Betaine as a dietary alkaloid has attracted the attention of patients with kidney diseases. This study aimed to investigate the effects of betaine on serum uric acid levels and kidney function, and explore their underlying mechanisms in potassium oxonate-induced hyperuricemic mice. Betaine at 5, 10, 20, and 40 mg/kg was orally administered to hyperuricemic mice for 7 days and found to significantly reduce serum uric acid levels and increase fractional excretion of uric acid in hyperuricemic mice in a dose-dependent manner. It effectively restored renal protein level alterations of urate transport-related molecular proteins urate transporter 1, glucose transporter 9, organic anion transporter 1, and ATP-binding cassette subfamily G member 2 in this model, possibly resulting in the enhancement of kidney urate excretion. Moreover, betaine reduced serum creatinine and blood urea nitrogen levels and affected urinary levels of beta-2-microglobulin and N-acetyl-beta-D-glucosaminidase as well as upregulated renal protein levels of organic cation/carnitine transporters OCT1, OCTN1, and OCTN2, resulting in kidney function improvement in hyperuricemic mice. The findings from this study provide evidence that betaine has anti-hyperuricemic and nephroprotective actions by regulating protein levels of these renal organic ion transporters in hyperuricemic mice.
Liu, Y.L., et al., Betaine Reduces Serum Uric Acid Levels and Improves Kidney Function in Hyperuricemic Mice. Planta Med, 2013
Monday, December 23, 2013
Saturday, December 21, 2013
Betaine attenuates hepatic steatosis by reducing methylation of the MTTP promoter and elevating genomic methylation in mice fed a high fat diet
Aberrant DNA methylation contributes to the abnormality of hepatic gene expression, one of the main factors in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Betaine is a methyl donor and has been considered to be a lipotropic agent. However, whether betaine supplementation improves NAFLD via its effect on the DNA methylation of specific genes and the genome has not been explored. Male C57BL/6 mice were fed either a control diet (CD) or high fat diet (HFD) supplemented with 0%, 1% and 2% betaine in water (wt/vol) for 12 weeks. Betaine supplementation ameliorated HFD-induced hepatic steatosis in a dose-dependent manner. HFD upregulated FAS and ACOX mRNA expression and downregulated PPARÃŽ±, ApoB and MTTP mRNA expression; however, these alterations were reversed by betaine supplementation except ApoB. MTTP mRNA expression was negatively correlated with the DNA methylation of its CpG sites at -184, -156, -63 and -60. Methylation of these CpG sites was lower in both the 1% and 2% betaine-supplemented groups than in the HFD group (averages; 25.55% and 14.33% vs. 30.13%). In addition, both 1% and 2% betaine supplementation significantly restored the methylation capacity (SAM concentration and SAM/SAH ratios) and genomic methylation level which had been decreased by HFD (0.37% and 0.47% vs. 0.25%). These results suggest that the regulation of aberrant DNA methylation by betaine might be a possible mechanism of the improvements in NAFLD upon betaine supplementation.
Wang, L.-j., et al., Betaine attenuates hepatic steatosis by reducing methylation of the MTTP promoter and elevating genomic methylation in mice fed a high fat diet. The Journal of Nutritional Biochemistry, 2013
Wang, L.-j., et al., Betaine attenuates hepatic steatosis by reducing methylation of the MTTP promoter and elevating genomic methylation in mice fed a high fat diet. The Journal of Nutritional Biochemistry, 2013
Survival and psychomotor development with early betaine treatment in patients with severe methylenetetrahydrofolate reductase deficiency
IMPORTANCE The impact of betaine treatment on outcome in patients with severe methylenetetrahydrofolate reductase (MTHFR) deficiency is presently unclear.
OBJECTIVE To investigate the effect of betaine treatment on development and survival in patients with severe MTHFR deficiency. DATA SOURCES MEDLINE, EMBASE, and Cochrane databases between January 1960 and December 2012. STUDY SELECTION Studies that described patients with severe MTHFR deficiency who received betaine treatment.
DATA EXTRACTION AND SYNTHESIS We identified 15 case reports and case series, totaling 36 patients. Data included the following: (1) families with 2 or more patients with severe MTHFR deficiency, of whom at least 1 received betaine, or (2) single patients with severe MTHFR deficiency treated with betaine. To define severe MTHFR deficiency, methionine, homocysteine, MTHFR enzyme activity in fibroblasts, or mutations (in the MTHFR gene) had to be described as well as the effect of treatment (survival and/or psychomotor development). We compared the outcome in treated vs untreated patients and early- vs late-treated patients. Sensitivity analysis was performed to address definition of early treatment. To further assess the impact of treatment on mortality, we performed a subanalysis in families with at least 1 untreated deceased patient.
MAIN OUTCOMES AND MEASURES Survival and psychomotor development.
RESULTS Eleven of 36 patients (31%) died. All deaths occurred in patients who did not receive treatment or in patients in whom treatment was delayed. In contrast, all 5 early-treated patients survived. Subgroup analysis of patients with deceased siblings-their genotypically identical controls-revealed that betaine treatment prevented mortality (P = .002). In addition, psychomotor development in surviving patients treated with betaine was normal in all 5 early-treated patients but in none of the 19 surviving patients with delayed treatment (P < .001).
CONCLUSIONS AND RELEVANCE Early betaine treatment prevents mortality and allows normal psychomotor development in patients with severe MTHFR deficiency, highlighting the importance of timely recognition through newborn screening.
Diekman, E.F., et al., Survival and Psychomotor Development With Early Betaine Treatment in Patients With Severe Methylenetetrahydrofolate Reductase Deficiency. JAMA Neurol, 2013
OBJECTIVE To investigate the effect of betaine treatment on development and survival in patients with severe MTHFR deficiency. DATA SOURCES MEDLINE, EMBASE, and Cochrane databases between January 1960 and December 2012. STUDY SELECTION Studies that described patients with severe MTHFR deficiency who received betaine treatment.
DATA EXTRACTION AND SYNTHESIS We identified 15 case reports and case series, totaling 36 patients. Data included the following: (1) families with 2 or more patients with severe MTHFR deficiency, of whom at least 1 received betaine, or (2) single patients with severe MTHFR deficiency treated with betaine. To define severe MTHFR deficiency, methionine, homocysteine, MTHFR enzyme activity in fibroblasts, or mutations (in the MTHFR gene) had to be described as well as the effect of treatment (survival and/or psychomotor development). We compared the outcome in treated vs untreated patients and early- vs late-treated patients. Sensitivity analysis was performed to address definition of early treatment. To further assess the impact of treatment on mortality, we performed a subanalysis in families with at least 1 untreated deceased patient.
MAIN OUTCOMES AND MEASURES Survival and psychomotor development.
RESULTS Eleven of 36 patients (31%) died. All deaths occurred in patients who did not receive treatment or in patients in whom treatment was delayed. In contrast, all 5 early-treated patients survived. Subgroup analysis of patients with deceased siblings-their genotypically identical controls-revealed that betaine treatment prevented mortality (P = .002). In addition, psychomotor development in surviving patients treated with betaine was normal in all 5 early-treated patients but in none of the 19 surviving patients with delayed treatment (P < .001).
CONCLUSIONS AND RELEVANCE Early betaine treatment prevents mortality and allows normal psychomotor development in patients with severe MTHFR deficiency, highlighting the importance of timely recognition through newborn screening.
