Systematic investigation of the relationships of trimethylamine N-oxide and L-carnitine with obesity in both humans and rodents.

Previous studies suggested the potential associations of trimethylamine N-oxide (TMAO) and its metabolic precursor l-carnitine with obesity. However, existing evidence is limited and inconsistent. In the present study, we perform a cross-sectional analysis of the associations of serum levels of TMAO and l-carnitine with obesity measures, including BMI, body fat distribution and body composition in 1081 participants from the general Newfoundland population. The dietary effects of TMAO and l-carnitine in preventing high fat diet-induced obesity in both male and female mice were also evaluated. We found significant associations between higher serum l-carnitine levels and obesity (higher BMI, body fat mass and VT%) in women, but not in men after controlling multiple confounding factors. Serum TMAO levels were positively associated with age, but not obesity in both men and women. Dietary TMAO had no influence on fat accumulation in high fat diet-fed mice. However, l-carnitine supplementation prevented high fat diet-fed induced obesity in both male and female mice by up-regulating lipolysis and down-regulating lipogenesis in white adipose tissues. The present study provides further evidence for the relationships between TMAO, l-carnitine and obesity.

Betaine or folate can equally furnish remethylation to methionine and increase transmethylation in methionine-restricted neonates.

Methionine partitioning between protein turnover and a considerable pool of transmethylation precursors is a critical process in the neonate. Transmethylation yields homocysteine, which is either oxidized to cysteine (i.e., transsulfuration), or is remethylated to methionine by folate- or betaine- (from choline) mediated remethylation pathways. The present investigation quantifies the individual and synergistic importance of folate and betaine for methionine partitioning in neonates. To minimize whole body remethylation, 4-8-d-old piglets were orally fed an otherwise complete diet without remethylation precursors folate, betaine and choline (i.e. methyl-deplete, MD-) (n=18). Dietary methionine was reduced from 0.3 to 0.2 g/(kg∙d) on day-5 to limit methionine availability, and methionine kinetics were assessed during a gastric infusion of [13C1]methionine and [2H3-methyl]methionine. Methionine kinetics were reevaluated 2 d after pigs were rescued with either dietary folate (38 µg/(kg∙d)) (MD + F) (n=6), betaine (235 mg/(kg∙d)) (MD + B) (n=6) or folate and betaine (MD + FB) (n=6). Plasma choline, betaine, dimethylglycine (DMG), folate and cysteine were all diminished or undetectable after 7 d of methyl restriction (P<.05). Post-rescue, plasma betaine and folate concentrations responded to their provision, and homocysteine and glycine concentrations were lower (P<.05). Post-rescue, remethylation and transmethylation rates were~70-80% higher (P<.05), and protein breakdown was spared by 27% (P<.05). However, rescue did not affect transsulfuration (oxidation), plasma methionine, protein synthesis or protein deposition (P>.05). There were no differences among rescue treatments; thus betaine was as effective as folate at furnishing remethylation. Supplemental betaine or folate can furnish the transmethylation requirement during acute protein restriction in the neonate.

Preoperative and Postoperative Assessments of Biochemical Parameters in Patients with Severe Obesity Undergoing Laparoscopic Sleeve Gastrectomy.

BACKGROUND: The study aim was to determine the prevalence of abnormal serum biochemistries associated with micronutrient deficiencies before and after laparoscopic sleeve gastrectomy (LSG). METHODS: Two hundred and one patients had LSG surgery between May 2011 and May 2014. Using a prospective cohort study design, data were collected on ferritin, hemoglobin (Hgb), mean cell volume (MCV), calcium, albumin, 25-hydroxyvitamin D (25-OH-D), PTH, and vitamin B12 with follow-up of 75.6% (n = 152), 63.7% (n = 128), 52.7% (n = 106), and 40.3% (n = 81) at 6, 12, 18, and 24 months, respectively. RESULTS: Patients were female (81.6%) with mean ± SD, BMI (48.8 ± 6.8 kg/m2), weight (135.1 ± 23.6 kg), and age (44.0 ± 9.6 years). Mean values for all biochemical parameters pre- and post-LSG were within reference limits. After adjusting for age, weight, and supplement use, trend tests post-LSG were significant for mean differences in ferritin (p = 0.002), calcium (p = 0.017), and vitamin B12 (p = 0.034). Pre-LSG, the proportion of patients with values below reference limits included 25-OH-D (20.4%), ferritin (12.3%), and Hgb (10.0%), while the proportion above reference limits included PTH (29.1%) and ferritin (17.4%). After adjustment, hypoalbuminemia was more prevalent after 1 year; the proportion of patients with PTH levels in the upper reference limit was higher 6 months post-LSG (p < 0.05). Multivitamin use increased presurgery from 44 to 88% 2 years postsurgery. Vitamin B12 supplementation increased from 7% before surgery to 32% 2 years postsurgery. CONCLUSION: Abnormal serum biochemistries indicative of micronutrient deficiencies were prevalent before surgery; reduced abnormal values were observed after surgery, likely due to an increased use of multivitamins.

