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

DHA is abundant in the 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 manuscript. First, we show by tracing 13C content (δ13C) of DHA via compound-specific isotope analysis, 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 compound-specific isotope analysis 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 KO 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 noncompetitive 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.

Urinary Metabolite Profiling to Non-Invasively Monitor the Omega-3 Index: An Exploratory Secondary Analysis of a Randomized Clinical Trial in Young Adults.

The Omega-3 Index (O3I) reflects eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) content in erythrocytes. While the O3I is associated with numerous health outcomes, its widespread use is limited. We investigated whether urinary metabolites could be used to non-invasively monitor the O3I in an exploratory analysis of a previous placebo-controlled, parallel arm randomized clinical trial in males and females (n = 88) who consumed either ~3 g/d olive oil (OO; control), EPA, or DHA for 12 weeks. Fasted blood and first-void urine samples were collected at baseline and following supplementation, and they were analyzed via gas chromatography and multisegment injection-capillary electrophoresis-mass spectrometry (MSI-CE-MS), respectively. We tentatively identified S-carboxypropylcysteamine (CPCA) as a novel urinary biomarker reflecting O3I status, which increased following both EPA and DHA (p < 0.001), but not OO supplementation, and was positively correlated to the O3I (R = 0.30, p < 0.001). Additionally, an unknown dianion increased following DHA supplementation, but not EPA or OO. In ROC curve analyses, CPCA outperformed all other urinary metabolites in distinguishing both between OO and EPA or DHA supplementation groups (AUC > 80.0%), whereas the unknown dianion performed best in discriminating OO from DHA alone (AUC = 93.6%). Candidate urinary biomarkers of the O3I were identified that lay the foundation for a non-invasive assessment of omega-3 status.

Liver triacylglycerol accumulation but not postprandial lipemia is reduced by a skim milk powder diet in male rats.

Increases in postprandial lipids are linked to the development of cardiometabolic and fatty liver disease. Prior work has suggested that dairy possesses beneficial cardiometabolic effects and thus the aim of the current investigation was to test the hypotheses that the habitual consumption of dairy, in the form of skim milk powder (SMP), would protect against increases in circulating lipids and liver lipid accumulation following an oral fat challenge in rats. Male rats were fed either a semipurified low-fat control diet with casein or a diet with an equivalent amount of protein (∼13% kcal) provided through skim milk powder (SMP) for 6 weeks (n = 40/group). Rats were then given an oral gavage of palm oil (5 mL/kg body weight) or an equivalent volume of water, and serum and liver were harvested 90 minutes or 4 hours after. Rats fed the SMP diet gained less weight than controls but there were no differences in glucose tolerance between groups. The fat gavage increased serum lipids in both diet groups, whereas there was a main effect of the fat challenge to increase, and the SMP diet, to decrease liver triacylglycerol accumulation. The percentage of saturated and monounsaturated fatty acids and the protein content/activity of lipogenic enzymes were reduced in livers from SMP-fed rats, whereas the percentage of polyunsaturated fatty acids was increased. In summary, we provide evidence that SMP consumption, although not protecting against postprandial lipemia, markedly attenuates triacylglycerol accumulation and the relative amount of saturated and monounsaturated fatty acids in the liver.

Lipidomic studies reveal two specific circulating phosphatidylcholines as surrogate biomarkers of the omega-3 index.

