Dietary docosahexaenoic acid (DHA) downregulates liver DHA synthesis by inhibiting eicosapentaenoic acid elongation.

DHA is abundant in brain where it regulates cell survival, neurogenesis and neuroinflammation. DHA can be obtained from the diet or synthesized from alpha-linolenic acid (ALA; 18:3n-3) via a series of desaturation and elongation reactions occurring in the liver. Tracer studies suggest that dietary DHA can downregulate its own synthesis, but the mechanism remains undetermined and is the primary objective of this paper. First, we show by tracing 13C content (δ13C) of DHA via compound-specific isotope analysis (CSIA), that following low dietary DHA, the brain receives DHA synthesized from ALA. We then show that dietary DHA increases mouse liver and serum EPA, which is dependant on ALA. Furthermore, by CSIA we demonstrate that the source of increased EPA is slowed EPA metabolism, not increased DHA retroconversion as previously assumed. DHA feeding alone or with ALA lowered liver elongation of very long-chain (ELOVL2, EPA elongation) enzyme activity despite no change in protein content. To further evaluate the role of ELOVL2, a liver-specific Elovl2 knockout was generated showing that DHA feeding in the presence or absence of a functional liver ELOVL2 yields similar results. An enzyme competition assay for EPA elongation suggests both uncompetitive and non-competitive inhibition by DHA depending on DHA levels. To translate our findings, we show that DHA supplementation in men and women increases EPA levels in a manner dependent on a SNP (rs953413) in the ELOVL2 gene. In conclusion, we identify a novel feedback inhibition pathway where dietary DHA downregulates its liver synthesis by inhibiting EPA elongation.

Neurofilament light-chain (NfL) and 18 kDa translocator protein in early psychosis and its putative high-risk.

Evidence of elevated peripheral Neurofilament light-chain (NfL) as a biomarker of neuronal injury can be utilized to reveal nonspecific axonal damage, which could reflect altered neuroimmune function. To date, only a few studies have investigated NfL as a fluid biomarker in schizophrenia primarily, though none in its putative prodrome (Clinical High-Risk, CHR) or in untreated first-episode psychosis (FEP). Further, it is unknown whether peripheral NfL is associated with 18 kDa translocator protein (TSPO), a validated neuroimmune marker. In this secondary study, we investigated for the first time (1) serum NfL in early stages of psychosis including CHR and FEP as compared to healthy controls, and (2) examined its association with brain TSPO, using [18F]FEPPA positron emission tomography (PET). Further, in the exploratory analyses, we aimed to assess associations between serum NfL and symptom severity in patient group and cognitive impairment in the combined cohort. A large cohort of 84 participants including 27 FEP (24 antipsychotic-naive), 41 CHR (34 antipsychotic-naive) and 16 healthy controls underwent structural brain MRI and [18F]FEPPA PET scan and their blood samples were obtained and assessed for serum NfL concentrations. We found no significant differences in serum NfL levels across clinical groups, controlling for age. We also found no significant association between NfL levels and brain TSPO in the entire cohort. We observed a negative association between serum NfL and negative symptom severity in CHR. Our findings suggest that neither active neuroaxonal deterioration as measured with NfL nor associated neuroimmune activation (TSPO) is clearly identifiable in an early mostly untreated psychosis sample including its putative high-risk.

Upregulated hepatic lipogenesis from dietary sugars in response to low palmitate feeding supplies brain palmitate.

Palmitic acid (PAM) can be provided in the diet or synthesized via de novo lipogenesis (DNL), primarily, from glucose. Preclinical work on the origin of brain PAM during development is scarce and contrasts results in adults. In this work, we use naturally occurring carbon isotope ratios (13C/12C; δ13C) to uncover the origin of brain PAM at postnatal days 0, 10, 21 and 35, and RNA sequencing to identify the pathways involved in maintaining brain PAM, at day 35, in mice fed diets with low, medium, and high PAM from birth. Here we show that DNL from dietary sugars maintains the majority of brain PAM during development and is augmented in mice fed low PAM. Importantly, the upregulation of hepatic DNL genes, in response to low PAM at day 35, demonstrates the presence of a compensatory mechanism to maintain total brain PAM pools compared to the liver; suggesting the importance of brain PAM regulation.

