Investigating the synergistic effects of hormone replacement therapy, apolipoprotein E and age on brain health in the UK Biobank.

Global prevalence of Alzheimer's Disease has a strong sex bias, with women representing approximately two-thirds of the patients. Yet, the role of sex-specific risk factors during midlife, including hormone replacement therapy (HRT) and their interaction with other major risk factors for Alzheimer's Disease, such as apolipoprotein E (APOE)-e4 genotype and age, on brain health remains unclear. We investigated the relationship between HRT (i.e., use, age of initiation and duration of use) and brain health (i.e., cognition and regional brain volumes). We then consider the multiplicative effects of HRT and APOE status (i.e., e2/e2, e2/e3, e3/e3, e3/e4 and e4/e4) via a two-way interaction and subsequently age of participants via a three-way interaction. Women from the UK Biobank with no self-reported neurological conditions were included (N = 207,595 women, mean age = 56.25 years, standard deviation = 8.01 years). Generalised linear regression models were computed to quantify the cross-sectional association between HRT and brain health, while controlling for APOE status, age, time since attending centre for completing brain health measure, surgical menopause status, smoking history, body mass index, education, physical activity, alcohol use, ethnicity, socioeconomic status, vascular/heart problems and diabetes diagnosed by doctor. Analyses of structural brain regions further controlled for scanner site. All brain volumes were normalised for head size. Two-way interactions between HRT and APOE status were modelled, in addition to three-way interactions including age. Results showed that women with the e4/e4 genotype who have used HRT had 1.82% lower hippocampal, 2.4% lower parahippocampal and 1.24% lower thalamus volumes than those with the e3/e3 genotype who had never used HRT. However, this interaction was not detected for measures of cognition. No clinically meaningful three-way interaction between APOE, HRT and age was detected when interpreted relative to the scales of the cognitive measures used and normative models of ageing for brain volumes in this sample. Differences in hippocampal volume between women with the e4/e4 genotype who have used HRT and those with the e3/e3 genotype who had never used HRT are equivalent to approximately 1-2 years of hippocampal atrophy observed in typical health ageing trajectories in midlife (i.e., 0.98%-1.41% per year). Effect sizes were consistent within APOE e4/e4 group post hoc sensitivity analyses, suggesting observed effects were not solely driven by APOE status and may, in part, be attributed to HRT use. Although, the design of this study means we cannot exclude the possibility that women who have used HRT may have a predisposition for poorer brain health.

Towards consistency in dietary pattern scoring: standardising scoring workflows for healthy dietary patterns using 24-h recall and two variations of a food frequency questionnair.

Healthy dietary patterns such as the Mediterranean diet (MeDi), Dietary Approaches to Stop Hypertension (DASH) and the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) have been evaluated for their potential association with health outcomes. However, the lack of standardisation in scoring methodologies can hinder reproducibility and meaningful cross-study comparisons. Here we provide a reproducible workflow for generating the MeDi, DASH and MIND dietary pattern scores from frequently used dietary assessment tools including the 24-h recall tool and two variations of FFQ. Subjective aspects of the scoring process are highlighted and have led to a recommended reporting checklist. This checklist enables standardised reporting with sufficient detail to enhance the reproducibility and comparability of their outcomes. In addition to these aims, valuable insights in the strengths and limitations of each assessment tool for scoring the MeDi, DASH and MIND diet can be utilised by researchers and clinicians to determine which dietary assessment tool best meets their needs.

Mediterranean diet adherence is associated with lower dementia risk, independent of genetic predisposition: findings from the UK Biobank prospective cohort study.

BACKGROUND: The identification of effective dementia prevention strategies is a major public health priority, due to the enormous and growing societal cost of this condition. Consumption of a Mediterranean diet (MedDiet) has been proposed to reduce dementia risk. However, current evidence is inconclusive and is typically derived from small cohorts with limited dementia cases. Additionally, few studies have explored the interaction between diet and genetic risk of dementia. METHODS: We used Cox proportional hazard regression models to explore the associations between MedDiet adherence, defined using two different scores (Mediterranean Diet Adherence Screener [MEDAS] continuous and Mediterranean diet Pyramid [PYRAMID] scores), and incident all-cause dementia risk in 60,298 participants from UK Biobank, followed for an average 9.1 years. The interaction between diet and polygenic risk for dementia was also tested. RESULTS: Higher MedDiet adherence was associated with lower dementia risk (MEDAS continuous: HR = 0.77, 95% CI = 0.65-0.91; PYRAMID: HR = 0.86, 95% CI = 0.73-1.02 for highest versus lowest tertiles). There was no significant interaction between MedDiet adherence defined by the MEDAS continuous and PYRAMID scores and polygenic risk for dementia. CONCLUSIONS: Higher adherence to a MedDiet was associated with lower dementia risk, independent of genetic risk, underlining the importance of diet in dementia prevention interventions.

