An Oral Mixed Fat Load Is Followed by a Modest Anti-inflammatory Adipocytokine Response in Overweight Patients with Metabolic Syndrome

We investigated the postprandial changes in plasma levels of adipocytokines in overweight patients with metabolic syndrome after an oral fat load. After an oral fat load and during a prolonged fast, blood was drawn at 0, 2, 3, 4 and 8 h for measurement of adiponectin, adipsin, cathepsin S, chemerin, hepatic growth factor, interferon‐γ‐inducible protein‐10, leptin, macrophage chemoattractant protein‐1, macrophage migration inhibitory factor, nerve growth factor, retinol binding protein‐4, resistin, serum amyloid A1, tissue inhibitor of metalloproteinase‐1 and thrombopoietin using a microbead‐based Luminex assay. Area under the curves (AUC) were calculated and compared. Plasma adiponectin levels were higher after an oral fat load compared to fasting at t = 2 h (950 ± 513 vs. ?1,881 ± 713 ng/ml) while the plasma levels for adipsin (?9 ± 5 vs. 16 ± 5 ng/ml), chemerin (?122 ± 35 vs. 13 ± 21 ng/ml), SAA‐1 (?391 ± 213 vs. 522 ± 173 ng/ml) and TPO (?335 ± 144 vs. 622 ± 216 ng/ml) were lower after an oral fat load compared to fasting. The baseline corrected AUC for IP‐10 was higher after fat load compared to fasting (median ?116 pg h/ml; IQR ?270 to 10 vs. ?21 pg h/ml; IQR ?136 to 418 (p = 0.047). In conclusion, in overweight male subjects with the metabolic syndrome, an oral fat load is accompanied with a modest anti‐inflammatory response of adipose tissue‐derived adipocytokines.     

Relationships between Very Low-Density Lipoproteins–Ceramides, −Diacylglycerols,and –Triacylglycerols in Insulin-Resistant Men

This short report describes the relationships between concentrations of ceramides (CER), diacylglycerols (DAG), triacylglycerols (TAG) in very low-density lipoproteins (VLDL) particles, and hepatic lipid accumulation. VLDL particles were isolated from male subjects (n = 12, mean ± SD, age 42.1 ± 5.4 years, BMI 37.4 ± 4.1 kg/m², ALT 45 ± 21 U/L) and apolipoprotein B100 (apoB100), VLDL-TAG, -CER, and -DAG quantified. The contents of all three lipids were highly correlated with VLDL particle number (r ≥ 0.768, p ≤ 0.003). The molar quantity of VLDL-TAG was 3× that of DAG and 137× that of CER (14,053 ± 5714, 5004 ± 2714, and 105 ± 49 mol/mol apoB100, respectively). Reduced VLDL-CER concentrations were associated with both higher insulin levels (r = −0.645, p = 0.024) and intrahepatic-TAG (r = −0.670, p = 0.017). In fatty liver, the secretion of hepatic TAG, CER, and DAG may be suppressed and contribute to intrahepatic lipotoxicity. The mechanisms by which hepatic-CER and -DAG synthesis and assembly into VLDL is coordinately controlled with TAG will be important in understanding the emerging role of elevated CER contributing to cardiometabolic disease.     

Lipidomic Profiling of Chylomicron Triacylglycerols in Response to High Fat Meals

Using lipidomic methodologies the impact that meal lipid composition and metabolic syndrome (MetS) exerts on the postprandial chylomicron triacylglycerol (TAG) response was examined. Males (9 control; 11 MetS) participated in a randomised crossover trial ingesting two high fat breakfast meals composed of either dairy-based foods or vegetable oil-based foods. The postprandial lipidomic molecular composition of the TAG in the chylomicron-rich (CM) fraction was analysed with tandem mass spectrometry coupled with liquid chromatography to profile CM TAG species and targeted TAG regioisomers. Postprandial CM TAG concentrations were significantly lower after the dairy-based foods compared with the vegetable oil-based foods for both control and MetS subjects. The CM TAG response to the ingested meals involved both significant and differential depletion of TAG species containing shorter- and medium-chain fatty acids (FA) and enrichment of TAG molecular species containing C16 and C18 saturated, monounsaturated and diunsaturated FA. Furthermore, there were significant changes in the TAG species between the food TAG and CM TAG and between the 3- and 5-h postprandial samples for the CM TAG regioisomers. Unexpectedly, the postprandial CM TAG concentration and CM TAG lipidomic responses did not differ between the control and MetS subjects. Lipidomic analysing of CM TAG molecular species revealed dynamic changes in the molecular species of CM TAG during the postprandial phase suggesting either preferential CM TAG species formation and/or clearance.     