Protein concentrations and activities of fatty acid desaturase and elongase enzymes in liver, brain, testicle, and kidney from mice: Substrate dependency.

The synthesis rates of n-3 and n-6 polyunsaturated fatty acids (PUFAs) in rodents and humans are not agreed upon and depend on substrate availability independently of the capacity for synthesis. Therefore, we aimed to assess the activities of the enzymes for n-3 and n-6 PUFA synthesis pathways in liver, brain, testicle, kidney, heart, and lung, in relation to their protein concentration levels. Eight-week-old Balb/c mice (n = 8) were fed a standard chow diet (6.2% fat, 18.6% protein, and 44.2% carbohydrates) until 14 weeks of age, anesthetized with isoflurane and tissue samples were collected (previously perfused) and stored at -80°C. The protein concentration of the enzymes (Δ-6D, Δ-5D, Elovl2, and Elovl5) were assessed by ELISA kits; their activities were assayed using specific PUFA precursors and measuring the respective PUFA products as fatty acid methyl esters by gas chromatographic analysis. The liver had the highest capacity for PUFA biosynthesis, with limited activity in the brain, testicles, and kidney, while we failed to detect activity in the heart and lung. The protein concentration and activity of the enzymes were significantly correlated. Furthermore, Δ-6D, Δ-5D, and Elovl2 have a higher affinity for n-3 PUFA precursors compared to n-6 PUFA. The capacity for PUFA synthesis in mice mainly resides in the liver, with enzymes having preference for n-3 PUFAs.

Blood and tissue docosahexaenoic acid (DHA, 22:6n-3) turnover rates from Ahiflower® oil are not different than from DHA ethyl ester oil in a diet switch mouse model.

Ahiflower® oil is high in α-linolenic and stearidonic acids, however, tissue/blood docosahexaenoic acid (DHA, 22:6n-3) turnover from dietary Ahiflower oil has not been investigated. In this study, we use compound-specific isotope analysis to determine tissue DHA synthesis/turnover from Ahiflower, flaxseed and DHA oils. Pregnant BALB/c mice (13-17 days) were placed on a 2 % algal DHA oil diet of high carbon-13 content (δ13C) and pups (n = 132) were maintained on the diet until 9 weeks old. Mice were then randomly allocated to a low δ13C-n-3 PUFA diet of either: 1) 4 % Ahiflower oil, 2) 4.35 % flaxseed oil or 3) 1 % fish DHA ethyl ester oil for 1, 3, 7, 14, 30, 60 or 120 days (n = 6). Serum, liver, adipose and brains were collected and DHA levels and δ13C were determined. DHA concentrations were highest (p < 0.05) in the liver and adipose of DHA-fed animals with no diet differences in serum or brain (p > 0.05). Based on the presence or absence of overlapping 95 % C.I.'s, DHA half-lives and synthesis/turnover rates were not different between Ahiflower and DHA diets in the liver, adipose or brain. DHA half-lives and synthesis/turnover rates from flaxseed oil were significantly slower than from the DHA diet in all serum/tissues. These findings suggest that the distinct Ahiflower oil n-3 PUFA composition could support tissue DHA needs at a similar rate to dietary DHA, making it a unique plant-based dietary option for maintaining DHA turnover comparably to dietary DHA.

Dietary triacetin, but not medium chain triacylglycerides, blunts weight gain in diet-induced rat model of obesity.

