Plasma oxylipins respond in a linear dose-response manner with increased intake of EPA and DHA: results from a randomized controlled trial in healthy humans.

BACKGROUND: The health effects of long-chain omega-3 polyunsaturated fatty acids (n-3 PUFAs) are partly mediated by their oxidized metabolites, i.e., eicosanoids and other oxylipins. Some intervention studies have demonstrated that eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) increase systemic concentrations of n-3 PUFA-derived oxylipins and moderately decrease arachidonic acid-derived oxylipins. There is no information on the dose-response of oxylipin concentrations after n-3 PUFA intake. OBJECTIVE: The aim of this study was to quantify oxylipins in human plasma samples from an intervention study in which participants were randomly assigned to different daily intakes of EPA and DHA for 12 mo. METHODS: Healthy adult men and women with low habitual fish consumption (n = 121) were randomly assigned to receive capsules providing doses of n-3 PUFAs reflecting 3 patterns of consumption of oily fish [1, 2, or 4 portions/wk with 3.27 g EPA + DHA (1:1.2, wt:wt) per portion] or placebo. Oxylipins were quantified in plasma after 3 and 12 mo. Relative and absolute changes of individual oxylipins were calculated and concentrations were correlated with the dose and the content of EPA and DHA in blood lipid pools. RESULTS: Seventy-three oxylipins, mostly hydroxy-, dihydroxy-, and epoxy-PUFAs, were quantified in the plasma samples. After 3 and 12 mo a linear increase with dose was observed for all EPA- and DHA-derived oxylipins. Cytochrome-P450-derived anti-inflammatory and cardioprotective epoxy-PUFAs increased linearly with n-3 PUFA dose and showed low interindividual variance (r2 > 0.95). Similarly, 5, 12-, and 15-lipoxygenase-derived hydroxy-PUFAs as well as those formed autoxidatively increased linearly. These include the precursors of so-called specialized pro-resolving lipid mediators (SPMs), e.g., 17-hydroxy-DHA and 18-hydroxy-EPA. CONCLUSIONS: Plasma concentrations of biologically active oxylipins derived from n-3 PUFAs, including epoxy-PUFAs and SPM-precursors, increase linearly with elevated intake of EPA and DHA. Interindividual differences in resulting plasma concentrations are low. This trial was registered at controlled-trials.com as ISRCTN48398526.

APOE4 Genotype Exerts Greater Benefit in Lowering Plasma Cholesterol and Apolipoprotein B than Wild Type (E3/E3), after Replacement of Dietary Saturated Fats with Low Glycaemic Index Carbohydrates.

We examined the impact of APOE genotype on plasma lipids and glucose in a secondary analysis of data from a five-arm, randomised controlled, parallel dietary intervention trial ('RISCK' study), to investigate the impact of replacing saturated fatty acids (SFA) with either monounsaturated fat (MUFA) or carbohydrate of high or low glycaemic index (GI) on CVD risk factors and insulin sensitivity. We tested the impact of APOE genotype (carriage of E2 and E4 alleles versus E3/E3), determined retrospectively, on plasma lipids, lipoproteins and glucose homeostasis at baseline (n = 469), and on the change in these variables after 24 weeks of dietary intervention (n = 389). At baseline, carriers of E2 (n = 70), E4 (n = 125) and E3/E3 (n = 274) expressed marked differences in total plasma cholesterol (TC, p = 0.001), low density lipoprotein cholesterol (LDL-C, p < 0.0001), apolipoprotein B (apo B, p < 0.0001) and total to high density lipoprotein cholesterol ratio (TC:HDL-C, p = 0.002), with plasma concentrations decreasing in the order E4 > E3/E3 > E2. Following intervention, there was evidence of a significant diet x genotype interaction with significantly greater decreases in TC (p = 0.02) and apo B (p = 0.006) among carriers of E4 when SFA was replaced with low GI carbohydrate on a lower fat diet (TC -0.28 mmol/L p = 0.03; apo B -0.1 g/L p = 0.02), and a relative increase in TC (in comparison to E3/E3) when SFA was replaced with MUFA and high GI carbohydrates (TC 0.3 mmol/L, p = 0.03). Among carriers of E2 (compared with E3/E3) there was an increase in triacylglycerol (TAG) when SFA was replaced with MUFA and low GI carbohydrates 0.46 mmol/L p = 0.001). There were no significant interactions between APOE genotype and diet for changes in indices of glucose homeostasis. In conclusion, variations in APOE genotype led to differential effects on the lipid response to the replacement of SFA with MUFA and low GI carbohydrates.

