Novel CB1-ligands maintain homeostasis of the endocannabinoid system in ω3- and ω6-long-chain-PUFA deficiency.

Mammalian ω3- and ω6-PUFAs are synthesized from essential fatty acids (EFAs) or supplied by the diet. PUFAs are constitutive elements of membrane architecture and precursors of lipid signaling molecules. EFAs and long-chain (LC)-PUFAs are precursors in the synthesis of endocannabinoid ligands of Gi/o protein-coupled cannabinoid receptor (CB)1 and CB2 in the endocannabinoid system, which critically regulate energy homeostasis as the metabolic signaling system in hypothalamic neuronal circuits and behavioral parameters. We utilized the auxotrophic fatty acid desaturase 2-deficient (fads2-/-) mouse, deficient in LC-PUFA synthesis, to follow the age-dependent dynamics of the PUFA pattern in the CNS-phospholipidome in unbiased dietary studies of three cohorts on sustained LC-PUFA-free ω6-arachidonic acid- and DHA-supplemented diets and their impact on the precursor pool of CB1 ligands. We discovered the transformation of eicosa-all cis-5,11,14-trienoic acid, uncommon in mammalian lipidomes, into two novel endocannabinoids, 20:35,11,14-ethanolamide and 2-20:35,11,14-glycerol. Their function as ligands of CB1 has been characterized in HEK293 cells. Labeling experiments excluded Δ8-desaturase activity and proved the position specificity of FADS2. The fads2-/- mutant might serve as an unbiased model in vivo in the development of novel CB1 agonists and antagonists.

Is vegetarianism healthy for children?

According to the Academy of Nutrition and Dietetics' influential position statement on vegetarianism, meat and seafood can be replaced with milk, soy/legumes, and eggs without any negative effects in children. The United States Department of Agriculture endorses a similar view. The present paper argues that the Academy of Nutrition and Dietetics ignores or gives short shrift to direct and indirect evidence that vegetarianism may be associated with serious risks for brain and body development in fetuses and children. Regular supplementation with iron, zinc, and B12 will not mitigate all of these risks. Consequently, we cannot say decisively that vegetarianism or veganism is safe for children.

Precision Nutrition and Omega-3 Polyunsaturated Fatty Acids: A Case for Personalized Supplementation Approaches for the Prevention and Management of Human Diseases.

BACKGROUND: Dietary essential omega-6 (n-6) and omega-3 (n-3) 18 carbon (18C-) polyunsaturated fatty acids (PUFA), linoleic acid (LA) and α-linolenic acid (ALA), can be converted (utilizing desaturase and elongase enzymes encoded by FADS and ELOVL genes) to biologically-active long chain (LC; >20)-PUFAs by numerous cells and tissues. These n-6 and n-3 LC-PUFAs and their metabolites (ex, eicosanoids and endocannabinoids) play critical signaling and structural roles in almost all physiologic and pathophysiologic processes. METHODS: This review summarizes: (1) the biosynthesis, metabolism and roles of LC-PUFAs; (2) the potential impact of rapidly altering the intake of dietary LA and ALA; (3) the genetics and evolution of LC-PUFA biosynthesis; (4) Gene-diet interactions that may lead to excess levels of n-6 LC-PUFAs and deficiencies of n-3 LC-PUFAs; and (5) opportunities for precision nutrition approaches to personalize n-3 LC-PUFA supplementation for individuals and populations. CONCLUSIONS: The rapid nature of transitions in 18C-PUFA exposure together with the genetic variation in the LC-PUFA biosynthetic pathway found in different populations make mal-adaptations a likely outcome of our current nutritional environment. Understanding this genetic variation in the context of 18C-PUFA dietary exposure should enable the development of individualized n-3 LC-PUFA supplementation regimens to prevent and manage human disease.

Fighting Oxidative Stress: Increased Resistance of Male Rat Cerebellum at Weaning Induced by Low Omega 6/Omega 3 Ratio in a Protein-Deficient Diet.