Consumption of a Western diet (WD) is known to increase the risk of obesity. Short or medium chain fatty acids influence energy metabolism, and triacetin, a synthetic short chain triacylglyceride, has been shown to lower body fat under normal conditions. This study aimed to investigate if triacetin as part of a WD modifies rat weight and body fat. Male rats were fed a control diet or WD for 8 weeks. At week 8, rats in the WD group were maintained on a WD diet or switched to a WD diet containing 30% energy from medium-chain triacylglyceride (WD-MCT) or triacetin (WD-T) for another 8 weeks. At week 16, rats were euthanized and liver, adipose and blood were collected. Tissue fatty acids (FAs) were quantified by gas chromatography (GC) and hepatic FAs were measured by GC-combustion-isotope ratio mass spectrometry for δ13 C-palmitic acid (PAM)-a novel marker of de novo lipogenesis (DNL). Rats fed WD-T had a body weight not statistically different to the control group, and gained less body weight than rats fed WD alone. Furthermore, WD-T fed rats had a lower fat mass, and lower total liver and plasma FAs compared to the WD group. Rats fed WD-T did not differ from WD in blood ketone or glucose levels, however, had a significantly lower hepatic δ13 C-PAM value than WD fed rats; suggestive of lower DNL. In summary, we show that triacetin has the potential to blunt weight gain and adipose tissue accumulation in a rodent model of obesity, possibly due to a decrease in DNL.

Circulating Endocannabinoids and N-Acylethanolamines in Individuals with Cannabis Use Disorder-Preliminary Findings.

BACKGROUND: Endocannabinoids and related N-acylethanolamines (NAEs) are bioactive lipids with important physiological functions and putative roles in mental health and addictions. Although chronic cannabis use is associated with endocannabinoid system changes, the status of circulating endocannabinoids and related NAEs in people with cannabis use disorder (CUD) is uncertain. METHODS: Eleven individuals with CUD and 54 healthy non-cannabis using control participants (HC) provided plasma for measurement by high-performance liquid chromatography-mass spectrometry of endocannabinoids (2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA)) and related NAE fatty acids (N-docosahexaenoylethanolamine (DHEA) and N-oleoylethanolamine (OEA)). Participants were genotyped for the functional gene variant of FAAH (rs324420, C385A) which may affect concentrations of AEA as well as other NAEs (OEA, DHEA). RESULTS: In overnight abstinent CUD, AEA, OEA and DHEA concentrations were significantly higher (31-40%; p < 0.05) and concentrations of the endocannabinoid 2-AG were marginally elevated (55%, p = 0.13) relative to HC. There were no significant correlations between endocannabinoids/NAE concentrations and cannabis analytes, self-reported cannabis use frequency or withdrawal symptoms. DHEA concentration was inversely related with marijuana craving (r = -0.86; p = 0.001). Genotype had no significant effect on plasma endocannabinoids/NAE concentrations. CONCLUSIONS: Our preliminary findings, requiring replication, might suggest that activity of the endocannabinoid system is elevated in chronic cannabis users. It is unclear whether this elevation is a compensatory response or a predating state. Studies examining endocannabinoids and NAEs during prolonged abstinence as well as the potential role of DHEA in craving are warranted.

Analysis of omega-3 and omega-6 polyunsaturated fatty acid metabolism by compound-specific isotope analysis in humans.

Natural variations in the 13C:12C ratio (carbon-13 isotopic abundance [δ13C]) of the food supply have been used to determine the dietary origin and metabolism of fatty acids, especially in the n-3 PUFA biosynthesis pathway. However, n-6 PUFA metabolism following linoleic acid (LNA) intake remains under investigation. Here, we sought to use natural variations in the δ13C signature of dietary oils and fatty fish to analyze n-3 and n-6 PUFA metabolism following dietary changes in LNA and eicosapentaenoic acid (EPA) + DHA in adult humans. Participants with migraine (aged 38.6 ± 2.3 years, 93% female, body mass index of 27.0 ± 1.1 kg/m2) were randomly assigned to one of three dietary groups for 16 weeks: 1) low omega-3, high omega-6 (H6), 2) high omega-3, high omega-6 (H3H6), or 3) high omega-3, low omega-6 (H3). Blood was collected at baseline, 4, 10, and 16 weeks. Plasma PUFA concentrations and δ13C were determined. The H6 intervention exhibited increases in plasma LNA δ13C signature over time; meanwhile, plasma LNA concentrations were unchanged. No changes in plasma arachidonic acid δ13C or concentration were observed. Participants on the H3H6 and H3 interventions demonstrated increases in plasma EPA and DHA concentration over time. Plasma δ13C-EPA increased in total lipids of the H3 group and phospholipids of the H3H6 group compared with baseline. Compound-specific isotope analysis supports a tracer-free technique that can track metabolism of dietary fatty acids in humans, provided that the isotopic signature of the dietary source is sufficiently different from plasma δ13C.