Optimal dietary intake of omega-3 long-chain polyunsaturated fatty acids (n3-LCPUFAs) is critical to human health across the lifespan. However, omega-3 index (O3I) determination is not routinely assessed due to complicated procedures for n3-LCPUFA analysis from the phospholipid (PL) fraction of erythrocytes. Herein, a high-throughput method for lipidomics based on multisegment injection-nonaqueous capillary electrophoresis-mass spectrometry was applied to identify circulating PLs as surrogate biomarkers of O3I in two randomized placebo-controlled trials. An untargeted lipidomic data workflow using a subgroup analysis of serum extracts from sunflower oil versus high-dose fish oil (FO)-supplemented participants revealed that ingested n3-LCPUFAs were primarily distributed as their phosphatidylcholines (PCs) relative to other PL classes. In both high-dose FO (5.0 g/day) and EPA-only trials (3.0 g/day), PC (16:0_20:5) was the most responsive PL, whereas PC (16:0_22:6) was selective to DHA-only supplementation. We also demonstrated that the sum concentration of both these PCs in fasting serum or plasma samples was positively correlated to the O3I following FO (r = 0.708, P = 1.02 × 10-11, n = 69) and EPA- or DHA-only supplementation (r = 0.768, P = 1.01 × 10-33, n = 167). Overall, DHA was more effective in improving the O3I (ΔO3I = 4.90 ± 1.33%) compared to EPA (ΔO3I = 2.99 ± 1.19%) in young Canadian adults who had a poor nutritional status with an O3I (3.50 ± 0.68%) at baseline. Our method enables the rapid assessment of the O3I by directly measuring two circulating PC species in small volumes of blood, which may facilitate screening applications for population and precision health.

Dietary and plasma retinoids are not associated with fatty acid desaturase indices in healthy young adults.

Past research in rodents suggests that fatty acid (FA) desaturase expression and activity may be modified by vitamin A; however, this has not been investigated in humans. The primary objective of this study was to examine associations between dietary retinoid intakes, plasma retinoid concentrations, and FA desaturase indices in young adults. As a secondary objective, biological sex and estrogen-containing contraceptive (EC) use were investigated due to prior evidence demonstrating that both can influence plasma retinol concentration and FA desaturase indices. Dietary retinoid intake (food frequency questionnaire), plasma retinoid concentrations (high-performance liquid chromatography-tandem mass spectrometry), plasma FA (gas chromatography), and FA desaturase indices (product-to-precursor ratios) from 945 adults recruited for the cross-sectional Toronto Nutrigenomics and Health study were analyzed. Participants were stratified into quartiles based on plasma retinol concentration and data analyzed by one-way analysis of covariance. Dietary retinoid intakes were not associated with the overall n-3 pathway, overall n-6 pathway, delta-5 desaturase, delta-6 desaturase, or delta-9 desaturase indices (all r < 0.10, p > 0.05). The overall n-6 pathway index was significantly higher (p = 0.0004) and the delta-5 desaturase index was significantly lower (p = 0.0003) in individuals with higher plasma retinol levels; however, these differences were lost when participants were grouped by biological sex and EC use. Although weak relationships were observed between plasma retinol and some FA desaturase indices in the total population, these associations appear to be driven by biological sex and EC usage rather than retinoids. We therefore find little evidence of a relationship between retinoids and FA desaturase indices in young, healthy adults.

A moderate-fat diet containing soy protein does not differentially impact energy balance in male and female mice compared to dairy protein.

Dairy and nondairy plant-based alternative proteins are reported to differentially influence body weight; however, most research has compared plant-based alternatives with isolated dairy proteins rather than a complete milk protein (containing casein and whey). This is notable given that people do not generally consume isolated dairy proteins. Therefore, the present study aimed to investigate the impact of a soy protein isolate (SPI) on factors influencing body weight gain in male and female mice in comparison to skim milk powder (SMP). Based on current knowledge in rodents, we hypothesized that SPI would promote body weight gain compared with SMP. Mice (n = 8 per sex per diet) consumed a moderate-fat diet (35% kcal from fat) containing either SPI or SMP for 8 weeks. Body weight and food intake were measured weekly. Energy expenditure, physical activity, and substrate use were measured using metabolic cages. Fecal energy content was measured with bomb calorimetry. Body weight gain and food intake during the 8-week feeding study was not different in mice consuming either SPI or SMP; however, males had a higher body weight, adiposity, and feed efficiency compared with females (all P < .05). Fecal energy content was approximately 7% higher in both male and female mice fed the SPI diet compared with the SMP diet. Neither protein source affected substrate utilization, physical activity, or energy expenditure. Physical activity in the dark phase trended higher in females compared with males (P = .0732). The present study suggests that the consumption of SPI in the context of a moderate-fat diet has little impact on numerous factors influencing body weight regulation in male and female mice compared with a complete milk protein.

