Yu Hong Lin

Dietary Linoleic Acid Elevates Endogenous 2‐AG and Anandamide and Induces Obesity

Suppressing hyperactive endocannabinoid tone is a critical target for reducing obesity. The backbone of both endocannabinoids 2‐arachidonoylglycerol (2‐AG) and anandamide (AEA) is the ω‐6 fatty acid arachidonic acid (AA). Here we posited that excessive dietary intake of linoleic acid (LA), the precursor of AA, would induce endocannabinoid hyperactivity and promote obesity. LA was isolated as an independent variable to reflect the dietary increase in LA from 1 percent of energy (en%) to 8 en% occurring in the United States during the 20th century. Mice were fed diets containing 1 en% LA, 8 en% LA, and 8 en% LA + 1 en% eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) in medium‐fat diets (35 en% fat) and high‐fat diets (60 en%) for 14 weeks from weaning. Increasing LA from 1 en% to 8 en% elevated AA‐phospholipids (PL) in liver and erythrocytes, tripled 2‐AG + 1‐AG and AEA associated with increased food intake, feed efficiency, and adiposity in mice. Reducing AA‐PL by adding 1 en% long‐chain ω‐3 fats to 8 en% LA diets resulted in metabolic patterns resembling 1 en% LA diets. Selectively reducing LA to 1 en% reversed the obesogenic properties of a 60 en% fat diet. These animal diets modeled 20th century increases of human LA consumption, changes that closely correlate with increasing prevalence rates of obesity. In summary, dietary LA increased tissue AA, and subsequently elevated 2‐AG + 1‐AG and AEA resulting in the development of diet‐induced obesity. The adipogenic effect of LA can be prevented by consuming sufficient EPA and DHA to reduce the AA‐PL pool and normalize endocannabinoid tone.

Suicide deaths of active-duty US military and omega-3 fatty-acid status: a case-control comparison.

BACKGROUND The recent escalation of US military suicide deaths to record numbers has been a sentinel for impaired force efficacy and has accelerated the search for reversible risk factors. OBJECTIVE To determine whether deficiencies of neuroactive, highly unsaturated omega-3 essential fatty acids (n-3 HUFAs), in particular docosahexaenoic acid (DHA), are associated with increased risk of suicide death among a large random sample of active-duty US military. METHOD In this retrospective case-control study, serum fatty acids were quantified as a percentage of total fatty acids among US military suicide deaths (n = 800) and controls (n = 800) matched for age, date of collection of sera, sex, rank, and year of incident. Participants were active-duty US military personnel (2002-2008). For cases, age at death ranged from 17-59 years (mean = 27.3 years, SD = 7.3 years). Outcome measures included death by suicide, postdeployment health assessment questionnaire (Department of Defense Form 2796), and ICD-9 mental health diagnosis data. RESULTS Risk of suicide death was 14% higher per SD of lower DHA percentage (OR = 1.14; 95% CI, 1.02-1.27; P < .03) in adjusted logistic regressions. Among men, risk of suicide death was 62% greater with low serum DHA status (adjusted OR = 1.62; 95% CI, 1.12-2.34; P < .01, comparing DHA below 1.75% [n = 1,389] to DHA of 1.75% and above [n = 141]). Risk of suicide death was 52% greater in those who reported having seen wounded, dead, or killed coalition personnel (OR = 1.52; 95% CI, 1.11-2.09; P < .01). CONCLUSION This US military population had a very low and narrow range of n-3 HUFA status. Although these data suggest that low serum DHA may be a risk factor for suicide, well-designed intervention trials are needed to evaluate causality.

Dietary linoleic acid elevates endogenous 2-arachidonoylglycerol and anandamide in Atlantic salmon ( Salmo salar L.) and mice, and induces weight gain and inflammation in mice

Dietary intake of linoleic acid (LA) has increased dramatically during the twentieth century and is associated with a greater prevalence of obesity. Vegetable oils are recognised as suitable alternatives to fish oil (FO) in feed for Atlantic salmon (Salmo salar L.) but introduce high amounts of LA in the salmon fillet. The effect on fish consumers of such a replacement remains to be elucidated. Here, we investigate the effect of excessive dietary LA from soyabean oil (SO) on endocannabinoid levels in Atlantic salmon and mice, and study the metabolic effects in mice when SO replaces FO in feed for Atlantic salmon. Atlantic salmon were fed FO and SO for 6 months, and the salmon fillet was used to produce feed for mice. Male C57BL/6J mice were fed diets of 35% of energy as fat based on FO- and SO-enriched salmon for 16 weeks. We found that replacing FO with SO in feed for Atlantic salmon increased LA, arachidonic acid (AA), decreased EPA and DHA, elevated the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA), and increased TAG accumulation in the salmon liver. In mice, the SO salmon diet increased LA and AA and decreased EPA and DHA in the liver and erythrocyte phospholipids, and elevated 2-AG and AEA associated with increased feed efficiency, weight gain and adipose tissue inflammation compared with mice fed the FO salmon diet. In conclusion, excessive dietary LA elevates endocannabinoids in the liver of salmon and mice, and increases weight gain and counteracts the anti-inflammatory properties of EPA and DHA in mice.