Association of Serum Very-Long-Chain Saturated Fatty Acids With Changes in Insulin Sensitivity and ß-Cell Function: The Prospective Metabolism and Islet Cell Evaluation (PROMISE) Cohort.

A unique group of circulating very-long-chain saturated fatty acids (VLCSFAs), including arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0), have been associated with a lower risk of type 2 diabetes, although associations with early metabolic risk phenotypes preceding type 2 diabetes have received limited study. We aimed to examine the associations of VLCSFAs with longitudinal changes in insulin sensitivity and ß-cell function in a cohort at risk for type 2 diabetes. VLCSFAs in the four main serum pools (phospholipid, triacylglycerol, cholesteryl ester, and nonesterified fatty acid) were extracted from fasting baseline samples (n = 467). Generalized estimating equations were used to determine the associations between VLCSFAs and changes over 9 years in validated indices of insulin sensitivity (HOMA2-%S [insulin sensitivity as percentage of normal population and ISI) and ß-cell function (insulinogenic index [IGI], IGI divided by HOMA-insulin resistance [IGI/IR], and insulin secretion sensitivity index 2 [ISSI-2]). Associations of VLCSFAs with outcomes were strongest in the triacylglycerol lipid pool: 20:0 was positively associated with both insulin sensitivity and ß-cell function (5.01% increase in HOMA2-%S and 4.01-6.28% increase in IGI/IR and ISSI-2 per SD increase in 20:0); 22:0 was positively associated with insulin sensitivity, with a 6.55% increase in HOMA2-%S and a 5.80% increase in ISI per SD increase in 22:0. Lastly, 24:0 was positively associated with insulin sensitivity and ß-cell function (7.94-8.45% increase in HOMA2-%S and ISI, and a 4.61-6.93% increase in IGI/IR and ISSI-2 per SD increase in 24:0). Fewer significant associations were observed in the cholesteryl ester and nonesterified pools. Overall, our results indicate positive longitudinal associations of VLCSFAs with insulin sensitivity and ß-cell function, especially within the triacylglycerol pool.

The Influence of APOE Genotype, DHA, and Flavanol Intervention on Brain DHA and Lipidomics Profile in Aged Transgenic Mice.

The apolipoprotein E4 (APOE4) genotype is predictive of Alzheimer's disease (AD). The brain is highly enriched with the omega-3 polyunsaturated fatty acid (n3-PUFA), docosahexaenoic acid (DHA). DHA's metabolism is defective in APOE4 carriers. Flavanol intake can play a role in modulating DHA levels. However, the impact of flavanol co-supplementation with fish oil on brain DHA uptake, status and partitioning, and according to APOE genotype is currently unknown. Here, using a humanised APOE3 and APOE4 targeted replacement transgenic mouse model, the interactive influence of cocoa flavanols (FLAV) and APOE genotype on the blood and subcortical brain PUFA status following the supplementation of a high fat (HF) enriched with DHA from fish oil (FO) was investigated. DHA levels increased in the blood (p < 0.001) and brain (p = 0.001) following supplementation. Compared to APOE3, a higher red blood cell (RBC) DHA (p < 0.001) was evident in APOE4 mice following FO and FLAV supplementation. Although FO did not increase the percentage of brain DHA in APOE4, a 17.1% (p < 0.05) and 20.0% (p < 0.001) higher DHA level in the phosphatidylcholine (PC) fraction in the HF FO and HF FO FLAV groups, and a 14.5% (p < 0.05) higher DHA level in the phosphatidylethanolamine (PE) fraction in the HF FO FLAV group was evident in these animals relative to the HF controls. The addition of FLAV (+/- FO) did not significantly increase the percentage of brain DHA in the group as a whole. However, a higher brain: RBC DHA ratio was evident in APOE3 only (p < 0.05) for HF FLAV versus HF. In conclusion, our data shows only modest effects of FLAV on the brain DHA status, which is limited to APOE3.

Oral health-related quality of life among women early postpartum: A cross-sectional study.