Lipidomics Profiling of Human Adipose Tissue Identifies a Pattern of Lipids Associated with Fish Oil Supplementation.

To understand the interaction between diet and health, biomarkers that accurately reflect consumption of foods of perceived health relevance are needed. The aim of this investigation was to use direct infusion-mass spectrometry (DI-MS) lipidomics to determine the effects of fish oil supplementation on lipid profiles of human adipose tissue. Adipose tissue samples from an n-3 polyunsaturated fatty acid (PUFA) supplementation study (n = 66) were analyzed to compare the pattern following supplementation equivalent to zero or four portions of oily fish per week. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were incorporated into highly unsaturated (≥5 double bonds) triglycerides (TGs), phosphocholines, and phosphoethanolamines as well as being detected directly as the nonesterified fatty acid forms. Multivariate statistics demonstrated that phospholipids were the most accurate and sensitive lipids for the assessing EPA and DHA incorporation into adipose tissue. Potential confounding factors (adiposity, age, and sex of the subject) were also considered in the analysis, and adiposity was also associated with an increase in highly unsaturated TGs as a result of incorporation of the n-6 PUFA arachidonic acid. DI-MS provides a high-throughput analysis of fatty acid status that can monitor oily fish consumption, suitable for use in cohort studies.

The Pattern of Fatty Acids Displaced by EPA and DHA Following 12 Months Supplementation Varies between Blood Cell and Plasma Fractions.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are increased in plasma lipids and blood cell membranes in response to supplementation. Whilst arachidonic acid (AA) is correspondingly decreased, the effect on other fatty acids (FA) is less well described and there may be site-specific differences. In response to 12 months EPA + DHA supplementation in doses equivalent to 0-4 portions of oily fish/week (1 portion: 3.27 g EPA+DHA) multinomial regression analysis was used to identify important FA changes for plasma phosphatidylcholine (PC), cholesteryl ester (CE) and triglyceride (TAG) and for blood mononuclear cells (MNC), red blood cells (RBC) and platelets (PLAT). Dose-dependent increases in EPA + DHA were matched by decreases in several n-6 polyunsaturated fatty acids (PUFA) in PC, CE, RBC and PLAT, but were predominantly compensated for by oleic acid in TAG. Changes were observed for all FA classes in MNC. Consequently the n-6:n-3 PUFA ratio was reduced in a dose-dependent manner in all pools after 12 months (37%-64% of placebo in the four portions group). We conclude that the profile of the FA decreased in exchange for the increase in EPA + DHA following supplementation differs by FA pool with implications for understanding the impact of n-3 PUFA on blood lipid and blood cell biology.

Fatty acid profile of plasma NEFA does not reflect adipose tissue fatty acid profile.

Adipose tissue (AT) fatty acid (FA) composition partly reflects habitual dietary intake. Circulating NEFA are mobilised from AT and might act as a minimally invasive surrogate marker of AT FA profile. Agreement between twenty-eight FA in AT and plasma NEFA was assessed using concordance coefficients in 204 male and female participants in a 12-month intervention using supplements to increase the intake of EPA and DHA. Concordance coefficients generally showed very poor agreement between AT FA and plasma NEFA at baseline SFA: 0·07; MUFA: 0·03; n-6 PUFA: 0·28; n-3 PUFA: 0·01). Participants were randomly divided into training (70 %) and validation (30 %) data sets, and models to predict AT and dietary FA were fitted using data from the training set, and their predictive ability was assessed using data from the validation set. AT n-6 PUFA and SFA were predicted from plasma NEFA with moderate accuracy (mean absolute percentage error n-6 PUFA: 11 % and SFA: 8 %), but predicted values were unable to distinguish between low, medium and high FA values, with only 25 % of n-6 PUFA and 33 % of SFA predicted values correctly assigned to the appropriate tertile group. Despite an association between AT and plasma NEFA EPA (P=0·001) and DHA (P=0·01) at baseline, there was no association after the intervention. To conclude, plasma NEFA are not a suitable surrogate for AT FA.