The cerebellum is vulnerable to malnutrition effects. Notwithstanding, it is able to incorporate higher amount of docosahexaenoic acid (DHA) than the cerebral cortex (Cx) when low n-6/n-3 fatty acid ratio is present in a multideficient diet. Considering importance of DHA for brain redox balance, we hypothesize that this cerebellum feature improves its antioxidant status compared to the Cx. A chronic malnutrition status was induced on dams before mating and kept until weaning or adulthood (offspring). A group nutritionally rehabilitated from weaning was also analyzed. Morphometric parameters, total-superoxide dismutase (t-SOD) and catalase activities, lipoperoxidation (LP), nitric oxide (NO), reduced (GSH) and oxidized (GSSG) glutathione, reactive oxygen species (ROS), and reduced nicotinamide adenine dinucleotide/phosphate levels were assessed. Both ROS and LP levels were increased (∼53 %) in the Cx of malnourished young animals while the opposite was seen in the cerebellum (72 and 20 % of the control, respectively). Consistently, lower (∼35 %) and higher t-SOD (∼153 %) and catalase (CAT) (∼38 %) activities were respectively detected in the Cx and cerebellum compared to the control. In malnourished adult animals, redox balance was maintained in the cerebellum and recovered in the Cx (lower ROS and LP levels and higher GSH/GSSG ratio). NO production was impaired by malnutrition at either age, mainly in the cerebellum. The findings suggest that despite a multinutrient deficiency and a modified structural development, a low dietary n-6/n-3 ratio favors early antioxidant resources in the male cerebellum and indicates an important role of astrocytes in the redox balance recovery of Cx in adulthood.

The effect of the paraoxonase 1 (PON1) T(-107)C polymorphism on serum PON1 activity in women is dependent on fatty acid intake.

Paraoxonase 1 (PON1) is an enzyme that prevents the peroxidation of lipoprotein and cell membranes. Our hypothesis is that the effect of the PON1 T(-107)C polymorphism on serum PON1 activity in healthy adult women is dependent on their fatty acid intake profile. This study included women (n = 39) who completed a food frequency questionnaire. Fatty acid intake was estimated based on the interview and a nutrient reference table. Blood samples were collected for genotyping and to measure serum PON1 activity. Serum PON1 activity was different among genotypes and was higher for women of the CC genotype (P < .001). Women in the study were categorized in 2 groups according to the median nutrient intake. Overall, there was a difference (P < .05) in serum PON1 activity between the CC and TT genotypes in women ingesting either above or below the median total fat, saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids, omega 3 (n-3) and omega 6 (n-6; P < .05). However, genotype effects on serum PON1 activity were not observed in women ingesting below the median (15:1) ratio of n-6/n-3 (P > .05) but were observed in women ingesting above the ratio of n-6/n-3 (P < .05). This is partly because women of the CC genotype had decreased PON1 activity when ingesting a lower ratio of n-6/n-3 diet (P < .05), while women of the TT genotype had increased PON1 activity (P < .05). In conclusion, the overall presence of the C allele was associated with increased serum PON1 activity, although a diet with high saturated fatty acid or a low ratio of n-6/n-3 reduced PON1 activity in women with the CC genotype.

Deficiency of n-6 polyunsaturated fatty acids is mainly responsible for atopic dermatitis-like pruritic skin inflammation in special diet-fed hairless mice.

Hairless mice fed a special diet, HR-AD, develop atopic dermatitis (AD)-like skin inflammation with skin barrier defects and itch-related scratching; however, the ingredient(s) causing the dermatitis remains unclear. In this study, we examined whether deficiency of certain polyunsaturated fatty acids (PUFAs) is involved in HR-AD-induced AD. High-purity PUFAs were given to HR-AD-fed mice by dietary supplementation or gavage. Fatty acid levels in the serum and skin were determined by using gas chromatography-mass spectrometry. In serum from HR-AD-fed mice, linoleic acid (LA, 18:2n-6) and α-linolenic acid (ALA, 18:3n-3), as well as their metabolites, were markedly decreased. When mice were fed HR-AD supplemented with LA or ALA in an amount equal to that contained in a normal diet, the development of AD-like symptoms was completely prevented by supplementation with LA but not with ALA. Relatively high dose of ALA slightly alleviated skin barrier defects, but did neither itch-related scratching nor skin inflammation. On the other hand, gavage administration of LA metabolites, such as γ-linolenic acid and arachidonic acid (AA), significantly ameliorated established dermatitis without increasing LA in the serum and skin. Moreover, AA-induced amelioration of dermatitis was not affected by pharmacological blockade of 5-lipoxygenase (5-LOX) and cyclooxygenase (COX), suggesting no involvement of 5-LOX- or COX-mediated AA metabolites in the amelioration. In conclusion, our results indicate that deficiency of n-6 PUFAs is mainly responsible for AD-like symptoms by HR-AD feeding. Thus, this model could be useful for studying the pathomechanisms associated with deficiency of n-6 PUFAs in AD.