BACKGROUND: Periodontal diseases can negatively impact the oral health-related quality of life (OHRQoL) of pregnant women. This study investigates the association between maternal oral inflammatory load (OIL), sociodemographic characteristics, and the OHRQoL in postpartum women. METHODS: In this cross-sectional study, breastfeeding mothers were recruited from St. Michael's Hospital, Toronto within 2-4 weeks postpartum. Mothers were categorized into "Normal/low" and "High" OIL groups based on the absolute counts of oral polymorphonuclear neutrophils (oPMNs). The Oral Health Impact Profile-14 questionnaire was used to assess the impact of the maternal OIL on the OHRQoL. Multiple linear regression analyses were performed to examine the association between maternal sociodemographic factors including age, marital status, education level, employment status, parity, and their OHRQoL. RESULTS: Forty-seven mothers were included in this study. Mothers with high OIL reported higher impact on their OHRQoL (30%) than mothers with normal/low OIL (21%), but these differences were not statistically different. There was a negative relationship between the mother's education level and the extent of impact of OHRQoL on the "physical pain" dimension (p < 0.05), and between the mothers' age and employment status and the "physical disability" dimension (p < 0.05). A positive correlation was noted between multi-parity and the extent of impact of OHRQoL on the "physical disability" dimension (p = 0.009), and between the marital status and the "psychological disability" dimension (p < 0.05). CONCLUSION: This study highlighted the significant impact of sociodemographic characteristics on the OHRQoL of mothers, showcasing the importance of considering these factors when implementing targeted preventive dental care programs for mothers.

Association of circulating branched chain fatty acids with insulin sensitivity and beta cell function in the PROMISE cohort.

Branched chain fatty acids (BCFAs) are mainly saturated fatty acids with a methyl branch on the penultimate or antepenultimate carbon atom. While BCFAs are endogenously produced via the catabolism of branched chain amino acids, the primary exogenous source of BCFAs in the human body is via the diet, including dairy products. Recently, BCFAs have been identified as having a potentially protective role in the etiology of cardiometabolic disorders although current literature is limited. We aimed to investigate the longitudinal associations of circulating BCFAs across four serum pools with insulin sensitivity, beta cell function, and glucose concentrations in the PROMISE Cohort. Estimates of insulin sensitivity were assessed using Matsuda's insulin sensitivity index (ISI) and the homeostasis model assessment of insulin sensitivity (HOMA2). Estimates of beta cell function were determined using the insulinogenic index divided by HOMA insulin resistance and the insulin secretion-sensitivity index-2 (ISSI-2). Baseline serum samples were analyzed for BCFAs using gas-chromatography flame ionization detection. Longitudinal associations were determined using generalized estimating equations. In the free fatty acid (FFA) pool, iso15:0 and anteiso15:0 were positively associated with logHOMA2 (iso15:0 logHOMA2-%S: ß = 6.86, 95% CI: [1.64, 12.36], p < 0.05, anteiso15:0 logHOMA2-%S: ß = 6.36, 95% CI: [0.63, 12.42], p < 0.05) while anteiso14:0 was inversely associated with measures of insulin sensitivity (iso14:0 logHOMA2-%S: ß = -2.35, 95% CI: [-4.26, -0.40], p < 0.05, logISI: ß = -2.30, 95% CI: [-4.32, -0.23], p < 0.05, anteiso14:0 logHOMA2-%S: ß = -4.72, 95% CI: [-7.81, -1.52], p < 0.05, logISI: ß = -6.13, 95% CI: [-9.49, -2.66], p < 0.01). Associations in other pools were less consistent. We identified the potential importance of specific BCFAs, specifically iso14:0, anteiso14:0, iso15:0, anteiso15:0, in cardiometabolic phenotypes underlying type 2 diabetes.

Measuring brain docosahexaenoic acid turnover as a marker of metabolic consumption.