Modelling the Interplay between Lifestyle Factors and Genetic Predisposition on Markers of Type 2 Diabetes Mellitus Risk.

The risk of developing type 2 diabetes mellitus (T2DM) is determined by a complex interplay involving lifestyle factors and genetic predisposition. Despite this, many studies do not consider the relative contributions of this complex array of factors to identify relationships which are important in progression or prevention of complex diseases. We aimed to describe the integrated effect of a number of lifestyle changes (weight, diet and physical activity) in the context of genetic susceptibility, on changes in glycaemic traits in overweight or obese participants following 12-months of a weight management programme. A sample of 353 participants from a behavioural weight management intervention were included in this study. A graphical Markov model was used to describe the impact of the intervention, by dividing the effects into various pathways comprising changes in proportion of dietary saturated fat, physical activity and weight loss, and a genetic predisposition score (T2DM-GPS), on changes in insulin sensitivity (HOMA-IR), insulin secretion (HOMA-B) and short and long term glycaemia (glucose and HbA1c). We demonstrated the use of graphical Markov modelling to identify the importance and interrelationships of a number of possible variables changed as a result of a lifestyle intervention, whilst considering fixed factors such as genetic predisposition, on changes in traits. Paths which led to weight loss and change in dietary saturated fat were important factors in the change of all glycaemic traits, whereas the T2DM-GPS only made a significant direct contribution to changes in HOMA-IR and plasma glucose after considering the effects of lifestyle factors. This analysis shows that modifiable factors relating to body weight, diet, and physical activity are more likely to impact on glycaemic traits than genetic predisposition during a behavioural intervention.

Effect of reducing portion size at a compulsory meal on later energy intake, gut hormones, and appetite in overweight adults.

OBJECTIVE: Larger portion sizes (PS) are associated with greater energy intake (EI), but little evidence exists on the appetitive effects of PS reduction. This study investigated the impact of reducing breakfast PS on subsequent EI, postprandial gastrointestinal hormone responses, and appetite ratings. METHODS: In a randomized crossover design (n = 33 adults; mean BMI 29 kg/m(2) ), a compulsory breakfast was based on 25% of gender-specific estimated daily energy requirements; PS was reduced by 20% and 40%. EI was measured at an ad libitum lunch (240 min) and snack (360 min) and by weighed diet diaries until bed. Blood was sampled until lunch in 20 participants. Appetite ratings were measured using visual analogue scales. RESULTS: EI at lunch (control: 2,930 ± 203; 20% reduction: 2,853 ± 198; 40% reduction: 2,911 ± 179 kJ) and over the whole day except breakfast (control: 7,374 ± 361; 20% reduction: 7,566 ± 468; 40% reduction: 7,413 ± 417 kJ) did not differ. Postprandial PYY, GLP-1, GIP, insulin, and fullness profiles were lower and hunger, desire to eat, and prospective consumption higher following 40% reduction compared to control. Appetite ratings profiles, but not hormone concentrations, were associated with subsequent EI. CONCLUSIONS: Smaller portions at breakfast led to reductions in gastrointestinal hormone secretion but did not affect subsequent energy intake, suggesting small reductions in portion size may be a useful strategy to constrain EI.

Compared with daily, weekly n-3 PUFA intake affects the incorporation of eicosapentaenoic acid and docosahexaenoic acid into platelets and mononuclear cells in humans.

