Omega-3 Polyunsaturated Fatty Acids with Adipose Tissue Inflammation: Longitudinal Analysis in the PROMISE Cohort.

OBJECTIVES: Although pre-clinical studies have shown a beneficial impact of omega-3 (n-3) polyunsaturated fatty acids (PUFAs) on adipose (AT) inflammation, the current literature from human studies is limited. Therefore, we aimed to evaluate the longitudinal associations of circulating levels of n-3 PUFAs with biomarkers of AT inflammation. METHODS: Longitudinal data from participants in the PROMISE cohort (n = 474) were used. AT inflammation was measured using circulating biomarkers at baseline and up to 2 follow-up visits. n-3 PUFAs were measured at baseline in four serum lipid fractions. Generalized estimating equations (GEE) analyses evaluated longitudinal associations between n-3 PUFAs and AT inflammation, adjusting for covariates. RESULTS: Fully adjusted GEE models indicated that higher baseline proportions of eicosapentaenoic acid (EPA), n-3 docosapentaenoic acid (n-3 DPA), and docosahexaenoic acid (DHA) in total serum were significantly inversely associated with longitudinal change in soluble CD163 (sCD163) (all p < 0.05). A significant positive association of n-3 DPA and DHA with longitudinal change in adiponectin (p < 0.05) was also observed. Generally consistent associations were observed between n-3 PUFAs and sCD163 and adiponectin in the four lipid fractions. CONCLUSIONS: These findings will add to the limited evidence on the potential role n-3 PUFAs have in the prevention and management of AT inflammation in humans and may help inform future interventions targeting chronic inflammation at the level of AT.

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.

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.

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.