Docosahexaenoic acid (DHA, 22:6n-3) accretion in brain phospholipids is critical for maintaining the structural fluidity that permits proper assembly of protein complexes for signaling. Furthermore, membrane DHA can be released by phospholipase A2 and act as a substrate for the synthesis of bioactive metabolites that regulate synaptogenesis, neurogenesis, inflammation, and oxidative stress. Thus, brain DHA is consumed through multiple pathways including mitochondrial ß-oxidation, autoxidation to neuroprostanes, as well as enzymatic synthesis of bioactive metabolites including oxylipins, synaptamide, fatty-acid amides, and epoxides. By using models developed by Rapoport and colleagues, brain DHA loss has been estimated to be 0.07-0.26 µmol DHA/g brain/d. Since ß-oxidation of DHA in the brain is relatively low, a large portion of brain DHA loss may be attributed to the synthesis of autoxidative and bioactive metabolites. In recent years, we have developed a novel application of compound specific isotope analysis to trace DHA metabolism. By the use of natural abundance in 13C-DHA in the food supply, we are able to trace brain phospholipid DHA loss in free-living mice with estimates ranging from 0.11 to 0.38 µmol DHA/g brain/d, in reasonable agreement with previous methods. This novel fatty acid metabolic tracing methodology should improve our understanding of the factors that regulate brain DHA metabolism.

Rationale, Design and Participants Baseline Characteristics of a Crossover Randomized Controlled Trial of the Effect of Replacing SSBs with NSBs versus Water on Glucose Tolerance, Gut Microbiome and Cardiometabolic Risk in Overweight or Obese Adult SSB Consumer: Strategies to Oppose SUGARS with Non-Nutritive Sweeteners or Water (STOP Sugars NOW) Trial and Ectopic Fat Sub-Study.

BACKGROUND: Health authorities are near universal in their recommendation to replace sugar-sweetened beverages (SSBs) with water. Non-nutritive sweetened beverages (NSBs) are not as widely recommended as a replacement strategy due to a lack of established benefits and concerns they may induce glucose intolerance through changes in the gut microbiome. The STOP Sugars NOW trial aims to assess the effect of the substitution of NSBs (the "intended substitution") versus water (the "standard of care substitution") for SSBs on glucose tolerance and microbiota diversity. DESIGN AND METHODS: The STOP Sugars NOW trial (NCT03543644) is a pragmatic, "head-to-head", open-label, crossover, randomized controlled trial conducted in an outpatient setting. Participants were overweight or obese adults with a high waist circumference who regularly consumed ≥1 SSBs daily. Each participant completed three 4-week treatment phases (usual SSBs, matched NSBs, or water) in random order, which were separated by ≥4-week washout. Blocked randomization was performed centrally by computer with allocation concealment. Outcome assessment was blinded; however, blinding of participants and trial personnel was not possible. The two primary outcomes are oral glucose tolerance (incremental area under the curve) and gut microbiota beta-diversity (weighted UniFrac distance). Secondary outcomes include related markers of adiposity and glucose and insulin regulation. Adherence was assessed by objective biomarkers of added sugars and non-nutritive sweeteners and self-report intake. A subset of participants was included in an Ectopic Fat sub-study in which the primary outcome is intrahepatocellular lipid (IHCL) by 1H-MRS. Analyses will be according to the intention to treat principle. BASELINE RESULTS: Recruitment began on 1 June 2018, and the last participant completed the trial on 15 October 2020. We screened 1086 participants, of whom 80 were enrolled and randomized in the main trial and 32 of these were enrolled and randomized in the Ectopic Fat sub-study. The participants were predominantly middle-aged (mean age 41.8 ± SD 13.0 y) and had obesity (BMI of 33.7 ± 6.8 kg/m2) with a near equal ratio of female: male (51%:49%). The average baseline SSB intake was 1.9 servings/day. SSBs were replaced with matched NSB brands, sweetened with either a blend of aspartame and acesulfame-potassium (95%) or sucralose (5%). CONCLUSIONS: Baseline characteristics for both the main and Ectopic Fat sub-study meet our inclusion criteria and represent a group with overweight or obesity, with characteristics putting them at risk for type 2 diabetes. Findings will be published in peer-reviewed open-access medical journals and provide high-level evidence to inform clinical practice guidelines and public health policy for the use NSBs in sugars reduction strategies. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03543644.

Heterogeneity in the response to n-3 polyunsaturated fatty acids.