Diekman, E.F., et al., Survival and Psychomotor Development With Early Betaine Treatment in Patients With Severe Methylenetetrahydrofolate Reductase Deficiency. JAMA Neurol, 2013
Friday, December 6, 2013
Betaine alleviates hypertriglycemia and tau hyperphosphorylation in db/db mice
Betaine supplementation has been shown to alleviate altered glucose and lipid metabolism in mice fed a high-fat diet or a high-sucrose diet. We investigated the beneficial effects of betaine in diabetic db/db mice. Alleviation of endoplasmic reticulum (ER) and oxidative stress was also examined in the livers and brains of db/db mice fed a betaine-supplemented diet. Male C57BL/KsJ-db/db mice were fed with or without 1% betaine for 5 wk (referred to as the db/db-betaine group and the db/db group, respectively). Lean non-diabetic db/db+ mice were used as the control group. Betaine supplementation significantly alleviated hyperinsulinemia in db/db mice. Betaine reduced hepatic expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha, a major transcription factor involved in gluconeogenesis. Lower serum triglyceride concentrations were also observed in the db/db-betaine group compared to the db/db group. Betaine supplementation induced hepatic peroxisome proliferator-activated receptor alpha and carnitine palmitoyltransferase 1a mRNA levels, and reduced acetyl-CoA carboxylase activity. Mice fed a betaine-supplemented diet had increased total glutathione concentrations and catalase activity, and reduced lipid peroxidation levels in the liver. Furthermore, betaine also reduced ER stress in liver and brain. c-Jun N-terminal kinase activity and tau hyperphosphorylation levels were lower in db/db mice fed a betaine-supplemented diet, compared to db/db mice. Our findings suggest that betaine improves hyperlipidemia and tau hyperphosphorylation in db/db mice with insulin resistance by alleviating ER and oxidative stress.
Jung, G.Y., et al., Betaine Alleviates Hypertriglycemia and Tau Hyperphosphorylation in Mice. Toxicol Res, 2013. 29(1): p. 7-14.
Jung, G.Y., et al., Betaine Alleviates Hypertriglycemia and Tau Hyperphosphorylation in Mice. Toxicol Res, 2013. 29(1): p. 7-14.
Monday, November 4, 2013
Choline and betaine intakes are associated with reduced risk of nasopharyngeal carcinoma
Background: Intakes of choline and betaine have been inversely related to the risk of various neoplasms, but scant data exist on nasopharyngeal carcinoma (NPC). We examined the association between consumption of choline and betaine and risk of NPC.
Methods: We conducted a case-control study with 600 incident NPC patients and 600 controls 1 : 1 matched by age, sex and household type in Guangdong, China. Dietary intake was assessed by a food frequency questionnaire through face-to-face interview.
Results: Intakes of total choline, betaine and choline+betaine were inversely related to NPC after adjustment for various lifestyle and dietary factors. Adjusted odds ratios (95% CI) for quartile 4 (vs quartile 1) were 0.42 (0.29, 0.61) for total choline, 0.50 (0.35, 0.72) for betaine and 0.44 (0.30, 0.64) for betaine+total choline. Regarding various sources of choline, lower NPC risk was associated with greater intakes of choline from phosphatidylcholine, free choline, glycerophosphocholine and phosphocholine, but not sphingomyelin.
Conclusion: These findings are consistent with a beneficial effect of choline and betaine intakes on carcinogenesis.
Zeng, F.F., et al., Choline and betaine intakes are associated with reduced risk of nasopharyngeal carcinoma in adults: a case-control study. Br J Cancer, 2013
Methods: We conducted a case-control study with 600 incident NPC patients and 600 controls 1 : 1 matched by age, sex and household type in Guangdong, China. Dietary intake was assessed by a food frequency questionnaire through face-to-face interview.
Results: Intakes of total choline, betaine and choline+betaine were inversely related to NPC after adjustment for various lifestyle and dietary factors. Adjusted odds ratios (95% CI) for quartile 4 (vs quartile 1) were 0.42 (0.29, 0.61) for total choline, 0.50 (0.35, 0.72) for betaine and 0.44 (0.30, 0.64) for betaine+total choline. Regarding various sources of choline, lower NPC risk was associated with greater intakes of choline from phosphatidylcholine, free choline, glycerophosphocholine and phosphocholine, but not sphingomyelin.
Conclusion: These findings are consistent with a beneficial effect of choline and betaine intakes on carcinogenesis.
Zeng, F.F., et al., Choline and betaine intakes are associated with reduced risk of nasopharyngeal carcinoma in adults: a case-control study. Br J Cancer, 2013
Monday, October 21, 2013
Cereal foods are the major source of betaine in the Western diet
Betaine and its precursor choline are important components of one-carbon metabolism, remethylating homocysteine into methionine and providing methyl groups for DNA methylation. Cereals are the main source of betaine in the diet, though there is little literature available on the content of betaine in cereal products, nor on betaine intake from cereals. Betaine and free-choline concentrations were measured by liquid-chromatography with tandem mass spectrometry in a wide range of commercially available cereal foods and cereal fractions. Whole grain wheat and related fractions were the best overall common source of betaine, while the pseudocereal quinoa had the highest amount of betaine measured (3900mug/g). Based on estimates of dietary intake data cereal foods provide approximately 60-67% of betaine in Western diets, and 20-40% of betaine in South-East Asian diets. Average intake of betaine was 131mg/d, well below those used in intervention studies using betaine to lower blood homocysteine.
Ross, A.B., A. Zangger, and S.P. Guiraud, Cereal foods are the major source of betaine in the Western diet - Analysis of betaine and free choline in cereal foods and updated assessments of betaine intake. Food Chem, 2014. 145C: p. 859-865
Ross, A.B., A. Zangger, and S.P. Guiraud, Cereal foods are the major source of betaine in the Western diet - Analysis of betaine and free choline in cereal foods and updated assessments of betaine intake. Food Chem, 2014. 145C: p. 859-865
Sunday, October 13, 2013
Supplementation with B12 vitamin, betaine or other methyl donors in addition to folic acid may further reduce NTD risk
Neural tube defects (NTDs) are common complex congenital malformations resulting from failure of the neural tube closure during embryogenesis. It is established that folic acid supplementation decreases the prevalence of NTDs, which has led to national public health policies regarding folic acid. To date, animal studies have not provided sufficient information to establish the metabolic and/or genomic mechanism(s) underlying human folic acid responsiveness in NTDs. However, several lines of evidence suggest that not only folates but also choline, B12 and methylation metabolisms are involved in NTDs. Decreased B12 vitamin and increased total choline or homocysteine in maternal blood have been shown to be associated with increased NTDs risk. Several polymorphisms of genes involved in these pathways have also been implicated in risk of development of NTDs. This raises the question whether supplementation with B12 vitamin, betaine or other methylation donors in addition to folic acid periconceptional supplementation will further reduce NTD risk. The objective of this article is to review the role of methylation metabolism in the onset of neural tube defects.
Imbard, A., J.F. Benoist, and H.J. Blom, Neural tube defects, folic Acid and methylation. Int J Environ Res Public Health, 2013. 10(9): p. 4352-89
Imbard, A., J.F. Benoist, and H.J. Blom, Neural tube defects, folic Acid and methylation. Int J Environ Res Public Health, 2013. 10(9): p. 4352-89
High fat-sucrose diet-induced liver fat accumulation was prevented by methyl donor supplementation
Non-alcoholic fatty liver disease is a primary hepatic manifestation of obesity and an important adverse metabolic syndrome trait. Animal models of diet-induced obesity promote liver fat accumulation putatively associated with alterations in epigenetic profile. Dietary methyl donor-supplementation may protect against this disturbance during early developmental stages affecting the molecular basis of gene regulation. The aim of this study was to investigate the transcriptomic and epigenetic mechanisms implicated in liver fat accumulation as a result of an obesogenic diet and the putative preventive role of dietary methyl donors. Forty-eight male Wistar rats were assigned into four dietary groups for 8weeks; control, control methyl-donor-supplemented with a dietary cocktail containing betaine, choline, vitamin B12 and folic acid, high-fat-sucrose and high-fat-sucrose methyl-donor-supplemented. Liver fat accumulation induced by a HFS diet was prevented by methyl donor supplementation in HFS-fed animals. A liver mRNA microarray, subsequently validated by real time-qPCR, showed modifications in some biologically relevant genes involved in obesity development and lipid metabolism (Lepr, Srebf2, Agpat3 and Esr1). Liver global DNA methylation was decreased by methyl donor supplementation in control-fed animals. Methylation levels of specific CpG sites from Srebf2, Agpat3 and Esr1 promoter regions showed changes due to the obesogenic diet and the supplementation with methyl donors. Interestingly, Srebf2 CpG23_24 methylation levels (-167bp and -156bp with respect to the transcriptional start site) correlated with HDLc plasma levels, whereas Esr1 CpG14 (-2623bp) methylation levels were associated with body and liver weights and fat content. Furthermore HFS diet-induced liver fat accumulation was prevented by methyl donor supplementation. In conclusion, both obesogenic diet and methyl donor supplementation modified the mRNA hepatic profile as well as the methylation of specific gene promoters and total DNA.