Consumption of oily fish is sporadic, whereas controlled intervention studies of n-3 (ω-3) fatty acids usually provide capsules containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as a daily dose. This methodologic study explored whether there are differences in the short-, medium-, and long-term incorporation of EPA and DHA into blood plasma and cells with the provision of identical amounts of EPA and DHA, equivalent to 2 oily fish servings per week (or 6.54 g/wk EPA and DHA), either intermittently (i.e., 1 portion twice per week) or continuously (i.e., divided into daily amounts). The study was part of a randomized, double-blind controlled intervention lasting 12 mo, with participants stratified by age and sex. There were 5 intervention groups, 2 of which are reported here: the 2 intermittent portions (2I) and 2 continuous portions (2C) groups. EPA and DHA were measured in plasma phosphatidylcholine, platelets, and blood mononuclear cells (MNCs) at 9 time points. Sixty-five participants completed the study (2I group, n = 30, mean age of 49.2 y; 2C group, n = 35, mean age of 50.6 y). The incorporation pattern over the 12-mo intervention was different between the 2 groups in all samples (P < 0.0001, time × treatment interaction). At the end of the 12-mo intervention, the 2C group had higher EPA, DHA, and EPA + DHA in platelets (all P < 0.01) and higher EPA and EPA + DHA in MNCs (both P < 0.05) compared with the 2I group. No significant differences were shown for plasma phosphatidylcholine EPA (P = 0.1), DHA (P = 0.15), EPA + DHA (P = 0.07), or MNC DHA (P = 0.06). In conclusion, the pattern of consumption does affect the incorporation of EPA and DHA into cells used as biomarkers of intake. The differences identified here need to be considered in the design of studies and when extrapolating results from continuous capsule-based intervention studies to dietary guidelines for oily fish consumption. This trial was registered at www.controlled-trials.com as ISRCTN48398526.

Age and sex differences in the incorporation of EPA and DHA into plasma fractions, cells and adipose tissue in humans.

The aim of the present study was to determine whether age and sex influence both the status and incorporation of EPA and DHA into blood plasma, cells and tissues. The study was a double-blind, randomised, controlled intervention trial, providing EPA plus DHA equivalent to 0, 1, 2 or 4 portions of oily fish per week for 12 months. The participants were stratified by age and sex. A linear regression model was used to analyse baseline outcomes, with covariates for age or sex groups and by adjusting for BMI. The change in outcomes from baseline to 12 months was analysed with additional adjustment for treatment and average compliance. Fatty acid profiles in plasma phosphatidylcholine, cholesteryl esters, NEFA and TAG, mononuclear cells (MNC), erythrocyte membranes, platelets, buccal cells (BU) and adipose tissue (AT) were determined. At baseline, EPA concentrations in plasma NEFA and DHA concentrations in MNC, BU and AT were higher in females than in males (all P< 0·05). The concentrations of EPA in AT (P= 0·003) and those of DHA in plasma TAG (P< 0·01) and AT (P< 0·001) were higher with increasing age. Following 12-month supplementation with EPA plus DHA, adjusted mean difference for change in EPA concentrations in plasma TAG was significantly higher in females than in males (P< 0·05) and was greater with increasing age (P= 0·02). Adjusted mean difference for change in DHA concentrations in AT was significantly smaller with increasing age (P= 0·02). Although small differences in incorporation with age and sex were identified, these were not of sufficient magnitude to warrant a move away from population-level diet recommendations for n-3 PUFA.

Genetic predisposition to an adverse lipid profile limits the improvement in total cholesterol in response to weight loss.

OBJECTIVE: Overweight and obesity are associated with a dyslipidaemia which can be improved by weight loss. Whether genetic predisposition to an adverse lipid profile modifies such beneficial effects of weight loss on lipid levels in overweight and obese individuals was examined. DESIGN AND METHODS: White European participants (n = 374) who completed a 12-month weight loss trial were genotyped for 36 lipid-associated single nucleotide polymorphisms (SNPs), previously identified in genome-wide association studies (GWAS). Genetic predisposition scores (GPSs) were calculated for four lipid traits by summing the number of risk alleles (RA) for each participant. The associations of each GPS with four lipid traits were assessed at baseline, and with lipid changes in response to weight change after 12 months. RESULTS: At baseline, the trait-specific GPSs were associated with 0.11 ± 0.04 mM higher total cholesterol/RA (P = 0.004), 0.05 ± 0.02 mM higher low density lipoprotein cholesterol/RA (P = 0.005), 0.03 ± 0.007 mM lower high density lipoprotein cholesterol/RA (P = 0.00002) and 0.04 ± 0.01 mM higher triglyceride/RA (P = 0.00002). After the intervention, weight loss was associated with improvements in all lipids (P < 0.01). GPS attenuated the weight loss-associated reduction in TC so those with a higher GPS had less improvement (interaction = 0.01 ± 0.005 mM/GPS/kg weight loss, P = 0.003). A similar pattern was observed for LDLC (interaction = 0.004 ± 0.002 mM/GPS/kg weight loss, P = 0.07). There was no evidence of a GPS-modifying effect for change in HDLC or TG. CONCLUSION: Genetic predisposition is an important determinant of lipid levels and appears to limit the improvement in TC and to some extent LDLC levels, but not in other plasma lipids, in response to weight loss. © 2013 American Institute of Chemical Engineers AIChE J, 2013.