PURPOSE OF REVIEW: A central goal in the study of long chain n-3 polyunsaturated fatty acids (PUFA) is to translate findings from the basic sciences to the population level to improve human health and prevent chronic diseases. A tenet of this vision is to think in terms of precision medicine and nutrition, that is, stratification of individuals into differing groups that will have different needs across the lifespan for n-3 PUFAs. Therefore, there is a critical need to identify the sources of heterogeneity in the human population in the dietary response to n-3 PUFA intervention. RECENT FINDINGS: We briefly review key sources of heterogeneity in the response to intake of long chain n-3 PUFAs. These include background diet, host genome, composition of the gut microbiome, and sex. We also discuss the need to integrate data from newer rodent models (e.g. population-based approaches), multi -omics, and analyses of big data using machine learning and data-driven cluster analyses. SUMMARY: Accounting for vast heterogeneity in the human population, particularly with the use of big data integrated with preclinical evidence, will drive the next generation of precision nutrition studies and randomized clinical trials with long-chain n-3 PUFAs.

Novel 13C enrichment technique reveals early turnover of DHA in peripheral tissues.

The brain is rich in DHA, which plays important roles in regulating neuronal function. Recently, using compound-specific isotope analysis that takes advantage of natural differences in carbon-13 content (13C/12C ratio or δ13C) of the food supply, we determined the brain DHA half-life. However, because of methodological limitations, we were unable to capture DHA turnover rates in peripheral tissues. In the current study, we applied compound-specific isotope analysis via high-precision GC combustion isotope ratio mass spectrometry to determine half-lives of brain, liver, and plasma DHA in mice following a dietary switch experiment. To model DHA tissue turnover rates in peripheral tissues, we added earlier time points within the diet switch study and took advantage of natural variations in the δ13C-DHA of algal and fish DHA sources to maintain DHA pool sizes and used an enriched (uniformly labeled 13C) DHA treatment. Mice were fed a fish-DHA diet (control) for 3 months, then switched to an algal-DHA treatment diet, the 13C enriched-DHA treatment diet, or they stayed on the control diet for the remainder of the study time course. In mice fed the algal and 13C enriched-DHA diets, the brain DHA half-life was 47 and 46 days, the liver half-life was 5.6 and 7.2 days, and the plasma half-life was 4.7 and 6.4 days, respectively. By using improved methodologies, we calculated DHA turnover rates in the liver and plasma, and our study for the first time, by using an enriched DHA source (very high δ13C), validated its utility in diet switch studies.

The Environmental Sustainability of Plant-Based Dietary Patterns: A Scoping Review.

BACKGROUND: A large part of the existential threat associated with climate change is the result of current human feeding patterns. Over the last decade, research evaluating the diet-related environmental impacts of plant-based diets has emerged, and a synthesis of the available data is now due. OBJECTIVES: The objectives of the study were as follows: 1) to compile and summarize the literature on diet-related environmental impacts of plant-based dietary patterns; 2) to assess the nature of the data on impacts of plant-based dietary patterns on both environmental parameters and health (e.g., if land use is reduced for a particular diet, is cancer risk also reduced?); and 3) to determine where sufficient data exist for meta-analyses, in addition to identifying gaps within the literature. METHODS: Global peer-reviewed studies on the environmental impacts of plant-based diets were searched in Ovid MEDLINE, EMBASE, and Web of Science. After removing duplicates, the screening identified 1553 records. After 2 stages of independent review by 2 reviewers, 65 records met the inclusion criteria and were eligible to be used in synthesis. RESULTS: Evidence suggests that plant-based diets may offer lower greenhouse gas emissions (GHGEs), land use, and biodiversity loss than offered by standard diets; however, the impact on water and energy use may depend on the types of plant-based foods consumed. Further, the studies were consistent in demonstrating that plant-based dietary patterns that reduce diet-related mortality also promote environmental sustainability. CONCLUSIONS: Overall, there was agreement across the studies regarding the impact of plant-based dietary patterns on GHGE, land used, and biodiversity loss despite varied plant-based diets assessed.

Lifestyle Factors Associated with Circulating Very Long-Chain Saturated Fatty Acids in Humans: A Systematic Review of Observational Studies.