Cordero, P., et al., Transcriptomic and epigenetic changes in early liver steatosis associated to obesity: Effect of dietary methyl donor supplementation. Mol Genet Metab, 2013
Cordero, P., et al., Transcriptomic and epigenetic changes in early liver steatosis associated to obesity: Effect of dietary methyl donor supplementation. Mol Genet Metab, 2013
Tuesday, September 17, 2013
The metabolic burden of methyl donor deficiency with focus on the betaine homocysteine methyltransferase pathway
Methyl groups are important for numerous cellular functions such as DNA methylation, phosphatidylcholine synthesis, and protein synthesis. The methyl group can directly be delivered by dietary methyl donors, including methionine, folate, betaine, and choline. The liver and the muscles appear to be the major organs for methyl group metabolism. Choline can be synthesized from phosphatidylcholine via the cytidine-diphosphate (CDP) pathway. Low dietary choline loweres methionine formation and causes a marked increase in S-adenosylmethionine utilization in the liver. The link between choline, betaine, and energy metabolism in humans indicates novel functions for these nutrients. This function appears to goes beyond the role of the nutrients in gene methylation and epigenetic control. Studies that simulated methyl-deficient diets reported disturbances in energy metabolism and protein synthesis in the liver, fatty liver, or muscle disorders. Changes in plasma concentrations of total homocysteine (tHcy) reflect one aspect of the metabolic consequences of methyl group deficiency or nutrient supplementations. Folic acid supplementation spares betaine as a methyl donor. Betaine is a significant determinant of plasma tHcy, particularly in case of folate deficiency, methionine load, or alcohol consumption. Betaine supplementation has a lowering effect on post-methionine load tHcy. Hypomethylation and tHcy elevation can be attenuated when choline or betaine is available.
Obeid, R., The metabolic burden of methyl donor deficiency with focus on the betaine homocysteine methyltransferase pathway. Nutrients, 2013. 5(9): p. 3481-95
Obeid, R., The metabolic burden of methyl donor deficiency with focus on the betaine homocysteine methyltransferase pathway. Nutrients, 2013. 5(9): p. 3481-95
Alleviation of alcoholic liver injury by betaine involves an enhancement of antioxidant defense via regulation of sulfur amino acid metabolism
Previous studies suggested that the hepatoprotective activity of betaine is associated with its effects on sulfur amino acid metabolism. We examined the mechanism by which betaine prevents the progression of alcoholic liver injury and its therapeutic potential. Rats received a liquid ethanol diet for 6 wk. Ethanol consumption elevated serum triglyceride and TNFalpha levels, alanine aminotransferase and aspartate aminotransferase activities, and lipid accumulation in liver. The oxyradical scavenging capacity of liver was reduced, and expression of CD14, TNFalpha, COX-2, and iNOS mRNAs was induced markedly. These ethanol-induced changes were all inhibited effectively by betaine supplementation. Hepatic S-adenosylmethionine, cysteine, and glutathione levels, reduced in the ethanol-fed rats, were increased by betaine supplementation. Methionine adenosyltransferase and cystathionine gamma-lyase were induced, but cysteine dioxygenase was down-regulated, which appeared to account for the increment in cysteine availability for glutathione synthesis in the rats supplemented with betaine. Betaine supplementation for the final 2 wk of ethanol intake resulted in a similar degree of hepatoprotection, revealing its potential therapeutic value in alcoholic liver. It is concluded that the protective effects of betaine against alcoholic liver injury may be attributed to the fortification of antioxidant defense via improvement of impaired sulfur amino acid metabolism.
Jung, Y.S., et al., Alleviation of alcoholic liver injury by betaine involves an enhancement of antioxidant defense via regulation of sulfur amino acid metabolism. Food Chem Toxicol, 2013
Jung, Y.S., et al., Alleviation of alcoholic liver injury by betaine involves an enhancement of antioxidant defense via regulation of sulfur amino acid metabolism. Food Chem Toxicol, 2013
Sunday, September 15, 2013
Betaine supplementation decreases plasma homocysteine in healthy adult participants: a meta-analysis
OBJECTIVE: Betaine supplementation has been shown to be an effective agent for decreasing plasma homocysteine in healthy adults. Studies in healthy volunteers show that 6 g/d of betaine lowers plasma homocysteine concentrations by 5% to 20%. The purpose of this study was to perform a meta-analysis of randomized placebo-controlled trials that used daily betaine supplementation to identify the range in betaine's effects on lowering homocysteine. METHODS: Five randomized controlled trials published between 2002 and 2010 were identified using MEDLINE and a manual search. All 5 studies used health adult participants who were supplemented with at least 4 g/d of betaine for between 6 and 24 weeks. A meta-analysis was carried out using a random-effects model, and the overall effect size was calculated for changes in plasma homocysteine. RESULTS: The pooled estimate of effect for betaine supplementation on plasma homocysteine was a reduction of 1.23 mumol/L, which was statistically significant (95% confidence interval, - 1.61 to - 0.85; P = .01). CONCLUSION: Supplementation with at least 4g/d of betaine for a minimum of 6 weeks can lower plasma homocysteine.
McRae, M.P., Betaine supplementation decreases plasma homocysteine in healthy adult participants: a meta-analysis. J Chiropr Med, 2013. 12(1): p. 20-5
McRae, M.P., Betaine supplementation decreases plasma homocysteine in healthy adult participants: a meta-analysis. J Chiropr Med, 2013. 12(1): p. 20-5
Friday, September 13, 2013
Betaine raises brain serotonin levels and produces antidepressant-like effects in rats
The purpose of the present study was to examine the effect of Lycii Radicis Cortex (LRC) and betaine (BT) on immobility and neurochemical change in the forced swimming test (FST) in the rat. LRC, BT or fluoxentine was administered intraperitoneally to Sprague-Dawley rats three times (1, 5 and 23.5 h) before the FST. To investigate antidepressant-like effect, serotonin (5-HT) and norepinephrine (NE) were examined in the hippocampus and hypothalamus of rats. LRC (100 mg/kg) and BT (30, 100 mg/kg) significantly decreased the immobility time in the FST. LRC (100 mg/kg) significantly increased both 5-HT and NE levels in the hypothalamus of rats exposed to FST. BT (100 mg/kg) significantly increased 5-HT levels in the hypothalamus and hippocampus of rats. Taken together, these results demonstrated that improvement in the behavioral changes after LRC and BT administration may be mediated by elevation of 5-HT level in the hypothalamus and hippocampus, indicating a possible antidepressant-like activity. The present results suggest that the efficacy of LRC and BT in an animal model of depression may provide anti-depressant effects in human, which remains to be determined.
Kim, S.J., et al., Antidepressant-like effects of lycii radicis cortex and betaine in the forced swimming test in rats. Biomol Ther (Seoul), 2013. 21(1): p. 79-83
Kim, S.J., et al., Antidepressant-like effects of lycii radicis cortex and betaine in the forced swimming test in rats. Biomol Ther (Seoul), 2013. 21(1): p. 79-83
Wednesday, September 4, 2013
Betaine supplementation improved body composition, arm size, bench press work capacity, attenuated the rise in urinary HCTL, and tended to improve power but not strength
BACKGROUND: This study investigated the effects of long term betaine supplementation on body composition, performance, and homocysteine thiolactone (HCTL) in experienced strength trained men. METHODS: Twenty-three subjects were matched for training experience (4.8 +/- 2.3 years) and body fat percentage (BF%: 16.9 +/- 8.0%), randomly assigned to either a placebo (PL; n = 12) or betaine group (BET; n = 11; 2.5 g/day), and completed a 6 week periodized training program consisting of 3 two-week micro-cycles. Bench press and back squat training volumes were recorded and changes in training volume were assessed at each micro-cycle. Fasting urine was collected at baseline (BL), weeks 2, 4 and 6, and assayed for HCTL. Subjects were tested prior to and following 6 weeks of treatment. Arm and thigh cross sectional area (CSA) was estimated via girth and skin fold measurements. Body density was estimated via skin fold calipers and used to estimate BF%, fat mass (FM), and lean body mass (LBM). Performance was assessed via vertical jump (VJ), bench press 1 RM (BP), and back squat 1 RM (BS).