Delta-6 desaturase (Fads2) deficiency alters triacylglycerol/fatty acid cycling in murine white adipose tissue.

The Δ-6 desaturase (D6D) enzyme is not only critical for the synthesis of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from α-linolenic acid (ALA), but recent evidence suggests that it also plays a role in adipocyte lipid metabolism and body weight; however, the mechanisms remain largely unexplored. The goal of this study was to investigate if a D6D deficiency would inhibit triacylglycerol storage and alter lipolytic and lipogenic pathways in mouse white adipose tissue (WAT) depots due to a disruption in EPA and DHA production. Male C57BL/6J D6D knockout (KO) and wild-type (WT) mice were fed either a 7% w/w lard or flax (ALA rich) diet for 21 weeks. Energy expenditure, physical activity, and substrate utilization were measured with metabolic caging. Inguinal and epididymal WAT depots were analyzed for changes in tissue weight, fatty acid composition, adipocyte size, and markers of lipogenesis, lipolysis, and insulin signaling. KO mice had lower body weight, higher serum nonesterified fatty acids, smaller WAT depots, and reduced adipocyte size compared to WT mice without altered food intake, energy expenditure, or physical activity, regardless of the diet. Markers of lipogenesis and lipolysis were more highly expressed in KO mice compared to WT mice in both depots, regardless of the diet. These changes were concomitant with lower basal insulin signaling in WAT. Collectively, a D6D deficiency alters triacylglycerol/fatty acid cycling in WAT by promoting lipolysis and reducing fatty acid re-esterification, which may be partially attributed to a reduction in WAT insulin signaling.

A reduction of skeletal muscle DHA content does not result in impaired whole body glucose tolerance or skeletal muscle basal insulin signaling in otherwise healthy mice.

Delta-6 desaturase (D6D), encoded by the Fads2 gene, catalyzes the first step in the conversion of α-linolenic acid to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The ablation of D6D in whole body Fads2-/- knockout (KO) mice results in an inability to endogenously produce EPA and DHA. Evidence supports a beneficial role for EPA and DHA on insulin-stimulated glucose disposal in skeletal muscle in the context of a metabolic challenge; however, it is unknown how low EPA and DHA levels impact skeletal muscle fatty acid composition and insulin signaling in a healthy context. The objective of this study was to examine the impact of ablating the endogenous production of EPA and DHA on skeletal muscle fatty acid composition, whole body glucose and insulin tolerance, and a key marker of skeletal muscle insulin signaling (pAkt). Male C57BL/6J wild-type (WT), Fads2+/- heterozygous, and Fads2-/- KO mice were fed a low-fat diet (16% kcal from fat) modified to contain either 7% w/w lard or 7% w/w flaxseed for 21 wk. No differences in total phospholipid (PL), triacylglycerol, or reactive lipid content were observed between genotypes. As expected, KO mice on both diets had significantly less DHA content in skeletal muscle PL. Despite this, KO mice did not have significantly different glucose or insulin tolerance compared with WT mice on either diet. Basal pAktSer473 was not significantly different between the genotypes within each diet. Ultimately, this study shows for the first time, to our knowledge, that the reduction of DHA in skeletal muscle is not necessarily detrimental to glucose homeostasis in otherwise healthy animals.NEW & NOTEWORTHY Skeletal muscle is the primary location of insulin-stimulated glucose uptake. EPA and DHA supplementation has been observed to improve skeletal muscle insulin-stimulated glucose uptake in models of metabolic dysfunction. Fads2-/- knockout mice cannot endogenously produce long-chain n-3 polyunsaturated fatty acids. Our results show that the absence of DHA in skeletal muscle is not detrimental to whole body glucose homeostasis in healthy mice.

Relationship between Cardiometabolic Factors and the Response of Blood Pressure to a One-Year Primary Care Lifestyle Intervention in Metabolic Syndrome Patients.