Effects of a mediterranean diet on the gut microbiota and microbial metabolites: A systematic review of randomized controlled trials and observational studies.

Consumption of the Mediterranean dietary pattern (MedDiet) is associated with reduced risk of numerous non-communicable diseases. Modulation of the composition and metabolism of the gut microbiota represents a potential mechanism through which the MedDiet elicits these effects. We conducted a systematic literature search (Prospero registration: CRD42020168977) using PubMed, The Cochrane Library, MEDLINE, SPORTDiscuss, Scopus and CINAHL databases for randomized controlled trials (RCTs) and observational studies exploring the impact of a MedDiet on gut microbiota composition (i.e., relative abundance of bacteria or diversity metrics) and metabolites (e.g., short chain fatty acids). Seventeen RCTs and 17 observational studies were eligible for inclusion in this review. Risk of bias across the studies was mixed but mainly identified as low and unclear. Overall, RCTs and observational studies provided no clear evidence of a consistent effect of a MedDiet on composition or metabolism of the gut microbiota. These findings may be related to the diverse methods across studies (e.g., MedDiet classification and analytical techniques), cohort characteristics, and variable quality of studies. Further, well-designed studies are warranted to advance understanding of the potential effects of the MedDiet using more detailed examination of microbiota and microbial metabolites with reference to emerging characteristics of a healthy gut microbiome.

Perspectives on the application of CONSORT guidelines to randomised controlled trials in nutrition.

PURPOSE: Reporting guidelines facilitate quality and completeness in research reporting. The CONsolidated Standards Of Reporting Trials (CONSORT) statement is widely applied to dietary and nutrition trials but has no extension specific to nutrition. Evidence suggests poor reporting in nutrition research. The Federation of European Nutrition Societies led an initiative to make recommendations for a nutrition extension to the CONSORT statement towards a more robust reporting of the evidence base. METHODS: An international working group was formed of nutrition researchers from 14 institutions in 12 different countries and on five continents. Using meetings over a period of one year, we interrogated the CONSORT statement specifically for its application to report nutrition trials. RESULTS: We provide a total of 28 new nutrition-specific recommendations or emphasised recommendations for the reporting of the introduction (three), methods (twelve), results (five) and discussion (eight). We also added two additional recommendations that were not allocated under the standard CONSORT headings. CONCLUSION: We identify a need to provide guidance in addition to CONSORT to improve the quality and consistency of the reporting and propose key considerations for further development of formal guidelines for the reporting of nutrition trials. Readers are encouraged to engage in this process, provide comments and conduct specific studies to inform further work on the development of reporting guidelines for nutrition trials.

APOE4 genotype exacerbates the impact of menopause on cognition and synaptic plasticity in APOE-TR mice.

The impact of sex and menopausal status in Alzheimer's disease remains understudied despite increasing evidence of greater female risk, particularly in APOE4 carriers. Utilizing female APOE-TR mice maintained on a high-fat diet background we induced ovarian failure through repeated VCD injections, to mimic human menopause. At 12 months of age, recognition memory and spatial memory were assessed using object recognition, Y-maze spontaneous alternation, and Barnes maze. A VCD*genotype interaction reduced the recognition memory (P < .05), with APOE4 VCD-treated animals unable to distinguish between novel and familiar objects. APOE4 mice displayed an additional 37% and 12% reduction in Barnes (P < .01) and Y-maze (P < .01) performance, indicative of genotype-specific spatial memory impairment. Molecular analysis indicated both VCD and genotype-related deficits in synaptic plasticity with BDNF, Akt, mTOR, and ERK signaling compromised. Subsequent reductions in the transcription factors Creb1 and Atf4 were also evident. Furthermore, the VCD*genotype interaction specifically diminished Ephb2 expression, while Fos, and Cnr1 expression reduced as a consequence of APOE4 genotype. Brain DHA levels were 13% lower in VCD-treated animals independent of genotype. Consistent with this, we detected alterations in the expression of the DHA transporters Acsl6 and Fatp4. Our results indicate that the combination of ovarian failure and APOE4 leads to an exacerbation of cognitive and neurological deficits.

