A variant in the heart-specific fatty acid transport protein 6 is associated with lower fasting and postprandial TAG, blood pressure and left ventricular hypertrophy.

Fatty acid transport protein 6 (FATP6) is primarily expressed in the heart and seems to be involved in cardiac fatty acid uptake. Therefore, we investigated whether a variation in the 5'-untranslated region of the FATP6 gene is associated with features of the metabolic syndrome and signs of myocardial alteration or heart failure. A total of 755 male participants from a Metabolic Intervention Cohort Kiel were genotyped for the FATP6-7T>A polymorphism (rs2526246) and phenotyped for features of the metabolic syndrome. Participants underwent a glucose tolerance test and the postprandial assessment of metabolic variables after a standardised mixed meal. Left ventricular heart function was evaluated in fifty-four participants. Fasting (P = 0·01) and postprandial (P = 0·02) TAG concentrations were significantly lower in AA homozygotes when compared with wild-type carriers. Homozygosity of allele A was associated with significantly lower postprandial insulin concentrations after a glucose load and significantly lower systolic (P = 0·01) and diastolic (P = 0·01) blood pressure values compared with wild-type carriers. Accordingly, left ventricular heart mass was significantly lower in twenty-seven AA homozygotes in comparison with twenty-seven TT homozygotes, matched for BMI (P = 0·04). In conclusion, the effects of the FATP6 polymorphism on TAG are mediated by affluent dietary fat. The FATP6-7T>A polymorphism may protect from traits of the metabolic syndrome and CVD.

CLA does not impair endothelial function and decreases body weight as compared with safflower oil in overweight and obese male subjects.

OBJECTIVE: Conjugated linoleic acid (CLA) showed a wide range of beneficial biological effects with relevance for cardiovascular health in animal models and humans. Most human studies used olive oil as a reference. This study assessed the effect of CLA as compared with safflower oil on endothelial function and markers of cardiovascular risk in overweight and obese men. Heated safflower oil and olive oil were given for additional descriptive control. METHODS: Eighty-five overweight men (aged 45-68 years, body mass index 25-35 kg/m(2)) were randomized to receive 4.5 g/d of the CLA isomeric mixture, safflower oil, heated safflower oil, or olive oil in a 4-week double-blind study. Endothelial function was assessed by peripheral arterial tonometry (PAT) index determination in the fasting and postprandial state (i.e., 4 hours after consumption of a fat- and sucrose-rich meal). RESULTS: CLA as compared with safflower oil consumption did not impair fasting or postprandial PAT index but decreased body weight. CLA as compared with safflower oil did not change total, low-density lipoprotein (LDL), or high-density lipoprotein (HDL) cholesterol; triglycerides; insulin sensitivity indices; C-reactive protein; soluble adhesion molecules; oxidized LDL; lipoprotein a (Lp[a]); paraoxonase; or platelet-activating factor acetylhydrolase (PAF-AH) activity, but significantly reduced arylesterase activity and increased concentrations of the F(2)-isoprostane 8-iso-prostaglandin F (PGF)(2α). CONCLUSION: CLA did not impair endothelial function. Other parameters associated with metabolic syndrome and oxidative stress were not changed or were slightly improved. Results suggest that CLA does not increase cardiovascular risk. Increased F(2)-isoprostane concentrations in this context may not indicate increased oxidative stress.

Human intestinal fatty acid binding protein 2 expression is associated with fat intake and polymorphisms.