Higher Dietary Choline and Betaine Intakes Are Associated with Better Body Composition in the Adult Population of Newfoundland, Canada.

BACKGROUND: Choline is an essential nutrient and betaine is an osmolyte and methyl donor. Both are important to maintain health including adequate lipid metabolism. Supplementation of dietary choline and betaine increase muscle mass and reduce body fat in animals. However, little data is available regarding the role of dietary choline and betaine on body composition in humans. OBJECTIVE: To investigate the association between dietary choline and betaine intakes with body composition in a large population based cross-sectional study. DESIGN: A total of 3214 subjects from the CODING (Complex Disease in Newfoundland population: Environment and Genetics) study were assessed. Dietary choline and betaine intakes were computed from the Willett Food Frequency questionnaire. Body composition was measured using dual-energy X-ray absorptiometry following a 12-hour fast. Major confounding factors including age, sex, total calorie intake and physical activity level were controlled in all analyses. RESULT: Significantly inverse correlations were found between dietary choline and betaine intakes, with all obesity measurements: total percent body fat (%BF), percent trunk fat (%TF), percent android fat (%AF), percent gynoid fat (%GF) and anthropometrics: weight, body mass index, waist circumference, waist-to-hip ratio in both women and men (r range from -0.13 to -0.47 for choline and -0.09 to -0.26 for betaine, p<0.001 for all). Dietary choline intake had stronger association than betaine. Moreover, obese subjects had the lowest dietary choline and betaine intakes, with overweight subjects in the middle, and normal weight subjects consumed the highest dietary choline and betaine (p<0.001). Vice versa, when subjects were ranked according to dietary choline and betaine intakes, subjects with the highest intake of both had the lowest %TF, %AF, %GF, %BF and highest %LM among the groups in both sexes. CONCLUSION: Our findings indicate that high dietary choline and betaine intakes are significantly associated with favorable body composition in humans.

Betaine is as effective as folate at re-synthesizing methionine for protein synthesis during moderate methionine deficiency in piglets.

PURPOSE: Both folate and betaine (synthesized from choline) are nutrients used to methylate homocysteine to reform the amino acid methionine following donation of its methyl group; however, it is unclear whether both remethylation pathways are of equal importance during the neonatal period when remethylation rates are high. Methionine is an indispensable amino acid that is in high demand in neonates not only for protein synthesis, but is also particularly important for transmethylation reactions, such as creatine and phosphatidylcholine synthesis. The objective of this study was to determine whether supplementation with folate, betaine, or a combination of both can equally re-synthesize methionine for protein synthesis when dietary methionine is limiting. METHODS: Piglets were fed a low methionine diet devoid of folate, choline, and betaine, and on day 6, piglets were supplemented with either folate, betaine, or folate + betaine (n = 6 per treatment) until day 10. [1-13C]-phenylalanine oxidation was measured as an indicator of methionine availability for protein synthesis both before and after 2 days of supplementation. RESULTS: Prior to supplementation, piglets had lower concentrations of plasma folate, betaine, and choline compared to baseline with no change in homocysteine. Post-supplementation, phenylalanine oxidation levels were 20-46 % lower with any methyl donor supplementation (P = 0.006) with no difference among different supplementation groups. Furthermore, both methyl donors led to similarly lower concentrations of homocysteine following supplementation (P < 0.05). CONCLUSIONS: These data demonstrate an equal capacity for betaine and folate to remethylate methionine for protein synthesis, as indicated by lower phenylalanine oxidation.