Systemic hypertension has been recognized as a modifiable traditional cardiovascular risk factor and influenced by many factors such as eating habits, physical activity, diabetes, and obesity. The objective of this cross-sectional study was to identify factors that predict changes in blood pressure induced by a one-year lifestyle intervention in primary care settings involving a collaboration between family physicians, dietitians, and exercise specialists. Patients with metabolic syndrome diagnosis were recruited by family physicians participating in primary care lifestyle intervention among several family care clinics across Canada. Participants for whom all cardiometabolic data at the beginning (T0) and the end (T12) of the one-year intervention were available were included in the present analysis (n = 101). Patients visited the dietitian and the exercise specialist weekly for the first three months and monthly for the last nine months. Diet quality, exercise capacity, anthropometric indicators, and cardiometabolic variables were evaluated at T0 and at T12. The intervention induced a statistically significant decrease in waist circumference (WC), systolic (SBP) and diastolic (DBP) blood pressure, and plasma triglycerides, and an increase in cardiorespiratory fitness (estimated VO2max). Body weight (p < 0.001), body mass index (BMI) (p < 0.001), and fasting blood glucose (p = 0.006) reduction, and VO2max increase (p = 0.048) were all related to changes in SBP. WC was the only variable for which changes were significantly correlated with those in both SBP (p < 0.0001) and DBP (p = 0.0004). Variations in DBP were not associated with changes in other cardiometabolic variables to a statistically significant extent. Twelve participants were identified as adverse responders (AR) in both SBP and DBP and displayed less favorable changes in WC. The beneficial effects of the primary care lifestyle intervention on blood pressure were significantly associated with cardiometabolic variables, especially WC. These findings suggest that a structured lifestyle intervention in primary care can help improve cardiometabolic risk factors in patients with metabolic syndrome and that WC should be systematically measured to better stratify the patient's hypertension risk.

Increases in plasma n-3 tetracosapentaenoic acid and tetracosahexaenoic acid following 12 weeks of EPA, but not DHA, supplementation in women and men.

Dietary feeding and stable isotope studies in rodents support that the 24-carbon omega-3 polyunsaturated fatty acids, tetracosapentaenoic acid (24:5n-3, TPAn-3) and tetracosahexaenoic acid (24:6n-3, THA), are immediate precursors to docosahexaenoic acid (DHA, 22:6n-3). In this study, we assessed for the first time, changes in TPAn-3 or THA levels following omega-3 PUFA supplementation in humans, providing insight into human omega-3 PUFA metabolism. In this secondary analysis of a double-blind randomized control trial, women and men (19 - 30 years, n = 10 - 14 per sex, per diet) were supplemented with 3 g/day EPA, DHA, or olive oil control for 12 weeks. Plasma TPAn-3 and THA concentrations were determined by gas chromatography-mass spectrometry to determine changes following supplementation in a sex-specific manner (sex x time). EPA supplementation significantly increased (p < 0.0001) plasma TPAn-3 by 215% (1.3 ± 0.1 - 4.1 ± 0.7, nmol/mL ± SEM) and THA by 112% (1.7 ± 0.2 - 3.6 ± 0.5, nmol/mL ± SEM). Furthermore, women had 111% and 99% higher plasma TPAn-3 and THA in the EPA supplemented group compared to men (p < 0.0001). There were no significant effects of time on plasma TPAn-3 or THA concentrations in the DHA supplemented or olive oil supplemented groups. In conclusion, EPA, but not DHA, supplementation in humans increased plasma TPAn-3 and THA levels, suggesting that THA accumulates prior to conversion to DHA in the n-3 PUFA synthesis pathway. Furthermore, women generally exhibit higher plasma TPAn-3 and THA concentrations compared with men, suggesting that women have a greater ability to accumulate 24-carbon n-3 PUFA in plasma via EPA and DPAn-3 elongation, which may explain the known higher DHA levels in women. Summary: In this secondary analysis of a double-blind randomized control trial, we assessed changes in omega-3 (n-3) tetracosapentaenoic acid (24:5n-3, TPAn-3) and tetracosahexaenoic acid (24:6n-3, THA) plasma levels in women and men (19 - 30 years, n = 10 - 14 per sex, per diet) following 12-weeks of n-3 PUFA supplementation (3 g/day EPA, DHA or olive oil). Women had higher plasma TPAn-3 in all supplementation groups and higher THA levels in the EPA and olive oil groups (p < 0.0001) compared to men. EPA supplementation increased (p < 0.0001) plasma TPAn-3 by 215% (1.3 ± 0.1 - 4.1 ± 0.7, nmol/mL ± SEM) and THA by 112% (1.7 ± 0.2 - 3.6 ± 0.5, nmol/mL ± SEM), but DHA supplementation had no effect. For the first time in humans, we show that plasma TPAn-3 and THA levels are higher in women and increased with EPA, but not DHA supplementation, suggesting an accumulation of THA prior to conversion to DHA in the n-3 PUFA synthesis pathway.