Atorvastatin Decreases Triacylglycerol-Associated Risk of Vascular Events in Coronary Heart Disease Patients

High triacylglycerol (TAG) levels may predict vascular risk. The effect of a statin-induced reduction in TAG levels, irrespective of HDL-C increase, on clinical outcome has not yet been addressed by an endpoint study in patients with coronary heart disease (CHD). The GREACE study compared usual with structured care aimed at achieving LDL-C = 100 mg/dL (2.6 mmol/L) by dose titration with atorvastatin. All patients had CHD and were followed for 3 years. This post hoc analysis of GREACE examines the effect of statins on TAG levels and their relation with cardiovascular disease (CVD) events in all patients and in the subgroup of patients with metabolic syndrome (MetS). Baseline TAG levels >150 mg/dL (1.7 mmol/L) were predictive of subsequent CVD events [cardiac mortality, non-fatal myocardial infarction (MI), unstable angina (UA), revascularisation, congestive heart failure (CHF), and stroke] only in statin untreated patients. Stepwise regression analysis showed that with every 20% statin-related TAG reduction there was a decrease in CVD risk by 12% (HR 0.88, 95% CI 0.75–0.95, P = 0.007) in the structured care group vs. the usual care group, by 8% (HR 0.92, 95% CI 0.81–0.97, P = 0.02) in all statin treated patients vs. the untreated ones and by 15% (HR 0.85, 95% CI 0.65–0.94, P = 0.005) in those with MetS treated with a statin vs. those untreated. Using the same analysis but only taking into consideration vascular events (cardiac mortality, non-fatal MI, UA, revascularisation, and stroke) there was a 18% (HR = 0.82, 95% CI 0.57–0.96, P = 0.03) decrease in risk in the MetS (+) patients treated with a statin vs. those not on a statin, and a decrease in risk by 16% (HR = 0.84, 95% CI 0.53–1.07, P = 0.08), when only hard vascular endpoints (cardiac mortality, non-fatal MI, and stroke) were considered. TAG levels are predictive of subsequent CVD events in statin untreated CHD patients. Statin (mainly atorvastatin)-induced decrease in TAG levels was related to a significant reduction in subsequent CVD events. This benefit was more pronounced in CHD MetS (+) patients.     

Comparison of Low Fat and Low Carbohydrate Diets on Circulating Fatty Acid Composition and Markers of Inflammation

Abnormal distribution of plasma fatty acids and increased inflammation are prominent features of metabolic syndrome. We tested whether these components of metabolic syndrome, like dyslipidemia and glycemia, are responsive to carbohydrate restriction. Overweight men and women with atherogenic dyslipidemia consumed ad libitum diets very low in carbohydrate (VLCKD) (1504 kcal:%CHO:fat:protein = 12:59:28) or low in fat (LFD) (1478 kcal:%CHO:fat:protein = 56:24:20) for 12 weeks. In comparison to the LFD, the VLCKD resulted in an increased proportion of serum total n-6 PUFA, mainly attributed to a marked increase in arachidonate (20:4n-6), while its biosynthetic metabolic intermediates were decreased. The n-6/n-3 and arachidonic/eicosapentaenoic acid ratio also increased sharply. Total saturated fatty acids and 16:1n-7 were consistently decreased following the VLCKD. Both diets significantly decreased the concentration of several serum inflammatory markers, but there was an overall greater anti-inflammatory effect associated with the VLCKD, as evidenced by greater decreases in TNF-α, IL-6, IL-8, MCP-1, E-selectin, I-CAM, and PAI-1. Increased 20:4n-6 and the ratios of 20:4n-6/20:5n-3 and n-6/n-3 are commonly viewed as pro-inflammatory, but unexpectedly were consistently inversely associated with responses in inflammatory proteins. In summary, a very low carbohydrate diet resulted in profound alterations in fatty acid composition and reduced inflammation compared to a low fat diet.     

Egg Consumption Modulates HDL Lipid Composition and Increases the Cholesterol-Accepting Capacity of Serum in Metabolic Syndrome

We recently demonstrated that daily whole egg consumption during moderate carbohydrate restriction leads to greater increases in plasma HDL-cholesterol (HDL-C) and improvements in HDL profiles in metabolic syndrome (MetS) when compared to intake of a yolk-free egg substitute. We further investigated the effects of this intervention on HDL composition and function, hypothesizing that the phospholipid species present in egg yolk modulate HDL lipid composition to increase the cholesterol-accepting capacity of subject serum. Men and women classified with MetS were randomly assigned to consume either three whole eggs (EGG, n = 20) per day or the equivalent amount of egg substitute (SUB, n = 17) throughout a 12-week moderate carbohydrate-restricted (25–30 % of energy) diet. Relative to other HDL lipids, HDL-cholesteryl ester content increased in all subjects, with greater increases in the SUB group. Further, HDL-triacylglycerol content was reduced in EGG group subjects with normal baseline plasma HDL-C, resulting in increases in HDL-CE/TAG ratios in both groups. Phospholipid analysis by mass spectrometry revealed that HDL became enriched in phosphatidylethanolamine in the EGG group, and that EGG group HDL better reflected sphingomyelin species present in the whole egg product at week 12 compared to baseline. Further, macrophage cholesterol efflux to EGG subject serum increased from baseline to week 12, whereas no changes were observed in the SUB group. Together, these findings suggest that daily egg consumption promotes favorable shifts in HDL lipid composition and function beyond increasing plasma HDL-C in MetS.     