Fructose and moderately high dietary salt-induced hypertension: prevention by a combination of N-acetylcysteine and L-arginine.

Diets containing 8% salt or 4% fructose (FR) cause insulin resistance and increase tissue methylglyoxal and advanced glycation end products (AGEs), platelet cytosolic-free calcium, and systolic blood pressure (SBP) in rats. In WKY rats, we have shown that moderately high salt, 4% NaCl (MHS) alone in diet does not cause hypertension, and when given along with 4% FR it does not have an additive effect. N-acetylcysteine (NAC) or L-arginine (ARG), treatment alone does not prevent hypertension in this model. The objectives of this study were to investigate the effect of NAC plus ARG in diet on SBP, platelet cytosolic-free calcium in a MHS + FR model, and to measure the plasma levels of methylglyoxal and the AGE, methylglyoxal-derived hydroimidazolone (MGH). At 7 weeks of age, WKY rats were divided into three groups: control group was given regular rat chow (0.7% NaCl) and water; MHS + FR group, diet containing 4% NaCl and 4% FR in drinking water; and MHS + FR + NAC + ARG group, MHS diet supplemented with 1.5% N-acetylcysteine (NAC) and 1.5% L-arginine (ARG), and 4% FR in drinking water, and followed for 6 weeks. NAC + ARG prevented the increase in platelet cytosolic-free calcium and SBP in MHS + FR treated rats. There was no difference in mean values of plasma methylglyoxal and MGH among the groups. In conclusion, NAC + ARG treatment is effective in preventing hypertension in a moderately high salt + FR-induced animal model. Plasma methylglyoxal and MGH may not represent tissue modification or, alternatively, other tissue AGEs, derived from methylglyoxal or other aldehydes, may be involved in hypertension in this model.

Seasonal variation of maternal serum vitamin D in Newfoundland and Labrador.

BACKGROUND: Research has suggested that vitamin D insufficiency and deficiency is common at northern latitudes, and that vitamin D insufficiency and deficiency may be common during pregnancy. We measured the serum 25-hydroxyvitamin D (25-[OH]D) status of pregnant women across the province of Newfoundland and Labrador in both summer and winter to investigate seasonal differences, age associations, and differences in geospatial distribution across the province. METHODS: We uniformly and randomly sampled blood from pregnant women in each of 79 census consolidated subdivisions across Newfoundland and Labrador from January to March 2007 and from July to September 2007. RESULTS: We obtained 304 samples from the end of winter (March) and 289 samples from the end of summer (September). Mean serum 25-(OH)D concentration was 52.1 nmol/L in winter and 68.6 nmol/L in summer (P < 0.001); 89% were vitamin D insufficient in the winter and 64% in the summer (P < 0.001); 6.6% were vitamin D deficient in winter and 1.7% in summer (P = 0.003), and younger women tended to be more vitamin D insufficient in the winter than older women. The geospatial distribution of vitamin D insufficiency tends to follow a north-south distribution in the winter. CONCLUSIONS: A significant proportion of pregnant women in Newfoundland and Labrador are vitamin D insufficient. Vitamin D insufficiency may have important adverse health consequences for both the mother and the fetus. Further study is necessary to address health outcomes and effects of vitamin D supplementation and lifestyle changes in this population.

Vitamin D insufficiency common in newborns, children and pregnant women living in Newfoundland and Labrador, Canada.

Vitamin D deficiency is associated with poor bone health, colorectal cancer, type 1 diabetes and multiple sclerosis. Two national health-related societies in Canada have made recommendations for vitamin D supplementation, yet little research has been reported on the vitamin D status of Canadians. Lifestyle changes, such as sunscreen use, spending less time outdoors and insufficient intake of vitamin D-containing foods as well as northern latitude, may be affecting human vitamin D status. A cross-sectional analysis of 25-hydroxyvitamin D [25-(OH)D] was conducted in pregnant women, newborns (umbilical cord blood) and children. Samples were analysed by liquid chromatography mass spectrometry. Published ranges for 25-(OH)D were used to determine vitamin D status. The prevalence of 25-(OH)D deficiency for the three groups studied revealed most concentrations in the 25-(OH)D deficiency or insufficiency ranges. There were significant differences in all groups studied between seasons, with the exception of maternal blood and female cord blood samples. 25-(OH)D insufficiency was common in all groups for winter and summer, more so in winter. 25-(OH)D insufficiency was common in the three groups studied. The Newfoundland and Labrador population may be at increased risk for vitamin D insufficiency because of factors such as northern latitude and lifestyle issues. Further research on the vitamin D status of this population is important, considering the potential adverse health-related outcomes and the recommendations on supplementation being made.