Stearidonic acid as a supplemental source of ω-3 polyunsaturated fatty acids to enhance status for improved human health.

There is substantial evidence to show that consumption and increased blood levels of the very long-chain (VLC) ω-3 polyunsaturated fatty acids (ω-3 PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are associated with health benefits. The consumption of oily fish is an effective way of increasing EPA and DHA intake and status, but intake in most Western countries remains below the levels recommended for optimal health. The reasons for this include not liking the taste, a concern about sustainability of fish supplies, or potential chemical and heavy metal contamination. Alternative dietary sources of ω-3 fatty acids to enhance EPA and DHA status in the body would therefore be beneficial. There are many non-fish food sources of the essential plant-derived ω-3 fatty acid α-linolenic acid, but conversion from this to longer-chain EPA and especially to DHA is poor. Stearidonic acid (SDA) is an intermediate fatty acid in the biosynthetic pathway from α-linolenic acid to VLC ω-3 PUFAs and the conversion from SDA is more efficient than from α-linolenic acid. However, there are few food sources rich in SDA. Oil crops naturally rich in SDA or enriched through genetic modification may offer an alternative supplemental oil to boost the population status of VLC ω-3 PUFAs. This review discusses the currently available evidence that increased SDA consumption can increase red blood cell EPA content, although this is less than the effect of supplementation directly with EPA. There is now a need for trials specifically designed to assess whether an increased SDA consumption would translate into improved human health outcomes.

Incorporation of eicosapentaenoic and docosahexaenoic acids into lipid pools when given as supplements providing doses equivalent to typical intakes of oily fish.

BACKGROUND: Estimation of the intake of oily fish at a population level is difficult. The measurement of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in biological samples may provide a useful biomarker of intake. OBJECTIVE: We identified the most appropriate biomarkers for the assessment of habitual oily fish intake and changes in intake by elucidating the dose- and time-dependent response of EPA and DHA incorporation into various biological samples that represent roles in fatty acid transport, function, and storage. DESIGN: This was a double-blind, randomized, controlled intervention trial in 204 men and women that lasted 12 mo. EPA and DHA capsules were provided in a manner to reflect sporadic consumption of oily fish (ie, 1, 2, or 4 times/wk). EPA and DHA were assessed at 9 time points over 12 mo in 9 sample types (red blood cells, mononuclear cells, platelets, buccal cells, adipose tissue, plasma phosphatidylcholine, triglycerides, cholesteryl esters, and nonesterified fatty acids). RESULTS: A dose response (P < 0.05) was observed for EPA and DHA in all pools except for red blood cell EPA (P = 0.057). EPA and DHA measures in plasma phosphatidylcholine and platelets were best for the discrimination between different intakes (P < 0.0001). The rate of incorporation varied between sample types, with the time to maximal incorporation ranging from days (plasma phosphatidylcholine) to months (mononuclear cells) to >12 mo (adipose tissue). CONCLUSIONS: Plasma phosphatidylcholine EPA plus DHA was identified as the most suitable biomarker of acute changes in EPA and DHA intake, and platelet and mononuclear cell EPA plus DHA were the most suitable biomarkers of habitual intake.

Genetic predisposition to type 2 diabetes is associated with impaired insulin secretion but does not modify insulin resistance or secretion in response to an intervention to lower dietary saturated fat.