Dietary n-6 PUFA deprivation for 15 weeks reduces arachidonic acid concentrations while increasing n-3 PUFA concentrations in organs of post-weaning male rats.

Few studies have examined effects of feeding animals a diet deficient in n-6 polyunsaturated fatty acids (PUFAs) but with an adequate amount of n-3 PUFAs. To do this, we fed post-weaning male rats a control n-6 and n-3 PUFA adequate diet and an n-6 deficient diet for 15 weeks, and measured stable lipid and fatty acid concentrations in different organs. The deficient diet contained nutritionally essential linoleic acid (LA,18:2n-6) as 2.3% of total fatty acids (10% of the recommended minimum LA requirement for rodents) but no arachidonic acid (AA, 20:4n-6), and an adequate amount (4.8% of total fatty acids) of alpha-linolenic acid (18:3n-3). The deficient compared with adequate diet did not significantly affect body weight, but decreased testis weight by 10%. AA concentration was decreased significantly in serum (-86%), brain (-27%), liver (-68%), heart (-39%), testis (-25%), and epididymal adipose tissue (-77%). Eicosapentaenoic (20:5n-3) and docosahexaenoic acid (22:6n-3) concentrations were increased in all but adipose tissue, and the total monounsaturated fatty acid concentration was increased in all organs. The concentration of 20:3n-9, a marker of LA deficiency, was increased by the deficient diet, and serum concentrations of triacylglycerol, total cholesterol and total phospholipid were reduced. In summary, 15 weeks of dietary n-6 PUFA deficiency with n-3 PUFA adequacy significantly reduced n-6 PUFA concentrations in different organs of male rats, while increasing n-3 PUFA and monounsaturated fatty acid concentrations. This rat model could be used to study metabolic, functional and behavioral effects of dietary n-6 PUFA deficiency.

Omega-6 and omega-3 fatty acids predict accelerated decline of peripheral nerve function in older persons.

Pre-clinical studies suggest that both omega-6 and omega-3 fatty acids have beneficial effects on peripheral nerve function. Rats feed a diet rich in polyunsaturated fatty acids (PUFAs) showed modification of phospholipid fatty acid composition in nerve membranes and improvement of sciatic nerve conduction velocity (NCV). We tested the hypothesis that baseline plasma omega-6 and omega-3 fatty acids levels predict accelerated decline of peripheral nerve function. Changes between baseline and the 3-year follow-up in peripheral nerve function was assessed by standard surface ENG of the right peroneal nerve in 384 male and 443 female participants of the InCHIANTI study (age range: 24-97 years). Plasma concentrations of selected fatty acids assessed at baseline by gas chromatography. Independent of confounders, plasma omega-6 fatty acids and linoleic acid were significantly correlated with peroneal NCV at enrollment. Lower plasma PUFA, omega-6 fatty acids, linoleic acid, ratio omega-6/omega-3, arachidonic acid and docosahexanoic acid levels were significantly predicted a steeper decline in nerve function parameters over the 3-year follow-up. Low plasma omega-6 and omega-3 fatty acids levels were associated with accelerated decline of peripheral nerve function with aging.

Whole-body utilization of n-3 PUFA in n-6 PUFA-deficient rats.

We evaluated the utilization of a-linolenic acid (18:3n-3) in growing rats consuming a diet deficient in n-6 PUFA. After 90 d, whole-body 18:3n-3 accumulation was 55% lower, total n-3 PUFA accumulation was 21% lower, and 18:3n-3 disappearance was 14% higher in n-6 PUFA-deficient rats. Part of the reduction of whole-body 18:3n-3 in n-6 PUFA-deficient rats was due to the 25% increase in net conversion of 18:3n-3 to long-chain n-3 PUFA. Despite adequate 18:3n-3 intake, n-6 PUFA deficiency decreased the accumulation of 18:3n-3 and total n-3 PUFA.