Key process features of personalized diet counselling in metabolic syndrome: secondary analysis of feasibility study in primary care.

BACKGROUND: Personalized diet counselling, as part of lifestyle change programs for cardiometabolic risk conditions (combinations of prediabetes or type 2 diabetes, hypertension, dyslipidemia and high waist circumference) has been shown to reduce progression to type 2 diabetes overall. To identify key process of care measures that could be linked to changes in diet, we undertook a secondary analysis of a Canadian pre-post study of lifestyle treatment of metabolic syndrome (MetS). Diet counselling process measures were documented and association with diet quality changes after 3 months were assessed. Results of the primary study showed 19% reversal of MetS after 1 year. METHODS: Registered dietitians (RDs) reported on contact time, specific food behaviour goals (FBG), behaviour change techniques (BCT; adapted from the Michie CALO-RE taxonomy) and teaching resources at each contact. Diet quality was measured by 2005 Canadian Healthy Eating Index (HEI-C) and assessed for possible associations with individual BCT and FBG. RESULTS: Food behaviour goals associated with improved HEI-C at 3 months were: poultry more than red meat, increased plant protein, increased fish, increased olive oil, increased fruits and vegetables, eating breakfast, increased milk and alternatives, healthier fats, healthier snacks and increased nuts, with an adverse association noted for more use (> 2 times/ 3 months) of the balanced meal concept (F test; p < 0.001). Of 16 BCT, goal setting accounted for 15% of all BCT recorded, yet more goal setting (> 3 times/3 months) was associated with poorer HEI-C at 3 months (F test; p = 0.007). Only self-monitoring, feedback on performance and focus on past success were associated with improved HEI-C. CONCLUSIONS: These results identify key aspects of process that impact diet quality. Documentation of both FBG and BCT is highly relevant in diet counselling and a summary diet quality score is a promising target for assessing short-term counselling success.

Δ5 and Δ6 desaturase indices are not associated with zinc intake as determined by dietary assessment or modified by a zinc-FADS1 rs174547 SNP interaction in young Canadian adults.

BACKGROUND: Zinc is an essential trace mineral that serves as a cofactor for the delta-5 and delta-6 desaturases (D5D, D6D) that are critical for long-chain polyunsaturated fatty acid (LC-PUFA) synthesis. While plasma zinc levels are generally reported to be associated with D5D and D6D indices in humans, it remains unclear if dietary zinc intake can be similarly associated with desaturase indices. Therefore, the present investigation examined if zinc intake determined by food frequency questionnaire (FFQ) is associated with desaturase indices in young Canadian adults. Additionally, we explored whether desaturase indices were modified by an interaction between dietary zinc intake and a common variant in the FADS1 gene. METHODS: Dietary zinc intake (FFQ), plasma fatty acids (gas chromatography) and the FADS1 rs174547 polymorphism were analyzed in young men and women (n = 803) from the cross-sectional Toronto Nutrigenomics and Health Study. Product-to-precursor fatty acid ratios were used to determine desaturase enzyme indices (D5D = 20:4n-6/20:3n-6; D6D = 18:3n-6/18:2n-6). Individuals were grouped according to dietary zinc intake, as well as by their rs174547 genotype (TT vs. TC+CC). Data were analyzed by 1-way and 2-way ANCOVA. RESULTS: Plasma fatty acids and D5D/D6D indices did not differ between individuals grouped according to dietary zinc intake. Further, the recently proposed biomarker of zinc intake, 20:3n-6/18:2n-6, was not associated with dietary zinc intake. Although the FADS1 rs174547 SNP was significantly associated with D5D and D6D indices in both men and women (p < 0.0001), we did not find evidence of a dietary zinc intake - FADS1 SNP interaction on D5D or D6D indices. CONCLUSION: Dietary zinc intake, as determined using FFQs, does not predict differences in desaturase indices, irrespective of FADS1 genotype.