Genome-wide association studies have identified SNPs reproducibly associated with type 2 diabetes (T2D). We examined the effect of genetic predisposition to T2D on insulin sensitivity and secretion using detailed phenotyping in overweight individuals with no diagnosis of T2D. Furthermore, we investigated whether this genetic predisposition modifies the responses in beta-cell function and insulin sensitivity to a 24-week dietary intervention. We genotyped 25 T2D-associated SNPs in 377 white participants from the RISCK study. Participants underwent an IVGTT prior to and following a dietary intervention that aimed to lower saturated fat intake by replacement with monounsaturated fat or carbohydrate. We composed a genetic predisposition score (T2D-GPS) by summing the T2D risk-increasing alleles of the 25 SNPs and tested for association with insulin secretion and sensitivity at baseline, and with the change in response to the dietary intervention. At baseline, a higher T2D-GPS was associated with lower acute insulin secretion (AIRg 4% lower/risk allele, P = 0.006) and lower insulin secretion for a given level of insulin sensitivity, assessed by the disposition index (DI 5% lower/risk allele, P = 0.002), but not with insulin sensitivity (Si). T2D-GPS did not modify changes in insulin secretion, insulin sensitivity or the disposition index in response to the dietary interventions to lower saturated fat. Participants genetically predisposed to T2D have an impaired ability to compensate for peripheral insulin resistance with insulin secretion at baseline, but this does not modify the response to a reduction in dietary saturated fat through iso-energetic replacement with carbohydrate or monounsaturated fat.

Adipocyte pyruvate dehydrogenase kinase 4 expression is associated with augmented PPARγ upregulation in early-life programming of later obesity.

We studied adipocytes from 8-week-old control rat offspring (CON) or rat offspring subjected to maternal low (8%) protein (MLP) feeding during pregnancy/lactation, a procedure predisposing to obesity. Acute exposure to isoproterenol or adenosine enhanced PDK4 and PPARγ mRNA gene expression in CON and MLP adipocytes. Enhanced adipocyte Pdk4 expression correlated with increased PPARγ expression. Higher levels of PDK4 and PPARγ were observed in MLP adipocytes. SCD1 is a PPARγ target. Isoproterenol enhanced adipocyte PDK4 and SCD1 gene expression in parallel. This could reflect augmented PPARγ expression together with enhanced lipolytic stimulation to supply endogenous PPARγ ligands, allowing enhanced adipocyte PDK4 and SCD1 expression via PPARγ activation. In contrast, the effect of adenosine to increase PDK4 expression is independent of stimulation of lipolysis and, as SCD1 expression was unaffected by adenosine, unlikely to reflect PPARγ activation. Increased adipocyte expression of both PDK4 and SCD1 in the MLP model could participate as components of a "thrifty" phenotype, favouring the development of obesity.

A distinct adipose tissue gene expression response to caloric restriction predicts 6-mo weight maintenance in obese subjects.

BACKGROUND: Weight loss has been shown to reduce risk factors associated with cardiovascular disease and diabetes; however, successful maintenance of weight loss continues to pose a challenge. OBJECTIVE: The present study was designed to assess whether changes in subcutaneous adipose tissue (scAT) gene expression during a low-calorie diet (LCD) could be used to differentiate and predict subjects who experience successful short-term weight maintenance from subjects who experience weight regain. DESIGN: Forty white women followed a dietary protocol consisting of an 8-wk LCD phase followed by a 6-mo weight-maintenance phase. Participants were classified as weight maintainers (WMs; 0-10% weight regain) and weight regainers (WRs; 50-100% weight regain) by considering changes in body weight during the 2 phases. Anthropometric measurements, bioclinical variables, and scAT gene expression were studied in all individuals before and after the LCD. Energy intake was estimated by using 3-d dietary records. RESULTS: No differences in body weight and fasting insulin were observed between WMs and WRs at baseline or after the LCD period. The LCD resulted in significant decreases in body weight and in several plasma variables in both groups. WMs experienced a significant reduction in insulin secretion in response to an oral-glucose-tolerance test after the LCD; in contrast, no changes in insulin secretion were observed in WRs after the LCD. An ANOVA of scAT gene expression showed that genes regulating fatty acid metabolism, citric acid cycle, oxidative phosphorylation, and apoptosis were regulated differently by the LCD in WM and WR subjects. CONCLUSION: This study suggests that LCD-induced changes in insulin secretion and scAT gene expression may have the potential to predict successful short-term weight maintenance. This trial was registered at clinicaltrials.gov as NCT00390637.

Nutritional supplementation during pregnancy and offspring cardiovascular disease risk in The Gambia.