Short-term effects of a Mediterranean-style dietary pattern on cognition and mental well-being: a systematic review of clinical trials.

Although the long-term effects of a Mediterranean-style dietary pattern (MDP) on cognition and overall mental well-being have been consistently described, the short-term effects of the MDP on cognitive performance, mood and anxiety have not been as widely reviewed. Therefore, the aims of this systematic review were to synthesise the evidence from randomised controlled trials (RCT), to examine whether a MDP can alter cognition and overall mental well-being in the short-term (up to 10 d). This will also be used to identify research gaps and to inform the design of future acute RCT in the area. Ovid Embase, Ovid MEDLINE and Web of Science Core Collection were searched from inception to 8 December 2020. The data were synthesised narratively with no quantitative synthesis. The detailed protocol is available on PROSPERO, with the registration number CRD42021221085. A total of 3002 studies were initially identified. After the deduplication and screening stages, four studies (three articles and one conference proceeding) were eligible to be included. Despite the very limited data obtained, the literature suggests that a MDP can improve cognition and mood in the short-term. Specifically, improvements in attention, alertness and contentment were consistently reported. A MDP appears as a promising strategy to improve short-term cognitive and mental health. A limitation of this review is the small number of studies identified; therefore, future studies are required to confirm these initial novel findings and to provide granularity as to which domains are most responsive and in which population subgroups.

Toward personalized cognitive diagnostics of at-genetic-risk Alzheimer's disease.

Spatial navigation is emerging as a critical factor in identifying preclinical Alzheimer's disease (AD). However, the impact of interindividual navigation ability and demographic risk factors (e.g., APOE, age, and sex) on spatial navigation make it difficult to identify persons "at high risk" of AD in the preclinical stages. In the current study, we use spatial navigation big data (n = 27,108) from the Sea Hero Quest (SHQ) game to overcome these challenges by investigating whether big data can be used to benchmark a highly phenotyped healthy aging laboratory cohort into high- vs. low-risk persons based on their genetic (APOE) and demographic (sex, age, and educational attainment) risk factors. Our results replicate previous findings in APOE ε4 carriers, indicative of grid cell coding errors in the entorhinal cortex, the initial brain region affected by AD pathophysiology. We also show that although baseline navigation ability differs between men and women, sex does not interact with the APOE genotype to influence the manifestation of AD-related spatial disturbance. Most importantly, we demonstrate that such high-risk preclinical cases can be reliably distinguished from low-risk participants using big-data spatial navigation benchmarks. By contrast, participants were undistinguishable on neuropsychological episodic memory tests. Taken together, we present evidence to suggest that, in the future, SHQ normative benchmark data can be used to more accurately classify spatial impairments in at-high-risk of AD healthy participants at a more individual level, therefore providing the steppingstone for individualized diagnostics and outcome measures of cognitive symptoms in preclinical AD.

Mediterranean Diet Increases Endothelial Function in Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: The endothelium plays a key role in the maintenance of vascular health and represents a potential physiological target for dietary and other lifestyle interventions designed to reduce the risk of cardiovascular diseases (CVD) including stroke or coronary heart disease. OBJECTIVE: To conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) investigating the effects of the Mediterranean dietary pattern (MedDiet) on endothelial function. METHODS: Medline, Embase, and Scopus databases were searched from inception until January 2019 for studies that met the following criteria: 1) RCTs including adult participants, 2) interventions promoting the MedDiet, 3) inclusion of a control group, and 4) measurements of endothelial function. A random-effects meta-analysis was conducted. Metaregression and subgroup analyses were performed to identify whether effects were modified by health status (i.e., healthy participants versus participants with existing comorbidities), type of intervention (i.e., MedDiet alone or with a cointervention), study duration, study design (i.e., parallel or crossover), BMI, and age of participants. RESULTS: Fourteen articles reporting data for 1930 participants were included in the meta-analysis. Study duration ranged from 4 wk to 2.3 y. We observed a beneficial effect of the MedDiet on endothelial function [standardized mean difference (SMD): 0.35; 95% CI: 0.17, 0.53; P <0.001; I2 = 73.68%]. MedDiet interventions improved flow-mediated dilation (FMD)-the reference method for noninvasive, clinical measurement of endothelial function-by 1.66% (absolute change; 95% CI: 1.15, 2.17; P <0.001; I2 = 0%). Effects of the MedDiet on endothelial function were not modified by health status, type of intervention, study duration, study design, BMI, or age of participants (P >0.05). CONCLUSIONS: MedDiet interventions improve endothelial function in adults, suggesting that the protective effects of the MedDiet are evident at early stages of the atherosclerotic process with important implications for the early prevention of CVD. This study has the PROSPERO registration number: CRD42018106188.