Inhibition of Δ-6 desaturase reduces fatty acid re-esterification in 3T3-L1 adipocytes independent of changes in n3-PUFA cellular content.

Δ-6 desaturase (D6D) is a key enzyme in the synthesis of long-chain polyunsaturated fatty acids (LC-PUFA). Evidence suggests that reduced D6D activity not only disrupts LC-PUFA production, but also impacts whole body lipid handling and body weight; however, the mechanisms remain largely unexplored. Therefore, we investigated the effect of D6D inhibition on the regulation of lipid accumulation in 3T3-L1 adipocytes with and without changes in n-3 PUFA content. 3T3-L1 cells were treated with a D6D inhibitor (SC-26196) in the presence or absence of α-linolenic acid (ALA) throughout differentiation. We found that D6D inhibition blocked the conversion of ALA to eicosapentaenoic acid (EPA) and docosapentaenoic acid (DPAn-3) when ALA was supplemented, while no changes in n-3 PUFA content were observed in cells treated with the D6D inhibitor alone. D6D inhibited cells had reduced triacylglycerol (TAG) accumulation despite an EPA/DPA deficiency. In addition, analyses of cellular protein markers, as well as non-esterified fatty acids and glycerol release in medium, suggested an increase in lipolysis and a decrease in fatty acid re-esterification in D6D-inhibited cells, independent of n-3 PUFA changes. To provide further evidence, we treated cells with the D6D inhibitor in the presence or absence of EPA and compared them with ALA-treated cells. Although EPA further reduced TAG content, the reduced markers of fatty acid re-esterification were not affected by ALA or EPA. Collectively, this study provides new insight showing that D6D inhibition reduces TAG accumulation and fatty acid re-esterification in adipocytes independent of changes in n-3 PUFA cellular content.

Nutrigenetics, omega-3 and plasma lipids/lipoproteins/apolipoproteins with evidence evaluation using the GRADE approach: a systematic review.

OBJECTIVES: Despite the uptake of nutrigenetic testing through direct-to-consumer services and healthcare professionals, systematic reviews determining scientific validity are limited in this field. The objective of this review was to: retrieve, synthesise and assess the quality of evidence (confidence) for nutrigenetic approaches related to the effect of genetic variation on plasma lipid, lipoprotein and apolipoprotein responsiveness to omega-3 fatty acid intake. DESIGN: A systematic review was conducted using three search engines (Embase, Web of Science and Medline) for articles published up until 1 August 2020. We aimed to systematically search, identify (select) and provide a narrative synthesis of all studies that assessed nutrigenetic associations/interactions for genetic variants (comparators) influencing the plasma lipid, lipoprotein and/or apolipoprotein response (outcomes) to omega-3 fatty acid intake (intervention/exposure) in humans-both paediatric and adult populations (population). We further aimed to assess the overall quality of evidence for specific priority nutrigenetic associations/interactions based on the following inclusion criteria: nutrigenetic associations/interactions reported for the same genetic variants (comparators) influencing the same plasma lipid, lipoprotein and/or apolipoprotein response (outcomes) to omega-3 fatty acid intake (intervention/exposure) in humans-both paediatric and adult populations (population) in at least two independent studies, irrespective of the findings. Risk of bias was assessed in individual studies. Evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach with a modification to further consider biological plausibility. RESULTS: Out of 1830 articles screened, 65 met the inclusion criteria for the narrative synthesis (n=23 observational, n=42 interventional); of these, 25 met the inclusion criteria for GRADE evidence evaluation. Overall, current evidence is insufficient for gene-diet associations related to omega-3 fatty acid intake on plasma apolipoproteins, total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein (LDL)-cholesterol and LDL particle size. However, there is strong (GRADE rating: moderate quality) evidence to suggest that male APOE-E4 carriers (rs429358, rs7412) exhibit significant triglyceride reductions in response to omega-3-rich fish oil with a dose-response effect. Moreover, strong (GRADE rating: high quality) evidence suggests that a 31-SNP nutrigenetic risk score can predict plasma triglyceride responsiveness to omega-3-rich fish oil in adults with overweight/obesity from various ethnicities. CONCLUSIONS: Most evidence in this area is weak, but two specific nutrigenetic interactions exhibited strong evidence, with generalisability limited to specific populations. PROSPERO REGISTRATION NUMBER: CRD42020185087.