BACKGROUND: Maternal nutritional intake during pregnancy may have important consequences for long-term health in offspring. OBJECTIVE: The objective was to follow up the offspring in 2 randomized trials of nutrient supplementation during pregnancy to investigate the effect on cardiovascular disease (CVD) risk in offspring. DESIGN: We recruited offspring born during 2 trials in The Gambia, West Africa. One trial provided protein-energy-dense food supplements (1015 kcal and 22 g protein/d) to pregnant (intervention, from 20 wk gestation until delivery) or lactating (control, for 20 wk from birth) women and was randomized at the village level. The second was a double-blind, individually randomized, placebo-controlled trial of calcium supplementation (1.5 g/d), which was also provided from 20 wk gestation until delivery. RESULTS: Sixty-two percent (n = 1267) of children (aged 11-17 y) born during the protein-energy trial were recruited and included in the analysis, and 64% (n = 350) of children (aged 5-10 y) born during the calcium trial were recruited and included in the analysis. Fasted plasma glucose was marginally lower in children born to mothers receiving protein-energy supplements during pregnancy than in those children of the lactating group (adjusted mean difference: -0.05 mmol/L; 95% CI: -0.10, -0.001 mmol/L). There were no other differences in CVD risk factors, including blood pressure, body composition, and cholesterol, between children born to intervention and control women from the protein-energy trial. Maternal calcium supplementation during pregnancy was unrelated to offspring blood pressure. CONCLUSION: These data suggest that providing supplements to pregnant women in the second half of pregnancy may have little effect on the CVD risk of their offspring, at least in this setting and at the ages studied here. This trial was registered at www.controlled-trials.com as ISRCTN96502494.

Variation in the FFAR1 gene modifies BMI, body composition and beta-cell function in overweight subjects: an exploratory analysis.

BACKGROUND: FFAR1 receptor is a long chain fatty acid G-protein coupled receptor which is expressed widely, but found in high density in the pancreas and central nervous system. It has been suggested that FFAR1 may play a role in insulin sensitivity, lipotoxicity and is associated with type 2 diabetes. Here we investigate the effect of three common SNPs of FFAR1 (rs2301151; rs16970264; rs1573611) on pancreatic function, BMI, body composition and plasma lipids. METHODOLOGY/PRINCIPAL FINDINGS: For this enquiry we used the baseline RISCK data, which provides a cohort of overweight subjects at increased cardiometabolic risk with detailed phenotyping. The key findings were SNPs of the FFAR1 gene region were associated with differences in body composition and lipids, and the effects of the 3 SNPs combined were cumulative on BMI, body composition and total cholesterol. The effects on BMI and body fat were predominantly mediated by rs1573611 (1.06 kg/m(2) higher (P = 0.009) BMI and 1.53% higher (P = 0.002) body fat per C allele). Differences in plasma lipids were also associated with the BMI-increasing allele of rs2301151 including higher total cholesterol (0.2 mmol/L per G allele, P = 0.01) and with the variant A allele of rs16970264 associated with lower total (0.3 mmol/L, P = 0.02) and LDL (0.2 mmol/L, P<0.05) cholesterol, but also with lower HDL-cholesterol (0.09 mmol/L, P<0.05) although the difference was not apparent when controlling for multiple testing. There were no statistically significant effects of the three SNPs on insulin sensitivity or beta cell function. However accumulated risk allele showed a lower beta cell function on increasing plasma fatty acids with a carbon chain greater than six. CONCLUSIONS/SIGNIFICANCE: Differences in body composition and lipids associated with common SNPs in the FFAR1 gene were apparently not mediated by changes in insulin sensitivity or beta-cell function.

Diet, obesity and diabetes: a current update.

The prevalence of obesity has been increasing at a rapid rate over the last few decades. Although the primary defect can be attributed to an imbalance of energy intake over energy expenditure, the regulation of energy balance is now recognized to be complex. Adipose-tissue factors play a central role in the control of energy balance and whole-body fuel homoeostasis. The regulation of adipose-tissue function, in particular its secretion of adipokines, is impaired by increases in adipose mass associated with obesity, and with the development of insulin resistance and Type 2 diabetes. This review analyses adipose-regulated energy input and expenditure, together with the impact of dietary macronutrient composition on energy balance in relation to susceptibility to the development of obesity and Type 2 diabetes, and how these metabolic conditions may be exacerbated by the consequences of abnormal adipose function. By gaining a greater understanding of how energy balance is controlled in normal, and in obese and diabetic states, a more practical approach can be employed to prevent and better treat obesity and metabolic disorders.