Altered SPMs and age-associated decrease in brain DHA in APOE4 female mice.

An apolipoprotein E (APOE) 4 genotype is the most important, common genetic determinant for Alzheimer disease (AD), and female APOE4 carriers present with an increased risk compared with males. The study quantified cortical and hippocampal fatty acid and phospholipid profiles along with select eicosapentaenoic acid (EPA)- and docosahexaenoic acid (DHA)-derived specialized proresolving mediators (SPMs) in 2-, 9-, and 18-mo-old APOE3 and APOE4 male and female mice. A 10% lower cortical DHA was evident in APOE4 females at 18 mo compared with 2 mo, with no significant decrease in APOE3 or APOE4 males. This decrease was associated with a reduction in DHA-phosphatidylethanolamine. Older APOE4 females had a 15% higher oleic acid content compared with young mice. Although no sex*APOE genotype interactions were observed for SPMs expressed as a ratio of their parent compound, higher cortical 18R/S-hydroxy-5Z,8Z,11Z,14Z,16E-EPA, resolvin D3, protectin D1, 10S,17S-dihydroxy-4Z,7Z,11E,13E,15Z,19Z-DHA (10S,17S-diHDHA), maresin 1, 17S-hydroxy-4Z,7Z,10Z,13Z,15E,19Z-DHA, and 14S-hydroxy-4Z,7Z,10Z,12E,16Z,19Z-DHA were evident in females, and lower cortical 17R-resolvin D1, 10S,17S-diHDHA, and 18-HEPE in APOE4. Our findings show a strong association between age, female sex, and an APOE4 genotype, with decreased cortical DHA and a number of SPMs, which together may contribute to the development of cognitive decline and AD pathology.-Martinsen, A., Tejera, N., Vauzour, D., Harden, G., Dick, J., Shinde, S., Barden, A., Mori, T. A., Minihane, A. M. Altered SPMs and age-associated decrease in brain DHA in APOE4 female mice.

APOE genotype influences the gut microbiome structure and function in humans and mice: relevance for Alzheimer's disease pathophysiology.

Apolipoprotein E (APOE) genotype is the strongest prevalent genetic risk factor for Alzheimer's disease (AD). Numerous studies have provided insights into the pathologic mechanisms. However, a comprehensive understanding of the impact of APOE genotype on microflora speciation and metabolism is completely lacking. In this study, we investigated the association between APOE genotype and the gut microbiome composition in human and APOE-targeted replacement (TR) transgenic mice. Fecal microbiota amplicon sequencing from matched individuals with different APOE genotypes revealed no significant differences in overall microbiota diversity in group-aggregated human APOE genotypes. However, several bacterial taxa showed significantly different relative abundance between APOE genotypes. Notably, we detected an association of Prevotellaceae and Ruminococcaceae and several butyrate-producing genera abundances with APOE genotypes. These findings were confirmed by comparing the gut microbiota of APOE-TR mice. Furthermore, metabolomic analysis of murine fecal water detected significant differences in microbe-associated amino acids and short-chain fatty acids between APOE genotypes. Together, these findings indicate that APOE genotype is associated with specific gut microbiome profiles in both humans and APOE-TR mice. This suggests that the gut microbiome is worth further investigation as a potential target to mitigate the deleterious impact of the APOE4 allele on cognitive decline and the prevention of AD.-Tran, T. T. T., Corsini, S., Kellingray, L., Hegarty, C., Le Gall, G., Narbad, A., Müller, M., Tejera, N., O'Toole, P. W., Minihane, A.-M., Vauzour, D. APOE genotype influences the gut microbiome structure and function in humans and mice: relevance for Alzheimer's disease pathophysiology.