The intestinal fatty acid binding protein (FABP2) is involved in lipid metabolism whereby variations in the promoter (haplotypes A/B) and exon 2 (Ala54Thr) are associated with dyslipidemia and insulin resistance. To elucidate which factors determine FABP2 expression in human mucosa, we investigated the association between fat intake, genotypes, biochemical variables, and FABP2 expression. FABP2 gene expression was assessed in duodenal specimens from 100 participants who answered a FFQ and who were genotyped and characterized for traits of metabolic syndrome and further biochemical data. Homozygotes for haplotype A tended to have lower fat intake than B-allele carriers (P = 0.066). Searching for an explanation, we evaluated the orexigenic glucose-dependent insulinotropic polypeptide (GIP) in a subset from the Metabolic Intervention Cohort Kiel. AA homozygotes had lower postprandial GIP concentrations than BB homozygotes. Duodenal FABP2 expression was correlated with (n-3) fatty acid (FA) intake in AA homozygotes (r = 0.49; P = 0.021). It was higher in AA homozygotes than in B-allele carriers after adjustment for (n-3) FA intake (P = 0.049) and was negatively correlated with serum FFA (r = -0.41; P < 0.01). Our data indicate that FABP2 expression depends on (n-3) FA intake and FABP2 genotypes. FABP2 might be involved in regulating food intake and intestinal FA utilization.

s-ICAM-1 and s-VCAM-1 in healthy men are strongly associated with traits of the metabolic syndrome, becoming evident in the postprandial response to a lipid-rich meal.

BACKGROUND: The importance of the postprandial state for the early stages of atherogenesis is increasingly acknowledged. We conducted assessment of association between postprandial triglycerides, insulin and glucose after ingestion of a standardized lipid-rich test meal, and soluble cellular adhesion molecules (sCAM) in young healthy subjects. METHODS: Metabolic parameters and sICAM-1, sVCAM-1 and E-selectin were measured before and hourly until 6 hours after ingestion of a lipid-rich meal in 30 healthy young men with fasting triglycerides <150 mg/dl and normal fasting glucose levels. Subjects were classified as either normal responders (NR) (postprandial triglyceride maxima < 260 mg/dl) or high responders (HR) (postprandial triglyceride maxima > 260 mg/dl). Levels of CAM were compared in HR and NR, and correlation with postprandial triglyceride, insulin and glucose response was assessed. RESULTS: Fasting sICAM-1 and sVCAM-1 levels were significantly higher in HR as compared to NR (p = 0.046, p = 0.03). For sE-selectin there was such a trend (p = 0.05). There was a strong positive and independent correlation between sICAM-1 and postprandial insulin maxima (r = 0.70, p < 0.001). sVCAM-1 showed significant correlation with postprandial triglycerides (AUC) (r = 0.37, p = 0.047). We found no correlation between sCAMs and fasting insulin or triglyceride concentrations. CONCLUSION: This independent association of postprandial triglycerides with sICAM-1 may indicate a particular impact of postprandial lipid metabolism on endothelial reaction.

Pentadecanoic and Heptadecanoic Acids: Multifaceted Odd-Chain Fatty Acids.

The odd-chain fatty acids (OCFAs) pentadecanoic acid (15:0) and heptadecanoic acid (17:0), which account for only a small proportion of total saturated fatty acids in milk fat and ruminant meat, are accepted biomarkers of dairy fat intake. However, they can also be synthesized endogenously, for example, from gut-derived propionic acid (3:0). A number of studies have shown an inverse association between OCFA concentrations in human plasma phospholipids or RBCs and risk of type 2 diabetes and cardiovascular disease. We propose a possible involvement in metabolic regulation from the assumption that there is a link between 15:0 and 17:0 and the metabolism of other short-chain, medium-chain, and longer-chain OCFAs. The OCFAs 15:0 and 17:0 can be elongated to very-long-chain FAs (VLCFAs) such as tricosanoic acid (23:0) and pentacosanoic acid (25:0) in glycosphingolipids, particularly found in brain tissue, or can be derived from these VLCFAs. Their chains can be shortened, yielding propionyl-coenzyme A (CoA). Propionyl-CoA, by succinyl-CoA, can replenish the citric acid cycle (CAC) with anaplerotic intermediates and, thus, improve mitochondrial energy metabolism. Mitochondrial function is compromised in a number of disorders and may be impaired with increasing age. Optimizing anaplerotic intermediate availability for the CAC may help to cope with demands in times of increased metabolic stress and with aging. OCFAs may serve as substrates for synthesis of both odd-numbered VLCFAs and propionyl-CoA or store away excess propionic acid.