Crohn's disease therapeutic dietary intervention (CD-TDI): study protocol for a randomised controlled trial.

INTRODUCTION: Dietary patterns that might induce remission in patients with active Crohn's disease (CD) are of interest to patients, but studies are limited in the published literature. We aim to explore the efficacy of the CD therapeutic dietary intervention (CD-TDI), a novel dietary approach developed from best practices and current evidence, to induce clinical and biomarker remission in adult patients with active CD. METHODS AND ANALYSIS: This study is a 13-week, multicentre, randomised controlled trial in patients with mild-to-moderate active CD at baseline. One hundred and two patients will be block randomised, by sex, 2:1 to the intervention (CD-TDI) or conventional management. Coprimary outcomes are clinical and biomarker remission, defined as a Harvey Bradshaw Index of <5 and a faecal calprotectin of <250 µg/g, respectively.Secondary outcomes include gut microbiota diversity and composition, faecal short-chain fatty acids, regulatory macrophage function, serum and faecal metabolomics, C reactive protein, peripheral blood mononuclear cell gene expression profiles, quality of life, sedentary time and physical activity at 7 and/or 13 weeks. Predictive models of clinical response to a CD-TDI will be investigated. ETHICS AND DISSEMINATION: The research protocol was approved by the Conjoint Health Research Ethics Board at the University of Calgary (REB19-0402) and the Health Research Ethics Board-Biomedical Panel at the University of Alberta (Pro00090772). Study findings will be presented at national and international conferences, submitted for publication in abstracts and manuscripts, shared on social media and disseminated through patient-education materials. TRIAL REGISTRATION NUMBER: NCT04596566.

Polymorphisms in the stearoyl-CoA desaturase gene modify blood glucose response to dietary oils varying in MUFA content in adults with obesity.

Diets varying in SFA and MUFA content can impact glycaemic control; however, whether underlying differences in genetic make-up can influence blood glucose responses to these dietary fatty acids is unknown. We examined the impact of dietary oils varying in SFA/MUFA content on changes in blood glucose levels (primary outcome) and whether these changes were modified by variants in the stearoyl-CoA desaturase (SCD) gene (secondary outcome). Obese men and women participating in the randomised, crossover, isoenergetic, controlled-feeding Canola Oil Multicenter Intervention Trial II consumed three dietary oils for 6 weeks, with washout periods of ˜6 weeks between each treatment. Diets studied included a high SFA/low MUFA Control oil (36·6 % SFA/28·2 % MUFA), a conventional canola oil (6·2 % SFA/63·1 % MUFA) and a high-oleic acid canola oil (5·8 % SFA/74·7 % MUFA). No differences in fasting blood glucose were observed following the consumption of the dietary oils. However, when stratified by SCD genotypes, significant SNP-by-treatment interactions on blood glucose response were found with additive models for rs1502593 (P = 0·01), rs3071 (P = 0·02) and rs522951 (P = 0·03). The interaction for rs3071 remained significant (P = 0·005) when analysed with a recessive model, where individuals carrying the CC genotype showed an increase (0·14 (sem 0·09) mmol/l) in blood glucose levels with the Control oil diet, but reductions in blood glucose with both MUFA oil diets. Individuals carrying the AA and AC genotypes experienced reductions in blood glucose in response to all three oils. These findings identify a potential new target for personalised nutrition approaches aimed at improving glycaemic control.

Evaluation of Latent Models Assessing Physical Fitness and the Healthy Eating Index in Community Studies: Time-, Sex-, and Diabetes-Status Invariance.