Attenuation of ciclosporin-induced nephrotoxicity by dietary supplementation of seal oil in Sprague-Dawley rats.

Fish oil, rich in omega-3 (n-3) polyunsaturated fatty acids (PUFAs), has been reported to attenuate nephrotoxicity induced by ciclosporin (cyclosporine A). Harp seal oil is a rich source of n-3 PUFAs. This study investigated the ability of dietary seal oil to reduce nephrotoxicity caused by ciclosporin. Sprague-Dawley rats were maintained on a standard diet (with sunflower oil as lipid, SFO) or a diet enriched with seal oil (with 85% seal oil and 15% sunflower oil as lipid, SO) for four weeks before and four weeks after intravenous administration of ciclosporin (15 mg kg(-1) daily). Kidney function was assessed by measuring blood urea nitrogen, creatinine clearance, urinary N-acetyl-1-beta-D-glucosaminidase, 6-keto-prostaglandin F(1alpha), thromboxane B(2) and malondialdehyde. Systolic blood pressure (SBP) was monitored. Ciclosporin concentrations in blood were measured using liquid chromatographytandem mass spectrometry (LC-MS/MS). The fatty acid compositions of the diets and erythrocyte membranes were analysed by gas chromatography (GC). The results showed that nephrotoxicity was induced by ciclosporin in rats maintained on both SO and SFO diets. However, rats fed on SO diet endured less toxicity than those on SFO diet. The n-3 and n-6 PUFAs in the erythrocyte membrane of rats maintained on SO diet were found to be 10.79% and 11.93%, while those in rats maintained on SFO diet were found to be 1.67% and 22.71%, respectively. In conclusion, dietary supplementation of seal oil was found to reduce ciclosporin-induced nephrotoxicity in rats.

A comprehensive evaluation of food fortification with folic acid for the primary prevention of neural tube defects.

BACKGROUND: Periconceptional use of vitamin supplements containing folic acid reduces the risk of a neural tube defect (NTD). In November 1998, food fortification with folic acid was mandated in Canada, as a public health strategy to increase the folic acid intake of all women of childbearing age. We undertook a comprehensive population based study in Newfoundland to assess the benefits and possible adverse effects of this intervention. METHODS: This study was carried out in women aged 19-44 years and in seniors from November 1997 to March 1998, and from November 2000 to March 2001. The evaluation was comprised of four components: I) Determination of rates of NTDs; II) Dietary assessment; III) Blood analysis; IV) Assessment of knowledge and use of folic acid supplements. RESULTS: The annual rates of NTDs in Newfoundland varied greatly between 1976 and 1997, with a mean rate of 3.40 per 1,000 births. There was no significant change in the average rates between 1991-93 and 1994-97 (relative risk [RR] 1.01, 95% confidence interval [CI] 0.76-1.34). The rates of NTDs fell by 78% (95% CI 65%-86%) after the implementation of folic acid fortification, from an average of 4.36 per 1,000 births during 1991-1997 to 0.96 per 1,000 births during 1998-2001 (RR 0.22, 95% CI 0.14-0.35). The average dietary intake of folic acid due to fortification was 70 µg/day in women aged 19-44 years and 74 µg/day in seniors. There were significant increases in serum and RBC folate levels for women and seniors after mandatory fortification. Among seniors, there were no significant changes in indices typical of vitamin B12 deficiencies, and no evidence of improved folate status masking haematological manifestations of vitamin B12 deficiency. The proportion of women aged 19-44 years taking a vitamin supplement containing folic acid increased from 17% to 28%. CONCLUSIONS: Based on these findings, mandatory food fortification in Canada should continue at the current levels. Public education regarding folic acid supplement use by women of childbearing age should also continue.