Metabolic Syndrome: Effects of n-3 PUFAs on a Model of Dyslipidemia,Insulin Resistance and Adiposity

Both genetic and environmental factors (e.g. nutrition, life style) contribute to the development of the plurimetabolic syndrome, which has a high prevalence in the world population. Dietary n-3 PUFAs specially those from marine oil (EPA and DHA) appear to play an important role against the adverse effects of this syndrome. The present work examined the effectiveness of fish oil (FO) in reversing or improving the dyslipidemia, insulin resistance and adiposity induced in rats by long-term feeding a sucrose-rich diet (SRD). We studied several metabolic and molecular mechanisms involved in both lipid and glucose metabolisms in different tissues (liver, skeletal muscle, fat pad) as well as insulin secretion patterns from perifused islets under the stimulation of different secretagogues. Dietary FO reverses dyslipidemia and improves insulin action and adiposity in the SRD fed rats. FO reduces adipocytes cell size and thus, the smaller adipocytes are more insulin sensitive and the release of fatty acids decreases. In muscle, FO normalizes both the oxidative and non-oxidative glucose pathways. Moreover, FO modifies the fatty acid composition of membrane phospholipids. In isolated β cells, lipid contents and glucose oxidation return to normal. All these effects could contribute to the normalization of glucose-stimulated insulin secretion and muscle insulin insensitivity.     

N-3 Polyunsaturated Fatty Acids: Relationship to Inflammation in Healthy Adults and Adults Exhibiting Features of Metabolic Syndrome

Individuals with metabolic syndrome (MetS) have a higher risk of type 2 diabetes and cardiovascular disease, therefore, research has been directed at reducing various components that contribute to MetS and associated metabolic impairments, including chronic low-grade inflammation. Epidemiological, human, animal and cell culture studies provide evidence that dietary n-3 polyunsaturated fatty acids (n-3 PUFA), including alpha-linolenic acid (18:3n-3, ALA), eicosapentaenoic acid (20:5n-3, EPA) and/or docosahexaenoic acid (22:6n-3, DHA) may improve some of the components associated with MetS. The current review will discuss recent evidence from human observational and intervention studies that focused on the effects of ALA, EPA or DHA on inflammatory markers in healthy adults and those with one or more features of MetS. Observational studies in healthy adults support the recommendation that a diet rich in n-3 fatty acids may play a role in preventing and reducing inflammation, whereas intervention studies in healthy adults have yielded inconsistent results. The majority of intervention studies in adults with features of MetS have reported a benefit for some inflammatory measures; however, other studies using high n-3 fatty acid doses and long supplementation periods have reported no effect. Overall, the data reviewed herein support recommendations for regular fatty fish consumption and point toward health benefits in terms of lowering inflammation in adults with one or more features of MetS.     

Metabolic Syndrome Affects Fatty Acid Composition of Plasma Lipids in Obese Prepubertal Children

The aim of the present study was to assess the plasma fatty acid composition of the total plasma lipids and lipid fractions in obese prepubertal children with and without metabolic syndrome (MS). Thirty-four obese prepubertal children were recruited: 17 who met MS criteria and 17 who did not; and twenty prepubertal children of normal weight. MS characteristics, insulin resistance (by homeostasis model assessment [HOMA-IR]), and plasma adiponectin (by radioimmunoassay) were recorded. Separation of lipid fractions was performed by liquid chromatography and the concentration of fatty acids in total plasma lipids and fractions was determined by gas-liquid chromatography. Concentrations of 16:1n-7, 16:1n-9, 18:3n-3, 22:6n-3, and n-3 PUFA in total plasma lipids (P < 0.05) and of 16:0, 16:1n-7, 18:1n-9, 18:2n-6, and n-6 PUFA in triacylglycerols (TG) (P < 0.05) were significantly higher in obese MS versus normal-weight children. Increased risk of MS was positively associated with plasma concentration of 16:1n-7 and negatively associated with proportion of 20:4n-6 (OR 2.76; P = 0.004; OR 0.56, P = 0.030, respectively). Saturated FA in TG were associated with HOMA-IR (R = 0.349, P = 0.017) and 22:5n-6 with adiponectin (R = 0.336, P = 0.05). In conclusion, increased concentrations of 16:1n-7 and decreased proportions of 20:4n-6 and 22:5n-6 in plasma lipids appear to be early markers of MS in children at prepubertal age.     