Accurate measurement requires assessment of measurement equivalence/invariance (ME/I) to demonstrate that the tests/measurements perform equally well and measure the same underlying constructs across groups and over time. Using structural equation modeling, the measurement properties (stability and responsiveness) of intervention measures used in a study of metabolic syndrome (MetS) treatment in primary care offices, were assessed. The primary study (N = 293; mean age = 59 years) had achieved 19% reversal of MetS overall; yet neither diet quality nor aerobic capacity were correlated with declines in cardiovascular disease risk. Factor analytic methods were used to develop measurement models and factorial invariance were tested across three time points (baseline, 3-month, 12-month), sex (male/female), and diabetes status for the Canadian Healthy Eating Index (2005 HEI-C) and several fitness measures combined (percentile VO2 max from submaximal exercise, treadmill speed, curl-ups, push-ups). The model fit for the original HEI-C was poor and could account for the lack of associations in the primary study. A reduced HEI-C and a 4-item fitness model demonstrated excellent model fit and measurement equivalence across time, sex, and diabetes status. Increased use of factor analytic methods increases measurement precision, controls error, and improves ability to link interventions to expected clinical outcomes.

Soy Consumption, but Not Dairy Consumption, Is Inversely Associated with Fatty Acid Desaturase Activity in Young Adults.

Past research using hepatic rat microsomes showed that soy protein suppressed delta-6 desaturase activity (D6D) compared to casein (a dairy protein). The effects of soy and dairy on desaturase pathway activity in humans remain poorly investigated. The objective of this analysis was to investigate the association between soy and dairy consumption with plasma fatty acids and estimate the desaturase pathway activity in a multiethnic Canadian population of young adults. We analyzed data from men (n = 319) and women (n = 764) previously collected for the Toronto Nutrigenomics and Health Study. Food frequency questionnaires and plasma fatty acids were assessed. Relationships between soy and dairy beverages and food consumption with estimated desaturase activities were assessed by regression models and by grouping participants according to beverage and food intake data. Weak inverse associations (p ≤ 0.05) were found between soy consumption and the overall desaturation pathway activity, specifically D6D activity. When participants were grouped based on soy and dairy consumption habits, omega-6 LC-PUFAs, as well as various estimates of the desaturase pathway activity, were significantly lower in individuals consuming soy (with or without dairy) compared to individuals consuming only fluid milk and dairy products. In conclusion, soy consumption, not dairy consumption, appears to suppress desaturase pathway activity.

Regulation of adipose tissue lipolysis by ghrelin is impaired with high-fat diet feeding and is not restored with exercise.

Ghrelin is released from the stomach as an anticipatory signal prior to a meal and decreases immediately after. Previous research has shown that both acylated (AG) and unacylated (UnAG) ghrelin blunt adrenoreceptor-stimulated lipolysis in rat white adipose tissue (WAT) ex vivo. We investigated whether acute or chronic consumption of a high fat diet (HFD) impaired the ability of ghrelin to regulate adipose tissue lipolysis, and if this impairment could be restored with exercise. After 5 days (5d) of a HFD, or 6 weeks (6 w) of a HFD (60% kcal from fat) with or without exercise training, inguinal and retroperitoneal WAT was collected from anesthetized rats for adipose tissue organ culture. Samples were treated with 1 µM CL 316,243 (CL; lipolytic control), 1 µM CL+150 ng/ml AG or 1 µM CL+150 ng/ml UnAG. Incubation media and tissue were collected after 2 hours. Colorometric assays were used to determine glycerol and free fatty acid (FFA) concentrations in media. Western blots were used to quantify the protein content of lipolytic enzymes and ghrelin receptors in both depots. CL stimulated lipolysis was evidenced by increases in glycerol (p < 0.0001) and FFA (p < 0.0001) concentrations in media compared to control. AG decreased CL-stimulated glycerol release in inguinal WAT from 5d LFD rats (p = 0.0097). Neither AG nor UnAG blunted lipolysis in adipose tissue from 5d or 6 w HFD-fed rats, and exercise did not restore ghrelin's anti-lipolytic ability in 6 w HFD-fed rats. Overall, this study demonstrates that HFD consumption impairs ghrelin's ability to regulate adipose tissue lipolysis.