APPLE-Tree (Active Prevention in People at risk of dementia: Lifestyle, bEhaviour change and Technology to REducE cognitive and functional decline) programme: Protocol.

BACKGROUND: Observational studies indicate that approximately a third of dementia cases are attributable to modifiable cardiometabolic, physical and mental health, and social and lifestyle risk factors. There is evidence that intensive behaviour change interventions targeting these factors can reduce cognitive decline. [Figure: see text] METHODS AND ANALYSIS: We will design and test a low intensity, secondary dementia-prevention programme (Active Prevention in People at risk of dementia: Lifestyle, bEhaviour change and Technology to REducE cognitive and functional decline, "APPLE-Tree") to slow cognitive decline in people with subjective cognitive decline with or without objective cognitive impairment. We will embed our work within social science research to understand how dementia prevention is currently delivered and structured. We will carry out systematic reviews and around 50 qualitative interviews with stakeholders, using findings to coproduce the APPLE-Tree intervention. We plan a 10-session group intervention, involving personalised goal-setting, with individual sessions for those unable or unwilling to attend groups, delivered by psychology assistants who will be trained and supervised by clinical psychologists. The coproduction group (including public and patient involvement [PPI], academic and clinical/third-sector professional representatives) will use the Behaviour Change Wheel theoretical framework to develop it. We will recruit and randomly allocate 704 participants, 1:1 to the intervention: informational control group. This sample size is sufficient to detect a between-group difference at 2 years of 0.15 on the primary outcome (cognition: modified neuropsychological test battery; 90% power, 5% significance, effect size 0.25, SD 0.6). DISSEMINATION: We will work with Public Health England and third-sector partners to produce an effective national implementation approach, so that if our intervention works, it is used in practice.

Study protocol: ASCRIBED: the impact of Acute SystematiC inflammation upon cerebRospinal fluId and blood BiomarkErs of brain inflammation and injury in dementia: a study in acute hip fracture patients.

BACKGROUND: Hip fracture represents a substantial acute inflammatory trauma, which may constitute a significant insult to the degenerating brain. Research suggests that an injury of this kind can affect memory and thinking in the future but it is unclear whether, and how, inflammatory trauma injures the brain. The impact of Acute SystematiC inflammation upon cerebRospinal fluId and blood BiomarkErs of brain inflammation and injury in Dementia: a study in acute hip fracture patients (ASCRIBED) explores this relationship, to understand the effect of inflammation on the progression of dementia. METHODS: This protocol describes a multi-centre sample collection observational study. The study utilises the unique opportunity provided by hip fracture operations undertaken via spinal anaesthesia to collect cerebrospinal fluid (CSF) and blood, to investigate the impact of acute brain inflammation caused by hip fracture on the exacerbation of dementia. We will recruit 200 hip fracture patients with a diagnosis or evidence of dementia; and 200 hip fracture patients without dementia. We will also recruit 'Suitable informants', individuals in regular contact with the patient, to provide further proxy evidence of a patient's potential cognitive decline. We will compare these 400 samples with existing CSF and blood samples from a cohort of dementia patients who had not experienced a systemic inflammatory response due to injury. This will provide a comparison between patients with and without dementia who are suffering a systemic inflammatory response; with stable patients living with dementia. DISCUSSION: We will test the hypothesis that hip fracture patients living with dementia show elevated markers of brain inflammation, as well as neuronal injury and Alzheimer-related plaque pathology, in comparison to (1) stable patients living with dementia and (2) hip fracture patients without dementia, as measured by biomarkers in CSF and blood. The findings will address the hypothesis that systemic inflammatory events can exacerbate underlying dementia and inform the search for new treatments targeting inflammation in dementia. TRIAL REGISTRATION: ISRCTN43803769 . Registered 11 May 2017.

Future prospects for dissecting inter-individual variability in the absorption, distribution and elimination of plant bioactives of relevance for cardiometabolic endpoints.