RESULTS: Arm CSA increased significantly (p < .05) in BET but not PL. No differences existed between group and time for changes in thigh CSA. Back squat training volume increased significantly (p < .05) for both groups throughout training. Bench press training volume was significantly (p < .05) improved for BET compared to PL at microcycles one and three. Body composition (BF%, FM, LBM) improved significantly (p < .05) in BET but not PL. No differences were found in performance variables (BP, BS, VJ) between groups, except there was a trend (p = .07) for increased VJ power in BET versus PL. A significant interaction (p < .05) existed for HCTL, with increases from BL to week 2 in PL, but not BET. Additionally, HCTL remained elevated at week 4 in PL, but not BET.
CONCLUSION: Six-weeks of betaine supplementation improved body composition, arm size, bench press work capacity, attenuated the rise in urinary HCTL, and tended to improve power (p = .07) but not strength.
Cholewa, J.M., et al., Effects of betaine on body composition, performance, and homocysteine thiolactone. J Int Soc Sports Nutr, 2013. 10(1): p. 39
RESULTS: Arm CSA increased significantly (p < .05) in BET but not PL. No differences existed between group and time for changes in thigh CSA. Back squat training volume increased significantly (p < .05) for both groups throughout training. Bench press training volume was significantly (p < .05) improved for BET compared to PL at microcycles one and three. Body composition (BF%, FM, LBM) improved significantly (p < .05) in BET but not PL. No differences were found in performance variables (BP, BS, VJ) between groups, except there was a trend (p = .07) for increased VJ power in BET versus PL. A significant interaction (p < .05) existed for HCTL, with increases from BL to week 2 in PL, but not BET. Additionally, HCTL remained elevated at week 4 in PL, but not BET.
CONCLUSION: Six-weeks of betaine supplementation improved body composition, arm size, bench press work capacity, attenuated the rise in urinary HCTL, and tended to improve power (p = .07) but not strength.
Cholewa, J.M., et al., Effects of betaine on body composition, performance, and homocysteine thiolactone. J Int Soc Sports Nutr, 2013. 10(1): p. 39
Sunday, September 1, 2013
Maternal methyl metabolism, offspring DNA methylation, and epigenetic consequences on later disease susceptibility
Evidence is growing for the long-term effects of environmental factors during early-life on later disease susceptibility. It is believed that epigenetic mechanisms (changes in gene function not mediated by DNA sequence alteration), particularly DNA methylation, play a role in these processes. This paper reviews the current state of knowledge of the involvement of C1 metabolism and methyl donors and cofactors in maternal diet-induced DNA methylation changes in utero as an epigenetic mechanism. Methyl groups for DNA methylation are mostly derived from the diet and supplied through C1 metabolism by way of choline, betaine, methionine or folate, with involvement of riboflavin and vitamins B6 and B12 as cofactors. Mouse models have shown that epigenetic features, for example DNA methylation, can be altered by periconceptional nutritional interventions such as folate supplementation, thereby changing offspring phenotype. Evidence of early nutrient-induced epigenetic change in human subjects is scant, but it is known that during pregnancy C1 metabolism has to cope with high fetal demands for folate and choline needed for neural tube closure and normal development. Retrospective studies investigating the effect of famine or season during pregnancy indicate that variation in early environmental exposure in utero leads to differences in DNA methylation of offspring. This may affect gene expression in the offspring. Further research is needed to examine the real impact of maternal nutrient availability on DNA methylation in the developing fetus.
Dominguez-Salas, P., et al., Maternal nutritional status, C(1) metabolism and offspring DNA methylation: a review of current evidence in human subjects. Proc Nutr Soc, 2012. 71(1): p. 154-65
Dominguez-Salas, P., et al., Maternal nutritional status, C(1) metabolism and offspring DNA methylation: a review of current evidence in human subjects. Proc Nutr Soc, 2012. 71(1): p. 154-65
Topical application of betaine limited progression of environmentally induced dry eye
Purpose: To evaluate the efficacy of osmoprotectants on prevention and treatment of dry eye in a murine model. Methods: Dry eye was induced in mice using an intelligently controlled environmental system (ICES). Osmoprotectants betaine, L-carnitine, erythritol, or vehicle (PBS) were topically administered to eyes 4 times daily following two schedules: Schedule 1 (modeling prevention): dosing started at the beginning of housing in ICES and lasted for 21 or 35 days; Schedule 2 (modeling treatment): dosing started after ICES-housed mice developed dry eye (Day 21), continuing till Day 35. Treatment efficacy was evaluated for corneal fluorescein staining; corneal epithelial apoptosis by TUNEL and caspase-3 assays; goblet cell numbers by PAS staining; and expression of inflammatory mediators, TNF-alpha, IL-17, IL-6 or IL-1beta using RT-PCR on Days 0, 14, 21 and/or 35.
Results: Compared to vehicle, prophylactic administration of betaine, L-carnitine or erythritol significantly decreased corneal staining and expression of TNF-alpha and IL-17 on Day 21 (Schedule 1). Treatment of mouse dry eye with osmoprotectants significantly reduced corneal staining on Day 35 compared to Day 21 (Schedule 2). Relative to vehicle, L-carnitine treatment of mouse dry eye for 14 days (Day 21 to 35) resulted in a significant reduction in corneal staining, number of TUNEL-positive cells, and expression of TNF-alpha, IL-17, IL-6, or IL-1beta, as well significantly increased number of goblet cells.
Conclusion: Topical application of betaine, L-carnitine or erythritol systematically limited progression of environmentally induced dry eye. L-carnitine can also reduce the severity of such dry eye conditions.
Chen, W., et al., Efficacy of Osmoprotectants on Prevention and Treatment of Murine Dry Eye. Invest Ophthalmol Vis Sci, 2013
Results: Compared to vehicle, prophylactic administration of betaine, L-carnitine or erythritol significantly decreased corneal staining and expression of TNF-alpha and IL-17 on Day 21 (Schedule 1). Treatment of mouse dry eye with osmoprotectants significantly reduced corneal staining on Day 35 compared to Day 21 (Schedule 2). Relative to vehicle, L-carnitine treatment of mouse dry eye for 14 days (Day 21 to 35) resulted in a significant reduction in corneal staining, number of TUNEL-positive cells, and expression of TNF-alpha, IL-17, IL-6, or IL-1beta, as well significantly increased number of goblet cells.
Conclusion: Topical application of betaine, L-carnitine or erythritol systematically limited progression of environmentally induced dry eye. L-carnitine can also reduce the severity of such dry eye conditions.
Chen, W., et al., Efficacy of Osmoprotectants on Prevention and Treatment of Murine Dry Eye. Invest Ophthalmol Vis Sci, 2013
Lower level of serum betaine is associated with an increased risk of microangiopathy in diabetics
BACKGROUND: Diabetes represents one of the greatest medical and socioeconomic emergencies worldwide and pathogenesis involved is complicated. The effect of methyl donors and genetic polymorphisms in metabolic enzymes on the risk of microangiopathy in patients with diabetes is not well understood. This study aims to investigate the association of homocysteine, choline, and betaine levels and phosphatidylethanolamine N-methyltransferase (PEMT) G774C (rs12325817) genotypes with the risk of diabetes and its related microangiopathic complications.
METHODS: Between January 2009 and June 2010, 184 diabetic patients and 188 non-diabetic control subjects were enrolled in the hospital-based case-control study. Serum concentrations of betaine and choline were determined by high performance liquid chromatography-mass spectrometry (HPLC-MS). Serum concentration of homocysteine was assayed using HPLC. PEMT gene mutations were detected by polymerase chain reaction and restriction fragment length polymorphism.
RESULTS: After adjustment for the potential confounders, serum total homocysteine had a significant dose-dependent positive association, and serum choline had an inverse association with the risks of diabetes and its microangiopathic complications (both p < 0.001). Although serum betaine was not associated with the risk of diabetes, it had a significant inverse association with diabetic microangiopathy. Compared with GG genotype, the CC genotype of PEMT G774C was associated with a decreased risk of diabetes (OR 0.559, 95%CI 0.338, 0.926) and its microangiopathy (OR 0.452, 95%CI 0.218, 0.937).