Carbohydrate Restriction has a More Favorable Impact on the Metabolic Syndrome than a Low Fat Diet

We recently proposed that the biological markers improved by carbohydrate restriction were precisely those that define the metabolic syndrome (MetS), and that the common thread was regulation of insulin as a control element. We specifically tested the idea with a 12-week study comparing two hypocaloric diets (~1,500 kcal): a carbohydrate-restricted diet (CRD) (%carbohydrate:fat:protein = 12:59:28) and a low-fat diet (LFD) (56:24:20) in 40 subjects with atherogenic dyslipidemia. Both interventions led to improvements in several metabolic markers, but subjects following the CRD had consistently reduced glucose (−12%) and insulin (−50%) concentrations, insulin sensitivity (−55%), weight loss (−10%), decreased adiposity (−14%), and more favorable triacylglycerol (TAG) (−51%), HDL-C (13%) and total cholesterol/HDL-C ratio (−14%) responses. In addition to these markers for MetS, the CRD subjects showed more favorable responses to alternative indicators of cardiovascular risk: postprandial lipemia (−47%), the Apo B/Apo A-1 ratio (−16%), and LDL particle distribution. Despite a threefold higher intake of dietary saturated fat during the CRD, saturated fatty acids in TAG and cholesteryl ester were significantly decreased, as was palmitoleic acid (16:1n-7), an endogenous marker of lipogenesis, compared to subjects consuming the LFD. Serum retinol binding protein 4 has been linked to insulin-resistant states, and only the CRD decreased this marker (−20%). The findings provide support for unifying the disparate markers of MetS and for the proposed intimate connection with dietary carbohydrate. The results support the use of dietary carbohydrate restriction as an effective approach to improve features of MetS and cardiovascular risk. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Serum Fatty Acid-Binding Protein 4 is Increased in Patients with Psoriasis

Psoriasis is associated with metabolic syndrome and cardiovascular disease. Fatty acid‐binding proteins (FABP) have been recognized as predictors of these systemic disorders. The aim of this study was to assess correlations between levels of serum heart and adipocyte fatty acid‐binding proteins (FABP3, FABP4) and disease severity, indicators of inflammation or metabolic disturbances, and topical treatment in psoriatic patients. Thirty‐seven patients with relapse of plaque‐type psoriasis and 16 healthy volunteers were recruited. Blood samples were collected before and after 14 days of therapy. Serum FABP concentrations were examined by enzyme‐linked immunosorbent assay for correlation with Psoriasis Area and Severity Index (PASI), body mass index (BMI), inflammatory or metabolic parameters, and treatment used. The median FABP4 serum levels were significantly increased (p = 0.038) in psoriatic patients, while FABP3 levels did not differ (p = 0.47) compared to the controls. No significant correlations were noted between the proteins and PASI, C‐reactive protein (CRP), BMI, or levels of glucose or lipids. FABP3 significantly correlated with white blood count (p = 0.03) and aspartate aminotransferase (p = 0.04). After topical treatment, there was no significant change in serum FABP3 [11.5 (4.9–30.3) vs. 12.9 (3.5–30.3) ng/ml] (p = 0.96), whereas FABP4 was decreased [27,286 (20,344–32,257) vs. 23,034 (18,320–29,874) pg/ml] (p = 0.12), losing its basal significance. FABP4 may be a marker of psoriasis, and FABP3 may be associated with inflammation or liver disorders in psoriatic patients. FABP do not appear to be useful for determining disease severity or the effectiveness of antipsoriatic treatment.     

Discovery of adamantyl heterocyclic ketones as potent 11β-hydroxysteroid dehydrogenase type 1 inhibitors

11β‐Hydroxysteroid dehydrogenase type 1 (11β‐HSD1) plays a key role in converting intracellular cortisone to physiologically active cortisol, which is implicated in the development of several phenotypes of metabolic syndrome. Inhibition of 11β‐HSD1 activity with selective inhibitors has beneficial effects on various conditions, including diabetes, dyslipidemia and obesity, and therefore constitutes a promising strategy to discover novel therapies for metabolic and cardiovascular diseases. A series of novel adamantyl heterocyclic ketones provides potent and selective inhibitors of human 11β‐HSD1. Lead compounds display low nanomolar inhibition against human and mouse 11β‐HSD1 and are selective with no activity against 11β‐HSD2 and 17β‐HSD1. Selected potent 11β‐HSD1 inhibitors show moderate metabolic stability upon incubation with human liver microsomes and weak inhibition of human CYP450 enzymes.