Effects of dietary milk- and soya-phospholipids on lipid-parameters and other risk indicators for cardiovascular diseases in overweight or obese men - two double-blind, randomised, controlled, clinical trials.

The present study examined the effect of milk phospholipids (milk-PL) on lipid metabolism and on other risk factors for CVD, in comparison with milk fat (control) or soya phospholipids (soya-PL), respectively. Two double-blind parallel-group intervention trials were conducted in overweight or obese male subjects. In the first trial (trial 1), sixty-two men consumed milk enriched with either 2 g milk-PL or 2 g milk fat (control) for 8 weeks. In trial 2, fifty-seven men consumed milk enriched with either 3 g milk-PL or 2·8 g soya-PL for 7 weeks. In trial 1, milk-PL as compared with control reduced waist circumference but did not affect plasma lipids (total, HDL- and LDL-cholesterol, total cholesterol:HDL-cholesterol ratio, TAG, phospholipids), apoB, apoA1, glucose, insulin, insulin sensitivity index, C-reactive protein, IL-6, soluble intracellular adhesion molecule and total homocysteine (tHcy). Serum activities of alanine transaminase and aspartate transaminase were not changed. Activity of γ-glutamyl transferase (GGT), a marker of fatty liver, increased in the control but not in the milk-PL group, with a significant intervention effect. In trial 2, milk-PL as compared with soya-PL did not affect the above-mentioned parameters, but decreased GGT. Subjects with the methylenetetrahydrofolate reductase mutations CT and TT had 11 % (P < 0·05) higher baseline tHcy concentrations than those with the wild-type CC. However, genotype did not modulate the phospholipid intervention effect on tHcy. In conclusion, supplementation with milk-PL as compared with control fat reduced waist circumference and, as compared with both control fat and soya-PL, GGT activity.

trans Palmitoleic acid arises endogenously from dietary vaccenic acid.

BACKGROUND: trans Palmitoleic acid (t-16:1n-7, or 16:1 t9 in the δ nomenclature usually applied to trans fatty acids and used herein) arouses great scientific interest because it has been suggested to serve as a biomarker for lower risks of type 2 diabetes and coronary artery disease. OBJECTIVE: Although 16:1 t9 has been assumed to derive from dietary sources, we examined the hypothesis that 16:1 t9 might also be endogenously produced from its metabolic precursor vaccenic acid (t-18:1n-7 or 18:1 t11). DESIGN: We reevaluated fatty acid data obtained from one human intervention study and one cellular model in both of which 18:1 t11 was supplemented. Both studies have already been published, but to our knowledge, 16:1 t9 has not yet been considered. This reanalysis of the datasets was reasonable because a new methodology for identifying 16:1 cis and trans isomers allowed us to address the subject presented in this article. RESULTS: Data showed that the systemic or intracellular increase in 16:1 t9 was strongly correlated with the increase in 18:1 t11 after the dietary intake or cellular uptake of 18:1 t11. The conversion rate in humans was, on average, 17%. CONCLUSION: Our findings suggest that endogenous 16:1 t9 is not, as has been assumed, exclusively diet derived but may also be produced by the partial ß oxidation of dietary 18:1 t11.

Influence of different CLA isomers on insulin resistance and adipocytokines in pre-diabetic, middle-aged men with PPARγ2 Pro12Ala polymorphism.