CONCLUSION: The GG genotype of the PEMT G774C polymorphism, higher level of serum homocysteine, and lower level of serum betaine are associated with an increased risk of microangiopathy in patients with diabetes.
Chen, L., et al., Higher homocysteine and lower betaine increases the risk of microangiopathy in patients with diabetes mellitus carrying the GG genotype of PEMT G774C. Diabetes Metab Res Rev, 2013
METHODS: Between January 2009 and June 2010, 184 diabetic patients and 188 non-diabetic control subjects were enrolled in the hospital-based case-control study. Serum concentrations of betaine and choline were determined by high performance liquid chromatography-mass spectrometry (HPLC-MS). Serum concentration of homocysteine was assayed using HPLC. PEMT gene mutations were detected by polymerase chain reaction and restriction fragment length polymorphism.
RESULTS: After adjustment for the potential confounders, serum total homocysteine had a significant dose-dependent positive association, and serum choline had an inverse association with the risks of diabetes and its microangiopathic complications (both p < 0.001). Although serum betaine was not associated with the risk of diabetes, it had a significant inverse association with diabetic microangiopathy. Compared with GG genotype, the CC genotype of PEMT G774C was associated with a decreased risk of diabetes (OR 0.559, 95%CI 0.338, 0.926) and its microangiopathy (OR 0.452, 95%CI 0.218, 0.937).
CONCLUSION: The GG genotype of the PEMT G774C polymorphism, higher level of serum homocysteine, and lower level of serum betaine are associated with an increased risk of microangiopathy in patients with diabetes.
Chen, L., et al., Higher homocysteine and lower betaine increases the risk of microangiopathy in patients with diabetes mellitus carrying the GG genotype of PEMT G774C. Diabetes Metab Res Rev, 2013
You are what your mother ate? A commentary on Dominguez-Salas, P., et al., Am J Clin Nutr, 2013. 97(6): p. 1217-27
First brought to scientific attention several decades ago by the report of a dose-response, inverse relation between birth weight and adult risk of cardiometabolic diseases (1), evidence that early nutrition, stress, and other similar environmental exposures can have lingering impacts on later health outcomes has now been widely documented in human populations and in experimental animal model work (2). A central problem in this field is identifying the mechanisms that underlie the biological “memory” of early nutrition and other exposures. Early proposals focused on growth alterations or changes in the function of organs such as the kidneys or liver, which it was speculated would be short-changed under conditions of fetal nutritional stress. Although this likely helps to explain some of the human findings (3), more recent work has consolidated around identifying epigenetic changes induced by prenatal or maternal experiences, which provide particularly attractive candidates (4, 5). Epigenetic modifications typically involve chemical changes to the chromatin that influence which genes can be expressed, silencing or amplifying gene production in a targeted fashion. DNA methylation refers to the addition of a methyl group to cytosine nucleotides in the vicinity of a gene promoter, which impedes gene transcription. It is among the best studied of epigenetic processes and one that is chemically stable enough to potentially account for late-life effects of early nutrition.
A long-running study in Keneba, Gambia, provides an unusual opportunity to probe the effect of maternal diet as an inducer of epigenetic change in offspring in a quasi-experimental fashion. Longitudinal studies of nutrition, growth, and health have been conducted in this region for more than 60 y (6). An important feature of the local ecology is a strong seasonal change in nutritional stress that is secondary to the annual harvest cycle and compounded by seasonal changes in workload in the fields and infectious disease. During the rainy season, workloads are high and crop stores are generally running thin, and, as a result, adults typically lose weight during this season (7). Not surprisingly, rainy-season birth weights also tend to be smaller.
A recent study of children in Keneba by Waterland et al (8) showed that methylation at putative “metastable epialleles”—regions where gene promoter methylation is stochastically rather than genetically based and environmentally sensitive during early development—was contingent on season of birth (8). The goal of the study was to evaluate whether a climatically driven seasonal change in nutritional stress experienced around the time of conception would predict differences in methylation in adulthood. This would help to establish that methylation at those loci was not simply genetically based while also demonstrating the stability of the induced changes. The authors did find differences in epigenetic marking by season of birth but were somewhat surprised to find that methylation was increased during the nutritionally stressful rainy season, when food supplies dwindle. This finding ran counter to their expectations because it suggested that methylation was in fact enhanced at times when one might expect the diet to be most deficient in methyl donors and related cofactors that are required of methylation. The authors speculated that seasonal changes in dietary availability of essential nutrients, rather than gross changes in calories or macronutrients, might account for the apparent increased methyl transfer capacity during times of dietary dearth.
A new study in this issue of the Journal by the same group (9) takes an important step toward evaluating this idea by measuring seasonal changes in dietary intake of methyl donors and related cofactors and at the same time by evaluating their circulating concentrations. The authors weighed household food intake and analyzed the concentrations of choline, betaine, folate, methionine, riboflavin, and vitamins B-6 and B-12 in 98 locally common foods to estimate intake of these nutrients. To evaluate whether dietary intake predicted circulating concentrations, the authors also collected monthly blood samples and measured blood levels of the same nutrients, along with several metabolites involved in methyl transfer. Their findings were a bit mixed, but they did find seasonal changes in intake of these essential nutrients and also changes in circulating biomarkers. In some instances, but not all, these changes were correlated. The authors also found evidence for seasonal shifts in the body’s reliance on different methyl donor pathways. Of importance, the changes in circulating biomarkers were generally in agreement with the finding of an increased capacity for methylation during the difficult rainy season.
Where does this new study leave us? To the extent that seasonal changes in dietary intake have remained relatively constant across a generation or so, the authors’ findings bolster the case that dietary methyl donors, rather than energy or macronutrient intake, help to explain season-of-birth–related variation in epigenetic state in the adult population. This is important and suggests that this population provides a natural experiment for probing the dietary determinants of long-term epigenetic programming in humans with greater specificity, and with an unusually strong basis for causal inference owing to the fact that dietary changes are driven primarily by climate and season rather than by more inherently confounded factors like socioeconomic status. Because methyl donor intake is elevated when energy and macronutrient intakes are most compromised, there is also greater assurance that the relations truly reflect an effect specific to these essential nutrients rather than being secondary to greater energy or macronutrient intake generally.
Although these factors are apparently important locally, it is not yet clear how important dietary intake of methyl donors and related cofactors are likely to be as influences on health in populations with diverse diets and ecologies. It seems unlikely, for instance, that the finding that helped launch this field—a dose-response relation between birth weight and cardiovascular disease risk across the entire birth-weight distribution, even in well-nourished, high-income populations—will be explained by gradients of dietary methyl donor intake. Indeed, earlier work in this population failed to find evidence that early-life nutritional stress or growth faltering predicted measures of diabetes and cardiometabolic disease as expected (10), raising questions about how this population might differ from others in which these relations have been found. Perhaps the fact that dietary methyl donor intake peaks during what is otherwise a season of nutritional stress will ultimately help to shed light on this negative finding.
Kuzawa, C.W., You are what your mother ate? Am J Clin Nutr, 2013. 97(6): p. 1157-8.
A long-running study in Keneba, Gambia, provides an unusual opportunity to probe the effect of maternal diet as an inducer of epigenetic change in offspring in a quasi-experimental fashion. Longitudinal studies of nutrition, growth, and health have been conducted in this region for more than 60 y (6). An important feature of the local ecology is a strong seasonal change in nutritional stress that is secondary to the annual harvest cycle and compounded by seasonal changes in workload in the fields and infectious disease. During the rainy season, workloads are high and crop stores are generally running thin, and, as a result, adults typically lose weight during this season (7). Not surprisingly, rainy-season birth weights also tend to be smaller.
