling in men with the MetS. Postprandial TAG concentrations decreased on the LFHCCn-3 diet, which could be (partly) explained by lower concentration of dietary FA in the circulation.

High-molecular-weight adiponectin is selectively reduced in women with polycystic ovary syndrome independent of body mass index and severity of insulin resistance.

CONTEXT: High-molecular-weight (HMW) adiponectin contributes to insulin resistance (IR), which is closely associated with the pathophysiology of polycystic ovary syndrome (PCOS). Abnormalities in adipocyte function have been identified in PCOS and potentially contribute to lower adiponectin concentrations. OBJECTIVE: Our objective was to determine which variables in plasma and adipose tissue influence HMW adiponectin in a well characterized cohort of women with PCOS. DESIGN: This was a cross-sectional study. SETTINGS AND PARTICIPANTS: A teaching hospital. Women with PCOS (n = 98) and body mass index (BMI)-matched controls (n = 103) (including 68 age-, BMI-, and IR-matched pairs). INTERVENTIONS: A standard 75-g oral glucose tolerance test was performed for each participant. Subcutaneous adipose tissue samples were taken by needle biopsy for a subset of PCOS women (n = 9) and controls (n = 8). MAIN OUTCOME MEASURES: Serum levels of HMW adiponectin and their relation to indices of insulin sensitivity, body composition, and circulating androgens as well as adipose tissue expression levels of ADIPOQ, TNFalpha, PPARgamma, and AR were assessed. RESULTS: HMW adiponectin was significantly lower in women with PCOS compared with both BMI- and BMI- and IR-matched controls (P = 0.009 and P = 0.027, respectively). Although BMI and IR were the main predictors of HMW adiponectin, an interaction between waist to hip ratio and plasma testosterone contributed to its variance (P = 0.026). Adipose tissue gene expression analysis demonstrated that AR and TNFalpha (P = 0.008 and P = 0.035, respectively) but not ADIPOQ mRNA levels were increased in PCOS compared with controls. CONCLUSIONS: HMW adiponectin is selectively reduced in women with PCOS, independent of BMI and IR. Gene expression analysis suggests that posttranscriptional/translational modification contributes to reduced HMW adiponectin in PCOS.

Divergent mechanisms of cis9, trans11-and trans10, cis12-conjugated linoleic acid affecting insulin resistance and inflammation in apolipoprotein E knockout mice: a proteomics approach.

Conjugated linoleic acids (CLA) affect atherogenesis, but mechanisms are not well understood. We explored how two isomers of CLA, cis9, trans11-CLA and trans10, cis12-CLA, affected lipid and glucose metabolism, as well as hepatic protein expression, in apolipoprotein E knockout mice. After 12 wk of intervention, plasma triglyceride, NEFA, and glucose concentrations were significantly higher in the trans10, cis12-CLA group, whereas plasma triglyceride, NEFA, glucose, and insulin concentrations were significantly lower in the cis9, trans11-CLA group, compared with control mice consuming linoleic acid. Proteomics identified significant up- or down-regulation of 113 liver cytosolic proteins by either CLA isomer. Principal component analysis revealed that the treatment effect of cis9, trans11-CLA was mainly explained by the up-regulation of different posttranslational forms of heat shock protein 70 kD. In contrast, the treatment effect of trans10, cis12-CLA was mainly explained by up-regulation of key enzymes in the gluconeogenic, beta-oxidation, and ketogenesic pathways. Correlation analysis again emphasized the divergent effects of both CLA isomers on different pathways, but also revealed a linkage between insulin resistance and increased levels of hepatic serotransferrin. Thus, our systems biology approach provided novel insights into the mechanisms by which individual CLA isomers differentially affect pathways related to atherogenesis, such as insulin resistance and inflammation.

The effects of conjugated linoleic acid supplementation on immune function in healthy volunteers.

OBJECTIVE: To assess the effects of dietary supplementation using two isomeric blends of conjugated linoleic acid (CLA) on immune function in healthy human volunteers. DESIGN: Double-blind, randomised, placebo-controlled intervention trial. SUBJECTS AND INTERVENTION: A total of 55 healthy volunteers (n=20 males, n=35 females) were randomised into one of three study groups who received 3 g/day of a fatty acid blend containing a 50:50 cis-9, trans-11: trans-10, cis-12 CLA isomer blend (2 g CLA), and 80:20 cis-9, trans-11: trans-10, cis-12 (80:20) CLA isomer blend (1.76 g CLA) or linoleic acid (control, 2 g linoleic acid) for 8 weeks. RESULTS: Supplementation with the 80:20 CLA isomer blend significantly (P< or =0.05) enhanced PHA-induced lymphocyte proliferation. CLA decreased basal interleukin (IL)-2 secretion (P< or =0.01) and increased PHA-induced IL-2 and tumor necrosis factor alpha (TNF(alpha)) production (P< or =0.01). However, these effects were not solely attributable to CLA as similar results were observed with linoleic acid. CLA supplementation had no significant effect on peripheral blood mononuclear cells IL-4 production, or on serum-soluble intercellular adhesion molecule-1 (sICAM-1) or plasma prostaglandin E2 (PGE2) or leukotreine B4 (LTB4) concentrations. CONCLUSIONS: This study shows that CLA supplementation had a minimal effect on the markers of human immune function. Furthermore, supplementation with CLA had no immunological benefit compared with linoleic acid.