Conjugated linoleic acids (CLAs) are natural PPARγ ligands, which showed conflicting effects on metabolism in humans. We examined metabolic effects of different isomers of CLA in subjects with PPARγ2 Pro12Ala polymorphisms. A total of 35 men underwent four intervention periods in a crossover study design: subjects with either genotypes received c9, t11 CLA or t10, c12 CLA, a commercially available 1:1 mix of both isomers or reference oil (linoleic acid (LA)). Adipocytokines, insulin, glucose and triglycerides were assessed in the fasting state and after a standardized mixed meal. Across all genotypes, there was a significant (p = 0.025) CLA treatment effect upon postprandial (pp) HOMA-IR values, with c9, t11 CLA and CLA isomer mix improving, but t10, c12 CLA isomer worsening. In Ala12Ala subjects, the t10, c12 isomer caused weight gain (p = 0.03) and tended to increase postprandial insulin levels (p = 0.05). In Pro12Pro subjects, t10, c12 resulted in reduction in waist circumference (p = 0.03). The comparison of the different genotype groups revealed statistically different changes in fasting and postprandial insulin, HOMA-IR and leptin after intervention. c9, t11 CLA and the commercial CLA mix showed beneficial effects on insulin sensitivity compared with LA, while t10, c12 CLA adversely affects body weight and insulin sensitivity in different PPAR genotypes. CLA isomers have different effects on metabolism in Ala and Pro carriers.

The effect of FABP2 promoter haplotype on response to a diet with medium-chain triacylglycerols.

The fatty-acid-binding protein-2 (FABP2) gene has been proposed as a candidate gene for diabetes because the encoded protein is involved in fatty acid absorption and therefore may affect insulin sensitivity and glucose metabolism. The rare haplotype (B) of its promoter was shown to be associated with a lower risk for type 2 diabetes. The aim of this study was to investigate whether a polymorphism in the FABP2 promoter does affect the metabolic response to either an medium-chain triacylglycerol (MCT) or an long-chain triacylglycerol (LCT) diet, which were suggested to differ in transport mechanisms, in affinity to FABP2, in activating transcription factors binding to the FABP2 promoter and in their effects on insulin sensitivity. We studied 82 healthy male subjects varying in the FABP2 promoter (42 homozygous for common haplotype (A), 40 homozygous for the rare haplotype (B)) in an interventional study with either an MCT or LCT diet over 2 weeks to examine gene-nutrient interaction. The saturation grade of MCT was adjusted to that of the LCT fat. We determined glucose, insulin, triacylglycerols (TGs), chylomicron triacylglycerols and cholesterol before and after a standardised mixed meal before and after the intervention. HDL cholesterol increased in all groups, which was most pronounced in subjects homozygous for the common promoter haplotype A who received MCT diet (P = 0.001), but not significant in homozygous rare haplotype B subjects who received MCT fat. Subjects homozygous for FABP2 haplotype A showed a significant decrease in fasting and postprandial glucose (P = 0.01, 0.04, respectively) and a decrease in insulin resistance (HOMA-IR, P = 0.04) during LCT diet. After correction for multiple testing, those effects did not remain significant. Fasting and postprandial triacylglycerols, LDL cholesterol, chylomicron TGs and cholesterol were not affected by genotype or diet. MCT diet increased HDL cholesterol dependent on the FABP2 promoter haplotype. The effects of the promoter haplotype B could be mediated by PPARγ, which is upregulated by medium-chain fatty acids.

Familial influences and obesity-associated metabolic risk factors contribute to the variation in resting energy expenditure: the Kiel Obesity Prevention Study.