Body burdens of mercury, lead, selenium and copper among Baltimore newborns.

Umbilical cord blood or serum concentrations of mercury, lead, selenium and copper were measured with inductively coupled plasma mass spectrometry in a population of 300 infants born in Baltimore, Maryland. Geometric mean values were 1.37 μg/L (95% confidence interval: 1.27, 1.48) for mercury; 0.66 μg/dL (95% CI: 0.61, 0.71) for lead; and 38.62 μg/dL (95% CI: 36.73, 40.61) for copper. Mean selenium was 70.10 μg/L (95% CI: 68.69, 70.52). Mercury, selenium and copper levels were within exposure ranges reported among similar populations, whereas the distribution of lead levels was lower than prior reports; only one infant had a cord blood lead above 10 μg/dL. Levels of selenium were significantly correlated with concentrations of lead (Spearmans ρ=0.20) and copper (Spearmans ρ=0.51). Multivariable analyses identified a number of factors associated with one of more of these exposures. These included: increase in maternal age (increased lead); Asian mothers (increased mercury and lead, decreased selenium and copper); higher umbilical cord serum n-3 fatty acids (increased mercury, selenium and copper), mothers using Medicaid (increased lead); increasing gestational age (increased copper); increasing birthweight (increased selenium); older neighborhood housing stock (increased lead and selenium); and maternal smoking (increased lead). This work provides additional information about contemporary prenatal element exposures and can help identify groups at risk of atypical exposures.

Compartmental analyses of 2H5-α-linolenic acid and C-U-eicosapentaenoic acid toward synthesis of plasma labeled 22:6n−3 in newborn term infants

BACKGROUND During early postnatal development, the nervous system accretes docosahexaenoic acid (DHA; 22:6n-3), a highly unsaturated n-3 (omega-3) fatty acid (FA) used in the formation of neural cell membranes. DHA, which is present in human breast milk, may also be biosynthesized from n-3 FAs such as 18:3n-3 [alpha-linolenic acid (ALA)] or 20:5n-3 [eicosapentaenoic acid (EPA)]. An important concern is to what extent these precursors can supply DHA to the developing infant. OBJECTIVE We analyzed measurements of fractional percentages of plasma (2)H(5)-ALA and (13)C-U-EPA directed toward the synthesis of labeled 22:6n-3 in 11 newborn infants by using compartmental modeling procedures. DESIGN One-week-old infants received doses of (2)H(5)-ALA and (13)C-U-EPA ethyl esters enterally. We drew blood from the infants periodically and analyzed the plasma for endogenous and labeled n-3 FAs. From the time-course concentrations of the labeled FAs, we determined rate constant coefficients, fractional synthetic rates, and plasma turnover rates of n-3 FAs. RESULTS In infants, approximately 0.04% of the (2)H(5)-ALA dose converted to plasma (2)H(5)-EPA. Plasma (2)H(5)-EPA and (2)H(5)-22:5n-3 [docosapentaenoic acid (DPA)] efficiently converted to (2)H(5)-DPA and (2)H(5)-DHA, respectively. The percentage of plasma (13)C-U-EPA directed toward the synthesis of (13)C-DHA was lower than the percentage of plasma (2)H(5)-EPA that originated from (2)H(5)-ALA. CONCLUSIONS Endogenously synthesized EPA was efficiently converted to DHA. In comparison, preformed EPA was less efficiently used for DHA biosynthesis, which suggests a differential metabolism of endogenous EPA compared with exogenous EPA. However, on a per mole basis, preformed EPA was 3.6 times more effective toward DHA synthesis than was ALA. Newborns required an intake of approximately 5 mg preformed DHA. kg(-1) x d(-1) to maintain plasma DHA homeostasis.