A recent study of children in Keneba by Waterland et al (8) showed that methylation at putative “metastable epialleles”—regions where gene promoter methylation is stochastically rather than genetically based and environmentally sensitive during early development—was contingent on season of birth (8). The goal of the study was to evaluate whether a climatically driven seasonal change in nutritional stress experienced around the time of conception would predict differences in methylation in adulthood. This would help to establish that methylation at those loci was not simply genetically based while also demonstrating the stability of the induced changes. The authors did find differences in epigenetic marking by season of birth but were somewhat surprised to find that methylation was increased during the nutritionally stressful rainy season, when food supplies dwindle. This finding ran counter to their expectations because it suggested that methylation was in fact enhanced at times when one might expect the diet to be most deficient in methyl donors and related cofactors that are required of methylation. The authors speculated that seasonal changes in dietary availability of essential nutrients, rather than gross changes in calories or macronutrients, might account for the apparent increased methyl transfer capacity during times of dietary dearth.
A new study in this issue of the Journal by the same group (9) takes an important step toward evaluating this idea by measuring seasonal changes in dietary intake of methyl donors and related cofactors and at the same time by evaluating their circulating concentrations. The authors weighed household food intake and analyzed the concentrations of choline, betaine, folate, methionine, riboflavin, and vitamins B-6 and B-12 in 98 locally common foods to estimate intake of these nutrients. To evaluate whether dietary intake predicted circulating concentrations, the authors also collected monthly blood samples and measured blood levels of the same nutrients, along with several metabolites involved in methyl transfer. Their findings were a bit mixed, but they did find seasonal changes in intake of these essential nutrients and also changes in circulating biomarkers. In some instances, but not all, these changes were correlated. The authors also found evidence for seasonal shifts in the body’s reliance on different methyl donor pathways. Of importance, the changes in circulating biomarkers were generally in agreement with the finding of an increased capacity for methylation during the difficult rainy season.
Where does this new study leave us? To the extent that seasonal changes in dietary intake have remained relatively constant across a generation or so, the authors’ findings bolster the case that dietary methyl donors, rather than energy or macronutrient intake, help to explain season-of-birth–related variation in epigenetic state in the adult population. This is important and suggests that this population provides a natural experiment for probing the dietary determinants of long-term epigenetic programming in humans with greater specificity, and with an unusually strong basis for causal inference owing to the fact that dietary changes are driven primarily by climate and season rather than by more inherently confounded factors like socioeconomic status. Because methyl donor intake is elevated when energy and macronutrient intakes are most compromised, there is also greater assurance that the relations truly reflect an effect specific to these essential nutrients rather than being secondary to greater energy or macronutrient intake generally.
Although these factors are apparently important locally, it is not yet clear how important dietary intake of methyl donors and related cofactors are likely to be as influences on health in populations with diverse diets and ecologies. It seems unlikely, for instance, that the finding that helped launch this field—a dose-response relation between birth weight and cardiovascular disease risk across the entire birth-weight distribution, even in well-nourished, high-income populations—will be explained by gradients of dietary methyl donor intake. Indeed, earlier work in this population failed to find evidence that early-life nutritional stress or growth faltering predicted measures of diabetes and cardiometabolic disease as expected (10), raising questions about how this population might differ from others in which these relations have been found. Perhaps the fact that dietary methyl donor intake peaks during what is otherwise a season of nutritional stress will ultimately help to shed light on this negative finding.
Kuzawa, C.W., You are what your mother ate? Am J Clin Nutr, 2013. 97(6): p. 1157-8.
Betaine protects against isoprenaline-induced myocardial infarction
We investigated the antioxidant preventive effect of betaine on isoprenaline-induced myocardial infarction in male albino rats. Isoprenaline induced myocardial infarction was manifested by a moderate elevation in the levels of diagnostic marker enzymes (alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and creatine phosphokinase) and homocysteine in plasma of experimental rats. Significant rise in the level of lipid peroxidation with a concomitant decline in the levels of myocardial non-enzymic (reduced glutathione) and enzymic antioxidants (glutathione peroxidase, glutathione-S-transferase, catalase and superoxide dismutase) was also observed. Oral pretreatment with betaine significantly prevented isoprenaline-induced alterations in the levels of diagnostic marker enzymes and homocysteine in plasma of experimental groups of rats. It counteracted the isoprenaline-induced lipid peroxidation and maintained the myocardial antioxidant defense system at near normal. Histopathological observations also confirmed the protective effect of betaine against isoprenaline-induced myocardial infarction. The results of the present investigation indicate that the protective effect of betaine is probably related to its ability to strengthen the myocardial membrane by its membrane stabilizing action or to a counteraction of free radicals by its antioxidant property.
Ganesan, B., et al., Antioxidant defense of betaine against isoprenaline-induced myocardial infarction in rats. Mol Biol Rep, 2010. 37(3): p. 1319-27
Ganesan, B., et al., Antioxidant defense of betaine against isoprenaline-induced myocardial infarction in rats. Mol Biol Rep, 2010. 37(3): p. 1319-27
Friday, August 30, 2013
Betaine supplementation inhibited liver fat accumulation in a nonalcoholic steatohepatitis (NASH) mouse model
The effects of betaine supplementation on non-alcoholic steatohepatitis (NASH) model mice were examined by measuring the accumulation of fat in the livers of NASH model mice compared to a control. Betaine from sugar beets was provided to the model mice as a dietary supplement. After 3 wk of dietary supplementation. there were no significant differences in body weight or liver weight between the groups. However, the liver to body weight ratio in the high-fat diet with betaine (HM) group was significantly higher than that in the high-fat diet (HF) group. There were no differences in scrum triglyceride (TG) concentrations. AST and ALT activities, or hepatic glutathione concentrations between the groups. Hepatic TG level in the Ha group was significantly lower than that in the HF group. Hepatic cells obtained from the HF group showed increased occurrence of explosive puff and necrosis as compared with those in the HFB group. Betaine supplementation had an inhibitory effect on fat accumulation in the liver: the Oil red-positive area in the Ha group (0.82 +/- 0.85%) was significantly smaller than that in the HF group (9.06 +/- 2.24%). These results indicate the potential of betaine to serve as an agent for amelioration of hepatic steatosis in NASH model mice.
Kawakami, S., et al., Effects of dietary supplementation with betaine on a nonalcoholic steatohepatitis ( NASH ) mouse model. Journal of Nutritional Science and Vitaminology, 2012. 58(5): p. 371-5
Kawakami, S., et al., Effects of dietary supplementation with betaine on a nonalcoholic steatohepatitis ( NASH ) mouse model. Journal of Nutritional Science and Vitaminology, 2012. 58(5): p. 371-5
Effects of Betaine on Energy Utilization in Growing Pigs - A Review
One of the well known biological functions of betaine is that of a methyl donor. Therefore, betaine may partly replace choline and methionine in the diet. Another widely documented role of betaine is to restore and maintain the osmotic balance. As an organic osmotic compound, betaine regulates the water balance, thus exerting a stabilizing influence on tissue metabolism, particularly within the digestive tract. As a donor of methyl groups necessary for various reactions in the body, betaine is indirectly involved in lipid metabolism. Due to its metabolic functions, betaine is also believed to play a significant role in energy metabolism in pigs. Of particular note are the results of experiments in which a positive effect of betaine supplementation was observed as the energy content of the diet was decreased.
Lipinski, K., et al., Effects of Betaine on Energy Utilization in Growing Pigs - A Review. Annals of Animal Science, 2012. 12(3): p. 291-300
Lipinski, K., et al., Effects of Betaine on Energy Utilization in Growing Pigs - A Review. Annals of Animal Science, 2012. 12(3): p. 291-300
Urinary betaine may be a good marker of diabetes and future risk of diabetes in cardiovascular patients
Abnormal urinary excretion of betaine has been demonstrated in patients with diabetes or metabolic syndrome. We aimed to identify the main predictors of excretion in cardiovascular patients and to make initial assessment of its feasibility as a risk marker of future diabetes development. We used data from 2396 patients participating in the Western Norway B-vitamin Intervention Trial, who delivered urine and blood samples at baseline, and in the majority at two visits during follow-up of median 39 months. Betaine in urine and plasma were measured by liquid-chromatography-tandem mass spectrometry. The strongest determinants of urinary betaine excretion by multiple regression were diabetes mellitus, age and estimated glomerular filtration rate. Patients with diabetes mellitus (n = 264) had a median excretion more than three times higher than those without. We found a distinct non-linear association between urinary betaine excretion and glycated hemoglobin, with a break-point at 6.5%, and glycated hemoglobin was the strongest determinant of betaine excretion in patients with diabetes mellitus. The discriminatory power for diabetes mellitus corresponded to an area under the curve by receiver-operating characteristics of 0.82, and betaine excretion had a coefficient of reliability of 0.73. We also found a significant, independent log-linear relation between baseline betaine excretion and the risk of developing new diabetes during follow-up. The good discriminatory power for diabetes, high test-retest stability and independent association with future risk of new diabetes should motivate further investigation on the role of betaine excretion in risk assessment and long-term follow-up of diabetes mellitus.