PURPOSE: The health-promoting potential of food-derived plant bioactive compounds is evident but not always consistent across studies. Large inter-individual variability may originate from differences in digestion, absorption, distribution, metabolism and excretion (ADME). ADME can be modulated by age, sex, dietary habits, microbiome composition, genetic variation, drug exposure and many other factors. Within the recent COST Action POSITIVe, large-scale literature surveys were undertaken to identify the reasons and extent of inter-individual variability in ADME of selected plant bioactive compounds of importance to cardiometabolic health. The aim of the present review is to summarize the findings and suggest a framework for future studies designed to investigate the etiology of inter-individual variability in plant bioactive ADME and bioefficacy. RESULTS: Few studies have reported individual data on the ADME of bioactive compounds and on determinants such as age, diet, lifestyle, health status and medication, thereby limiting a mechanistic understanding of the main drivers of variation in ADME processes observed across individuals. Metabolomics represent crucial techniques to decipher inter-individual variability and to stratify individuals according to metabotypes reflecting the intrinsic capacity to absorb and metabolize bioactive compounds. CONCLUSION: A methodological framework was developed to decipher how the contribution from genetic variants or microbiome variants to ADME of bioactive compounds can be predicted. Future study design should include (1) a larger number of study participants, (2) individual and full profiling of all possible determinants of internal exposure, (3) the presentation of individual ADME data and (4) incorporation of omics platforms, such as genomics, microbiomics and metabolomics in ADME and efficacy studies.

n-3 Fatty acids combined with flavan-3-ols prevent steatosis and liver injury in a murine model of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) affects 25% of adults and at present no licensed medication has been approved. Despite its complex patho-physiology, dietary strategies aiming at delaying or preventing NAFLD have taken a reductionist approach, examining the impact of single components. Accumulating evidence suggests that n-3 LC-PUFAs are efficacious in regulating lipogenesis and fatty acid oxidation. In addition, plant derived flavonoids are also emerging as a dietary strategy for NAFLD prevention, with efficacy attributed to their insulin sensitising and indirect antioxidant effects. Based on knowledge of their complementary molecular targets, we aimed to demonstrate that the combination of n-3 LC-PUFA (n-3) and flavan-3-ols (FLAV) prevents NAFLD. In a high-fat high-fructose (HF/HFr) fed C57Bl/6J mouse model, the independent and interactive impact of n-3 and FLAV on histologically defined NAFLD, insulin sensitivity, weight gain, intestinal and hepatic gene expression, intestinal bile acids were examined. Only the combination of FLAV and n-3 (FLAVn-3) prevented steatosis as evidenced by a strong reduction in hepatocyte ballooning. While FLAV reduced body (-28-30%), adipose tissue (-45-50%) weights and serum insulin (-22-25%) as observed following an intra-peritoneal glucose tolerance test, n-3 downregulated the expression of Srebf1 and the lipogenic genes (Acaca, Fasn). Significant impacts of interventions on intestinal bile acid metabolism, farnesoid X receptor (Fxr) signalling in the intestine and liver, and hepatic expression of fatty acid transporters (Fabp4, Vldlr, Cd36) were also evident. FLAVn-3 may be a novel intervention for NAFLD. Future research should aim to demonstrate its efficacy in the prevention and treatment of human NAFLD.

The effect of dietary fish oil on weight gain and insulin sensitivity is dependent on APOE genotype in humanized targeted replacement mice.

We investigated the independent and interactive impact of the common APOE genotype and marine n-3 polyunsaturated fatty acids (PUFAs) on the development of obesity and associated cardiometabolic dysfunction in a murine model. Human APOE3 and APOE4 targeted replacement mice were fed either a control high-fat diet (HFD) or an HFD supplemented with 3% n-3 PUFAs from fish oil (HFD + FO) for 8 wk. We established the impact of intervention on food intake, body weight, and visceral adipose tissue (VAT) mass; plasma, lipids (cholesterol and triglycerides), liver enzymes, and adipokines; glucose and insulin during an intraperitoneal glucose tolerance test; and Glut4 and ApoE expression in VAT. HFD feeding induced more weight gain and higher plasma lipids in APOE3 compared to APOE4 mice (P < 0.05), along with a 2-fold higher insulin and impaired glucose tolerance. Supplementing APOE3, but not APOE4, animals with dietary n-3 PUFAs decreased body-weight gain, plasma lipids, and insulin (P < 0.05) and improved glucose tolerance, which was associated with increased VAT Glut4 mRNA levels (P < 0.05). Our findings demonstrate that an APOE3 genotype predisposes mice to develop obesity and its metabolic complications, which was attenuated by n-3 PUFA supplementation.-Slim, K. E., Vauzour, D., Tejera, N., Voshol, P. J., Cassidy, A., Minihane, A. M. The effect of dietary fish oil on weight gain and insulin sensitivity is dependent on APOE genotype in humanized targeted replacement mice.