BACKGROUND: A low metabolic rate may be inherited and predispose to obesity, whereas a higher metabolic rate in obesity may be acquired by obesity-associated cardiometabolic risk. OBJECTIVE: We aimed to explain the interindividual variation in resting energy expenditure (REE) by assessing 1) the association between REE and body composition, thyroid hormones, and obesity-related cardiometabolic risk factors, and 2) the familial (genetic and environmental) contribution to REE. DESIGN: REE and metabolic risk factors (ie, blood pressure and plasma insulin, glucose, and C-reactive protein concentrations) were assessed in 149 two- or three-generation families, including at least one overweight or obese member. Heritability of REE, respiratory quotient (RQ), thyroid hormones [thyrotropin (TSH), free triiodothyronine (FT3) and free thyroxine (FT4)], and body composition (fat-free mass and fat mass) were estimated by using variance components-based quantitative genetic models. RESULTS: REE adjusted for body composition, sex, and age (REEadj) significantly correlated with systolic and diastolic blood pressure, plasma insulin and glucose concentrations, and the homeostasis model assessment (HOMA) (r = 0.14-0.31, P < 0.05). Thyroid hormones had a modest influence on REE variance only. Heritability was 0.30 +/- 0.07 for REEadj and 0.29 +/- 0.08 for REE after additional adjustment for thyroid hormones and metabolic risk. Furthermore, heritability was estimated to be 0.22 +/- 0.08 for RQ, 0.37 +/- 0.08 for TSH, 0.68 +/- 0.06 for FT4, and 0.69 +/- 0.05 for FT3 (all significantly larger than zero). CONCLUSIONS: Obesity-related cardiometabolic risk factors contribute to interindividual variation in REE, with hypertension and insulin resistance being associated with a higher REE. REE was moderately heritable, independent of body composition, sex, age, thyroid function, and cardiometabolic risk.

Use of height3:waist circumference3 as an index for metabolic risk assessment?

Current anthropometric indices for health risk assessment are indirect measures of total or visceral body fat mass that do not consider the inverse relationship of lean body mass to metabolic risk as well as the non-linear relationship between central obesity and insulin resistance. We examined a new anthropometric index that reflects the relationship of waist circumference (WC) as a risk factor to fat-free mass (FFM) as a protective parameter of body composition. In a population of 335 adults (191 females and 144 males; mean age 53 (SD 13.9) years) with a high prevalence of obesity (27%) and metabolic syndrome (30%) we derived FFM:WC(3) from the best fit of the relationship with metabolic risk factors (plasma triacylglycerol levels and insulin resistance by homeostasis model assessment index). Because FFM is known to be proportional to the cube of height, FFM was subsequently replaced by height(3) yielding height(3):WC(3) as an easily applicable anthropometric index. Significant inverse relationships of height(3):WC(3) to metabolic risk factors were observed for both sexes. They slightly exceeded those of conventional anthropometric indices such as BMI, WC or WC:hip ratio in women but not in men. The exponential character of the denominator WC(3) implies that at a given FFM with gradually increasing WC the increase in metabolic risk is lower than proportional. Further studies are needed to evaluate height(3):WC(3) as an anthropometric index for health risk assessment.

A common functional exon polymorphism in the microsomal triglyceride transfer protein gene is associated with type 2 diabetes, impaired glucose metabolism and insulin levels.

The microsomal triglyceride transfer protein (MTP) is required for the assembly and secretion of apolipoprotein B-containing lipoproteins. Emerging evidence has indicated that the functional MTP exon polymorphism I128T is associated with dyslipidemia and other traits of the insulin-resistance syndrome, and the T128 variant seems to confer a reduced stability of MTP, resulting in reduced binding of LDL particles. The aim of the study was to elucidate the association of this MTP polymorphism with parameters of postprandial metabolism. A total of 716 male subjects from a postprandially characterized cohort (MICK) and a nested case-control study (EPIC) of 190 incident type 2 diabetes cases and 380 sex- or age-matched controls were genotyped for the I128T exon polymorphism. In comparison to homozygote subjects of the wild allele, carriers of the less common allele of the MTP T128 genotype showed significantly lower postprandial insulin levels (P=0.017), lower diastolic blood pressure (P=0.049) and had a lower prevalence of impaired glucose metabolism and diabetes type 2 (P=0.03) in the MICK. Consistent with this, we found a lower incidence of type 2 diabetes in male subjects of the nested case-control study in the T128 genotype (P=0.007). These results suggest that the rare allele of the MTP I128T polymorphism may be protective against impaired glucose tolerance, type 2 diabetes and other parameters of the metabolic syndrome.