Schartum-Hansen, H., et al., Assessment of urinary betaine as a marker of diabetes mellitus in cardiovascular patients. PLoS One, 2013. 8(8): p. e69454
Schartum-Hansen, H., et al., Assessment of urinary betaine as a marker of diabetes mellitus in cardiovascular patients. PLoS One, 2013. 8(8): p. e69454
Creatine but not betaine supplementation increases muscle phosphorylcreatine content and strength performance
We aimed to investigate the role of betaine supplementation on muscle phosphorylcreatine (PCr) content and strength performance in untrained subjects. Additionally, we compared the ergogenic and physiological responses to betaine versus creatine supplementation. Finally, we also tested the possible additive effects of creatine and betaine supplementation. This was a double-blind, randomized, placebo-controlled study. Subjects were assigned to receive betaine (BET; 2 g/day), creatine (CR; 20 g/day), betaine plus creatine (BET + CR; 2 + 20 g/day, respectively) or placebo (PL). At baseline and after 10 days of supplementation, we assessed muscle strength and power, muscle PCr content, and body composition. The CR and BET + CR groups presented greater increase in muscle PCr content than PL (p = 0.004 and p = 0.006, respectively). PCr content was comparable between BET versus PL (p = 0.78) and CR versus BET + CR (p = 0.99). CR and BET + CR presented greater muscle power output than PL in the squat exercise following supplementation (p = 0.003 and p = 0.041, respectively). Similarly, bench press average power was significantly greater for the CR-supplemented groups. CR and BET + CR groups also showed significant pre- to post-test increase in 1-RM squat and bench press (CR: p = 0.027 and p < 0.0001; BET + CR: p = 0.03 and p < 0.0001 for upper- and lower-body assessments, respectively) No significant differences for 1-RM strength and power were observed between BET versus PL and CR versus BET + CR. Body composition did not differ between the groups. In conclusion, we reported that betaine supplementation does not augment muscle PCr content. Furthermore, we showed that betaine supplementation combined or not with creatine supplementation does not affect strength and power performance in untrained subjects.
Del Favero, S., et al., Creatine but not betaine supplementation increases muscle phosphorylcreatine content and strength performance. Amino Acids, 2012. 42(6): p. 2299-2305
Del Favero, S., et al., Creatine but not betaine supplementation increases muscle phosphorylcreatine content and strength performance. Amino Acids, 2012. 42(6): p. 2299-2305
Betaine supplementation causes increase in carnitine metabolites in the muscle and liver of mice fed a high-fat diet as studied by nontargeted LC-MS metabolomics approach
SCOPE: Betaine (BET) reduces diet-induced liver lipid accumulation, and may relieve obesity-related metabolic disturbances. The aim of our study was to analyze metabolite alterations after supplementation of BET, polydextrose (PDX, a soluble dietary fiber), or their combination (BET PDX) via drinking water to C57BL/6J mice fed a high-fat (HF) diet.
METHODS AND RESULTS: BET supplementation increased BET levels in plasma, muscle, and liver (p < 0.05), and the nontargeted LC-MS metabolite profiling revealed an increase in several metabolites in the carnitine biosynthesis pathway after BET supplementation both in liver and muscle. These included carnitine and acetylcarnitine (1.4-fold, p < 0.05), propionylcarnitine and gamma-butyrobetaine (1.5-fold, p < 0.05), and several other short-chain acylcarnitines (p < 0.05) in muscle. These changes were slightly higher in the BET PDX group. Furthermore, BET reduced the HF diet induced accumulation of triglycerides in liver (p < 0.05). The supplementations did not attenuate the HF diet induced increase in body weight gain or the increase in adipose tissue mass. Instead, the combination of BET and PDX tended to increase adiposity. CONCLUSION: Our results suggest that increased availability of BET in different tissues, especially in muscle, after BET supplementation has an impact on carnitine metabolism, and this could further explain the link between BET and lipid metabolism.
Pekkinen, J., et al., Betaine supplementation causes increase in carnitine metabolites in the muscle and liver of mice fed a high-fat diet as studied by nontargeted LC-MS metabolomics approach. Mol Nutr Food Res, 2013
METHODS AND RESULTS: BET supplementation increased BET levels in plasma, muscle, and liver (p < 0.05), and the nontargeted LC-MS metabolite profiling revealed an increase in several metabolites in the carnitine biosynthesis pathway after BET supplementation both in liver and muscle. These included carnitine and acetylcarnitine (1.4-fold, p < 0.05), propionylcarnitine and gamma-butyrobetaine (1.5-fold, p < 0.05), and several other short-chain acylcarnitines (p < 0.05) in muscle. These changes were slightly higher in the BET PDX group. Furthermore, BET reduced the HF diet induced accumulation of triglycerides in liver (p < 0.05). The supplementations did not attenuate the HF diet induced increase in body weight gain or the increase in adipose tissue mass. Instead, the combination of BET and PDX tended to increase adiposity. CONCLUSION: Our results suggest that increased availability of BET in different tissues, especially in muscle, after BET supplementation has an impact on carnitine metabolism, and this could further explain the link between BET and lipid metabolism.
Pekkinen, J., et al., Betaine supplementation causes increase in carnitine metabolites in the muscle and liver of mice fed a high-fat diet as studied by nontargeted LC-MS metabolomics approach. Mol Nutr Food Res, 2013
Betaine supplement enhances skeletal muscle differentiation in murine myoblasts via IGF-1 signaling activation
BACKGROUND: Betaine (BET) is a component of many foods, including spinach and wheat. It is an essential osmolyte and a source of methyl groups. Recent studies have hypothesized that BET might play a role in athletic performance. However, BET effects on skeletal muscle differentiation and hypertrophy are still poorly understood.
METHODS: We examined BET action on neo myotubes maturation and on differentiation process, using C2C12 murine myoblastic cells. We used RT2-PCR array, Western blot and immunofluorescence analysis to study the BET effects on morphological features of C2C12 and on signaling pathways involved in muscle differentiation and hypertrophy.
RESULTS: We performed a dose--response study, establishing that 10 mM BET was the dose able to stimulate morphological changes and hypertrophic process in neo myotubes. RT2-PCR array methodology was used to identify the expression profile of genes encoding proteins involved in IGF-1 pathway. A dose of 10 mM BET was found to promote IGF-1 receptor (IGF-1 R) expression. Western blot and immunofluorescence analysis, performed in neo myotubes, pointed out that 10 mM BET improved IGF-1 signaling, synthesis of Myosin Heavy Chain (MyHC) and neo myotubes length.In addition, we investigated BET role on myoblasts proliferation and differentiation. During proliferation, BET did not modify C2C12 proliferative rate, but promoted myogenic induction, enhancing MyoD protein content and cellular elongation. During differentiation, BET caused an increase of muscle-specific markers and IGF-1 R protein levels. CONCLUSIONS: Our findings provide the first evidence that BET could promote muscle fibers differentiation and increase myotubes size by IGF-1 pathway activation, suggesting that BET might represent a possible new drug/integrator strategy, not only in sport performance but also in clinical conditions characterized by muscle function impairment.
Senesi, P., et al., Betaine supplement enhances skeletal muscle differentiation in murine myoblasts via IGF-1 signaling activation. J Transl Med, 2013. 11(1): p. 174
METHODS: We examined BET action on neo myotubes maturation and on differentiation process, using C2C12 murine myoblastic cells. We used RT2-PCR array, Western blot and immunofluorescence analysis to study the BET effects on morphological features of C2C12 and on signaling pathways involved in muscle differentiation and hypertrophy.