Differential effects of EPA versus DHA on postprandial vascular function and the plasma oxylipin profile in men.

Our objective was to investigate the impact of EPA versus DHA on arterial stiffness and reactivity and underlying mechanisms (with a focus on plasma oxylipins) in the postprandial state. In a three-arm crossover acute test meal trial, men (n = 26, 35-55 years) at increased CVD risk received a high-fat (42.4 g) test meal providing 4.16 g of EPA or DHA or control oil in random order. At 0 h and 4 h, blood samples were collected to quantify plasma fatty acids, long chain n-3 PUFA-derived oxylipins, nitrite and hydrogen sulfide, and serum lipids and glucose. Vascular function was assessed using blood pressure, reactive hyperemia index, pulse wave velocity, and augmentation index (AIx). The DHA-rich oil significantly reduced AIx by 13% (P = 0.047) with the decrease following EPA-rich oil intervention not reaching statistical significance. Both interventions increased EPA- and DHA-derived oxylipins in the acute postprandial state, with an (1.3-fold) increase in 19,20-dihydroxydocosapentaenoic acid evident after DHA intervention (P < 0.001). In conclusion, a single dose of DHA significantly improved postprandial arterial stiffness as assessed by AIx, which if sustained would be associated with a significant decrease in CVD risk. The observed increases in oxylipins provide a mechanistic insight into the AIx effect.

A Transgenic Camelina sativa Seed Oil Effectively Replaces Fish Oil as a Dietary Source of Eicosapentaenoic Acid in Mice.

BACKGROUND: Fish currently supplies only 40% of the eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) required to allow all individuals globally to meet the minimum intake recommendation of 500 mg/d. Therefore, alternative sustainable sources are needed. OBJECTIVE: The main objective was to investigate the ability of genetically engineered Camelina sativa (20% EPA) oil (CO) to enrich tissue EPA and DHA relative to an EPA-rich fish oil (FO) in mammals. METHODS: Six-week-old male C57BL/6J mice were fed for 10 wk either a palm oil-containing control (C) diet or diets supplemented with EPA-CO or FO, with the C, low-EPA CO (COL), high-EPA CO (COH), low-EPA FO (FOL), and high-EPA FO (FOH) diets providing 0, 0.4, 3.4, 0.3, and 2.9 g EPA/kg diet, respectively. Liver, muscle, and brain were collected for fatty acid analysis, and blood glucose and serum lipids were quantified. The expression of selected hepatic genes involved in EPA and DHA biosynthesis and in modulating their cellular impact was determined. RESULTS: The oils were well tolerated, with significantly greater weight gain in the COH and FOH groups relative to the C group (P < 0.001). Significantly lower (36-38%) blood glucose concentrations were evident in the FOH and COH mice relative to C mice (P < 0.01). Hepatic EPA concentrations were higher in all EPA groups relative to the C group (P < 0.001), with concentrations of 0.0, 0.4, 2.9, 0.2, and 3.6 g/100 g liver total lipids in the C, COL, COH, FOL, and FOH groups, respectively. Comparable dose-independent enrichments of liver DHA were observed in mice fed CO and FO diets (P < 0.001). Relative to the C group, lower fatty acid desaturase 1 (Fads1) expression (P < 0.005) was observed in the COH and FOH groups. Higher fatty acid desaturase 2 (Fads2), peroxisome proliferator-activated receptor α (Ppara), and peroxisome proliferator-activated receptor γ (Pparg) (P < 0.005) expressions were induced by CO. No impact of treatment on liver X receptor α (Lxra) or sterol regulatory element-binding protein 1c (Srebp1c) was evident. CONCLUSIONS: Oil from transgenic Camelina is a bioavailable source of EPA in mice. These data provide support for the future assessment of this oil in a human feeding trial.