Altered Essential Fatty Acid Metabolism and Composition in Rat Liver, Plasma, Heart and Brain After Microalgal DHA Addition to the Diet

To investigate the effect of docosahexaenoic acid (DHA) without other highly unsaturated fatty acids (HUFA) on n-3 and n-6 essential fatty acid (EFA) metabolism and fatty acid composition in mammals, a stable isotope tracer technique was used in adult rats fed diets with or without 1.3% of algal DHA in a base diet containing 15% of linoleic acid and 3% of alpha-linolenic acid over 8 weeks. The rats were administered orally a mixed oil containing 48 mg/kg body weight of deuterated linoleic and alpha-linolenic acids and euthanized at 4, 8, 24, 96, 168, 240, 360 and 600 h after administration of the isotopes. Fatty acid compositions and the concentrations of deuterated precursors and their respective metabolites were determined in rat liver, plasma, heart and brain as a function of time. DHA, docosapentaenoic acid and eicosapentaenoic acid in the n-3 EFA family were significantly increased in all organs tested in the DHA-fed group, ranging from 5% to 200% greater in comparison with the control group. The accumulation of the metabolites, deuterated-DHA and deuterated-docosapentaenoic acid n-6 was greatly decreased by 1.5- to 2.5-fold in the dietary DHA group. In summary, feeding preformed DHA led to a marked increase in n-3 HUFA content of rat organs at the expense of n-6 HUFA and also prevented the accumulation of newly synthesized deuterated end products. This is the first study which has isolated the effects of DHA on the de novo metabolism on both the n-6 and n-3 EFA pathways.

Compartmental Analyses of Plasma 13C- and 2H-Labeled n-6 Fatty Acids Arising from Oral Administrations of 13C-U-18:2n-6 and 2H5-20:3n-6 in Newborn Infants

Efficacy of 13C-U-18:2n-6 and 2H5-20:3n-6 toward synthesis of labeled-20:4n-6 was studied in newborn infants utilizing compartmental models of plasma labeled n-6 fatty acids (FA). Ten infants received oral doses of 13C-U-18:2n-6 and 2H5-20:3n-6 ethyl esters (100 and 2 mg/kg, respectively). Rate constant coefficients and half-lives (t½) of n-6 FA were determined from the time-course concentrations of labeled-FA. Plasma n-6 FA values approximated steady state concentrations. Synthetic and utilization rates were calculated. Eight percent (range, 2–21%) of plasma 13C-U-18:2n-6 was used for synthesis of 13C-18:3n-6, -20:2n-6, and -20:3n-6. Seventy percent of 13C-20:3n-6 (mean, CV: 0.26) was available for synthesis of 13C-20:4n-6. The percentage of 2H5-20:3n-6 converted to 2H5-20:4n-6 was lower (mean: 26%, p < 0.02) than the 13C-labeled analogue. Turnover of 18:2n-6 in subjects and of 20:4n-6 in plasma was 4.2 g/kg/d (CV: 0.58) and 4.3 mg/kg/d (CV: 0.81), respectively. Intake of 18:2n-6 and 20:4n-6 were estimated to be 3.0 g/kg/d (±1.7) and 2.8 mg/kg/d (± 2.2), respectively. Infants required additional 18:2n-6 and 20:4n-6 (mean: 1.2 g and 1.5 mg/kg/d) above predicted intake amounts to maintain plasma concentrations of 18:2n-6 and 20:4n-6, in order to spare FA from fat stores.

Suckling rats actively recycle carbon from α-linolenate into newly synthesized lipids even during extreme dietary deficiency of n-3 polyunsaturates

Docosahexaenoate is usually considered to be the principal endpoint of α-linolenate metabolism in mammals. Nevertheless, several studies over the past 30 y have shown that more carbon from α-linolenate is recycled into newly synthesized lipids than is used to make docosahexaenoate. Our objective in this study was to assess carbon recycling from α-linolenate in suckling rats made deficient in n-3 polyunsaturated fatty acids (PUFA). Female Long-Evans rats were given a diet deficient in n-3 PUFA at weaning and then bred 8 wk later. Pups from the second generation were nursed by their respective dams and gavaged with 1 mg [U-13C]-α-linolenate at 10 d old. Brain and liver were obtained 24 h later, and the fatty acid profiles and 13C enrichment analyzed. Docosahexaenoate was markedly depleted in brain (−82%) and liver (−97%) of the n-3 PUFA–deficient rats. In the controls, 13C enrichment in products of carbon recycling (cholesterol and fatty acids other than n-3 PUFA) exceeded that in docosahexaenoate by 2.4-fold (liver) and 7.5-fold (brain). n-3 PUFA deficiency reduced the ratio of 13C enrichment in products of carbon recycling compared with 13C incorporated into docosahexaenoate by 63% in the brain but not in the liver. Despite severe n-3 PUFA deficiency, carbon recycling still consumed 50% more 13C from α-linolenate than went into docosahexaenoate in the liver and 2.8-fold more in the brain. We conclude that carbon recycling is an integral part of neonatal metabolism of α-linolenate and is not simply an overflow pathway arising from excess availability of preformed docosahexaenoate.