Recent observational studies have documented inverse associations of circulating very long-chain saturated fatty acids (VLCSFAs), namely arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0), with cardiometabolic outcomes. In addition to their endogenous production, it has been suggested that dietary intake or an overall healthier lifestyle may influence VLCSFA concentrations; however, a systematic review of the modifiable lifestyle contributors to circulating VLCSFAs is lacking. Therefore, this review aimed to systematically assess the effects of diet, physical activity, and smoking on circulating VLCSFAs. Following registration on PROSPERO (International Prospective Register of Systematic Reviews) (ID: CRD42021233550), a systematic search of observational studies was conducted in MEDLINE, EMBASE, and The Cochrane databases up to February 2022. A total of 12 studies consisting of mostly cross-sectional analyses were included in this review. The majority of the studies documented the associations of dietary intake with total plasma or red blood cell VLCSFAs, in which a range of macronutrients and food groups were examined. Two cross-sectional analyses showed a consistent positive association between total fat and peanut intake with 22:0 and 24:0 and an inverse association between alcohol intake and 20:0 and 22:0. Furthermore, a moderate positive association between physical activity and 22:0 and 24:0 was observed. Lastly, there were conflicting results on the effects of smoking on VLCSFA. Although most studies had a low risk of bias; the findings of this review are limited by the bi-variate analyses presented in the majority of the included studies, therefore, the impact of confounding is unclear. In conclusion, although the current observational literature examining lifestyle determinants of VLCSFAs is limited, existing evidence suggests that circulating 22:0 and 24:0 may be influenced by higher total and saturated fat consumption and nut intake.

Digestion of human milk processed by high pressure processing and Holder pasteurization using a dynamic in vitro model of the preterm infant.

Holder pasteurization (HoP) (62.5 °C, 30 min) of donor human milk is widely used to inactivate potential pathogens but may lead to denaturation and aggregation of bioactive proteins, reducing their functionality. In contrast, high pressure processing (HPP) is a non-thermal technique that minimally affects assessed bioactive components; however, it is unclear how HPP affects protein digestion, and retention of functional bioactive proteins. Raw or processed (HoP; HPP[500 MPa,10 min]) pools of milk (N = 3, from 9 donors) were subjected in triplicate to in vitro digestion simulating the preterm infant gastrointestinal tract. Compared to raw or HPP, HoP increased intestinal proteolysis of lactoferrin and bioactive milk fat globule membrane proteins. Lysozyme activity was impacted by digestion following HoP (72 % to 7 %)-significantly more than HPP (75 % to 34 %) or raw (100 % to 39 %), which did not differ. Proteins in HPP-treated donor milk are digested no different than raw milk, while preserved bioactivity remains functional upon digestion.

Oleic acid-bound FABP7 drives glioma cell proliferation through regulation of nuclear lipid droplet formation.

Fatty acid-binding protein 7 (FABP7), one of the fatty acid (FA) chaperones involved in the modulation of intracellular FA metabolism, is highly expressed in glioblastoma, and its expression is associated with decreased patients' prognosis. Previously, we demonstrated that FABP7 requires its binding partner to exert its function and that a mutation in the FA-binding site of FABP7 affects tumour biology. Here, we explored the role of FA ligand binding for FABP7 function in tumour proliferation and examined the mechanism of FABP7 and ligand interaction in tumour biology. We discovered that among several FA treatment, oleic acid (OA) boosted cell proliferation of FABP7-expressing cells. In turn, OA increased FABP7 nuclear localization, and the accumulation of FABP7-OA complex in the nucleus induced the formation of nuclear lipid droplet (nLD), as well as an increase in colocalization of nLD with promyelocytic leukaemia (PML) nuclear bodies. Furthermore, OA increased mRNA levels of proliferation-related genes in FABP7-expressing cells through histone acetylation. Interestingly, these OA-boosted functions were abrogated in FABP7-knockout cells and mutant FABP7-overexpressing cells. Thus, our findings suggest that FABP7-OA intracellular interaction may modulate nLD formation and the epigenetic status thereby enhancing transcription of proliferation-regulating genes, ultimately driving tumour cell proliferation.