Cord Blood Methylmercury and Fetal Growth Outcomes in Baltimore Newborns: Potential Confounding and Effect Modification by Omega-3 Fatty Acids, Selenium, and Sex

Background Methylmercury (MeHg) may affect fetal growth; however, prior research often lacked assessment of mercury speciation, confounders, and interactions. Objective Our objective was to assess the relationship between MeHg and fetal growth as well as the potential for confounding or interaction of this relationship from speciated mercury, fatty acids, selenium, and sex. Methods This cross-sectional study includes 271 singletons born in Baltimore, Maryland, 2004–2005. Umbilical cord blood was analyzed for speciated mercury, serum omega-3 highly unsaturated fatty acids (n-3 HUFAs), and selenium. Multivariable linear regression models controlled for gestational age, birth weight, maternal age, parity, prepregnancy body mass index, smoking, hypertension, diabetes, selenium, n-3 HUFAs, and inorganic mercury (IHg). Results Geometric mean cord blood MeHg was 0.94 μg/L (95% CI: 0.84, 1.07). In adjusted models for ponderal index, βln(MeHg) = –0.045 (g/cm3) × 100 (95% CI: –0.084, –0.005). There was no evidence of a MeHg × sex interaction with ponderal index. Contrastingly, there was evidence of a MeHg × n-3 HUFAs interaction with birth length [among low n-3 HUFAs, βln(MeHg) = 0.40 cm, 95% CI: –0.02, 0.81; among high n-3 HUFAs, βln(MeHg) = –0.15, 95% CI: –0.54, 0.25; p-interaction = 0.048] and head circumference [among low n-3 HUFAs, βln(MeHg) = 0.01 cm, 95% CI: –0.27, 0.29; among high n-3 HUFAs, βln(MeHg) = –0.37, 95% CI: –0.63, –0.10; p-interaction = 0.042]. The association of MeHg with birth weight and ponderal index was affected by n-3 HUFAs, selenium, and IHg. For birth weight, βln(MeHg) without these variables was –16.8 g (95% CI: –75.0, 41.3) versus –29.7 (95% CI: –93.9, 34.6) with all covariates. Corresponding values for ponderal index were –0.030 (g/cm3) × 100 (95% CI: –0.065, 0.005) and –0.045 (95% CI: –0.084, –0005). Conclusion We observed an association of increased MeHg with decreased ponderal index. There is evidence for interaction between MeHg and n-3 HUFAs; infants with higher MeHg and n-3 HUFAs had lower birth length and head circumference. These results should be verified with additional studies. Citation Wells EM, Herbstman JB, Lin YH, Jarrett J, Verdon CP, Ward C, Caldwell KL, Hibbeln JR, Witter FR, Halden RU, Goldman LR. 2016. Cord blood methylmercury and fetal growth outcomes in Baltimore newborns: potential confounding and effect modification by omega-3 fatty acids, selenium, and sex. Environ Health Perspect 124:373–379; http://dx.doi.org/10.1289/ehp.1408596

Methyl mercury, but not inorganic mercury, associated with higher blood pressure during pregnancy

&NA; Prior studies addressing associations between mercury and blood pressure have produced inconsistent findings; some of this may result from measuring total instead of speciated mercury. This cross‐sectional study of 263 pregnant women assessed total mercury, speciated mercury, selenium, and n‐3 polyunsaturated fatty acids in umbilical cord blood and blood pressure during labor and delivery. Models with a) total mercury or b) methyl and inorganic mercury were evaluated. Regression models adjusted for maternal age, race/ethnicity, prepregnancy body mass index, neighborhood income, parity, smoking, n‐3 fatty acids and selenium. Geometric mean total, methyl, and inorganic mercury concentrations were 1.40 &mgr;g/L (95% confidence interval: 1.29, 1.52); 0.95 &mgr;g/L (0.84, 1.07); and 0.13 &mgr;g/L (0.10, 0.17), respectively. Elevated systolic BP, diastolic BP, and pulse pressure were found, respectively, in 11.4%, 6.8%, and 19.8% of mothers. In adjusted multivariable models, a one‐tertile increase of methyl mercury was associated with 2.83 mmHg (0.17, 5.50) higher systolic blood pressure and 2.99 mmHg (0.91, 5.08) higher pulse pressure. In the same models, an increase of one tertile of inorganic mercury was associated with −1.18 mmHg (−3.72, 1.35) lower systolic blood pressure and −2.51 mmHg (−4.49, −0.53) lower pulse pressure. No associations were observed with diastolic pressure. There was a non‐significant trend of higher total mercury with higher systolic blood pressure. We observed a significant association of higher methyl mercury with higher systolic and pulse pressure, yet higher inorganic mercury was significantly associated with lower pulse pressure. These results should be confirmed with larger, longitudinal studies. HighlightsWe compared total, methyl and inorganic mercury with blood pressure in pregnancy.Models controlled for n‐3 fatty acids, selenium, and other variables.Methyl mercury was associated with higher systolic blood pressure and pulse pressure.Inorganic mercury was associated reduced pulse pressure.There were no significant associations of total mercury with blood pressure.