RESULTS: We performed a dose--response study, establishing that 10 mM BET was the dose able to stimulate morphological changes and hypertrophic process in neo myotubes. RT2-PCR array methodology was used to identify the expression profile of genes encoding proteins involved in IGF-1 pathway. A dose of 10 mM BET was found to promote IGF-1 receptor (IGF-1 R) expression. Western blot and immunofluorescence analysis, performed in neo myotubes, pointed out that 10 mM BET improved IGF-1 signaling, synthesis of Myosin Heavy Chain (MyHC) and neo myotubes length.In addition, we investigated BET role on myoblasts proliferation and differentiation. During proliferation, BET did not modify C2C12 proliferative rate, but promoted myogenic induction, enhancing MyoD protein content and cellular elongation. During differentiation, BET caused an increase of muscle-specific markers and IGF-1 R protein levels. CONCLUSIONS: Our findings provide the first evidence that BET could promote muscle fibers differentiation and increase myotubes size by IGF-1 pathway activation, suggesting that BET might represent a possible new drug/integrator strategy, not only in sport performance but also in clinical conditions characterized by muscle function impairment.
Senesi, P., et al., Betaine supplement enhances skeletal muscle differentiation in murine myoblasts via IGF-1 signaling activation. J Transl Med, 2013. 11(1): p. 174
Monday, July 22, 2013
Betaine protects against high-fat-diet-induced NAFLD and improves liver function
BACKGROUND AND OBJECTIVES: Previous studies have shown that betaine prevents alcohol-induced liver injury and improves liver function. The purpose of this study was to investigate the hepatoprotective effects of betaine on nonalcoholic fatty liver disease (NAFLD) and to observe changes of HMGB1/TLR4 signaling.
METHODS: Thirty rats were randomly divided into control, model, and betaine groups. The rats in the model and betaine groups were fed a high-fat diet for 12 weeks to induce an animal model of NAFLD. The rats in the betaine group were then intragastrically administered betaine solution at a dose of 400 mg/kg per day for four weeks. Liver histology was examined. Serum levels of ALT, AST, TC, TG, HDL-C, LDL-C, FFA, HMGB1, NF-kappaB, TLR4, and tHcy were determined and intrahepatic TC, TG, and Hcy levels were assayed. mRNA expression and protein levels of HMGB1, NF-kappaB, and TLR4 in liver tissue were also determined.
RESULTS: Compared with the control group, rats in the model group developed severe liver injury, accompanied by significant increases in serum levels of ALT, AST, TC, TG, LDL-C, FFA, HMGB1, NF-kappaB, and TLR4, intrahepatic TC, TG, and Hcy content, histological scores for steatosis, inflammation, and necrosis, and mRNA expression and protein levels of HMGB1, NF-kappaB, and TLR4, and a significant decrease in serum HDL-C (P < 0.05). Compared with the model group, all these indicators were significantly improved by administration of betaine (P < 0.05).
CONCLUSIONS: Betaine effectively protects against high-fat-diet-induced NAFLD and improves liver function; the mechanism is probably related to inhibition of HMGB1/TLR4 signaling pathways.
Zhang, W., et al., Betaine Protects Against High-Fat-Diet-Induced Liver Injury by Inhibition of High-Mobility Group Box 1 and Toll-Like Receptor 4 Expression in Rats. Dig Dis Sci, 2013
METHODS: Thirty rats were randomly divided into control, model, and betaine groups. The rats in the model and betaine groups were fed a high-fat diet for 12 weeks to induce an animal model of NAFLD. The rats in the betaine group were then intragastrically administered betaine solution at a dose of 400 mg/kg per day for four weeks. Liver histology was examined. Serum levels of ALT, AST, TC, TG, HDL-C, LDL-C, FFA, HMGB1, NF-kappaB, TLR4, and tHcy were determined and intrahepatic TC, TG, and Hcy levels were assayed. mRNA expression and protein levels of HMGB1, NF-kappaB, and TLR4 in liver tissue were also determined.
RESULTS: Compared with the control group, rats in the model group developed severe liver injury, accompanied by significant increases in serum levels of ALT, AST, TC, TG, LDL-C, FFA, HMGB1, NF-kappaB, and TLR4, intrahepatic TC, TG, and Hcy content, histological scores for steatosis, inflammation, and necrosis, and mRNA expression and protein levels of HMGB1, NF-kappaB, and TLR4, and a significant decrease in serum HDL-C (P < 0.05). Compared with the model group, all these indicators were significantly improved by administration of betaine (P < 0.05).
CONCLUSIONS: Betaine effectively protects against high-fat-diet-induced NAFLD and improves liver function; the mechanism is probably related to inhibition of HMGB1/TLR4 signaling pathways.
Zhang, W., et al., Betaine Protects Against High-Fat-Diet-Induced Liver Injury by Inhibition of High-Mobility Group Box 1 and Toll-Like Receptor 4 Expression in Rats. Dig Dis Sci, 2013
Tuesday, May 28, 2013
Plasma choline metabolites associate with metabolic stress among young overweight men in a genotype-specific manner
We aimed to test the hypotheses that (i) plasma choline metabolites differ between normal (body mass index (BMI)<25 and="and" kg="kg" m="m" overweight="overweight">/=25 kg m(-2)) men, and (ii) an elevated BMI alters associations between plasma choline metabolites and indicators of metabolic stress.
DESIGN: This was a cross-sectional study. A one-time fasting blood sample was obtained for measurements of the choline metabolites and metabolic stress indicators (that is, serum alanine aminotransferase (ALT), glucose, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides and homocysteine), and for genotype determination.
SUBJECTS: The analysis was conducted with 237 Mexican American men with a median age of 22 years.
RESULTS: Compared with men with a normal BMI (n=98), those with an elevated BMI (n=139) had 6% lower (P=0.049) plasma betaine and an 11% lower (P=0.002) plasma betaine to choline ratio. Among men with an elevated BMI, plasma betaine and the plasma betaine to choline ratio positively associated (P</=0.044) with a favorable serum cholesterol profile, and inversely associated (P=0.001) with serum ALT, a marker of liver dysfunction. The phosphatidylethanolamine N-methyltransferase (PEMT) 5465Gshort right arrowA (rs7946) genotype interacted (P</=0.007) with the plasma betaine to choline ratio to modulate indicators of metabolic stress with stronger inverse associations observed among overweight men with the PEMT 5465GG genotype.
CONCLUSIONS: Plasma choline metabolites predict metabolic stress among overweight men often in a genotype-specific manner. The diminished betaine among overweight men coupled with the inverse association between betaine and metabolic stress suggest that betaine supplementation may be effective in mitigating some of the metabolic insults arising from lipid overload.
Yan, J., et al., Plasma choline metabolites associate with metabolic stress among young overweight men in a genotype-specific manner. Nutr Diabetes, 2012. 2: p. e49
DESIGN: This was a cross-sectional study. A one-time fasting blood sample was obtained for measurements of the choline metabolites and metabolic stress indicators (that is, serum alanine aminotransferase (ALT), glucose, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides and homocysteine), and for genotype determination.
SUBJECTS: The analysis was conducted with 237 Mexican American men with a median age of 22 years.
RESULTS: Compared with men with a normal BMI (n=98), those with an elevated BMI (n=139) had 6% lower (P=0.049) plasma betaine and an 11% lower (P=0.002) plasma betaine to choline ratio. Among men with an elevated BMI, plasma betaine and the plasma betaine to choline ratio positively associated (P</=0.044) with a favorable serum cholesterol profile, and inversely associated (P=0.001) with serum ALT, a marker of liver dysfunction. The phosphatidylethanolamine N-methyltransferase (PEMT) 5465Gshort right arrowA (rs7946) genotype interacted (P</=0.007) with the plasma betaine to choline ratio to modulate indicators of metabolic stress with stronger inverse associations observed among overweight men with the PEMT 5465GG genotype.
CONCLUSIONS: Plasma choline metabolites predict metabolic stress among overweight men often in a genotype-specific manner. The diminished betaine among overweight men coupled with the inverse association between betaine and metabolic stress suggest that betaine supplementation may be effective in mitigating some of the metabolic insults arising from lipid overload.
Yan, J., et al., Plasma choline metabolites associate with metabolic stress among young overweight men in a genotype-specific manner. Nutr Diabetes, 2012. 2: p. e49
Betaine protects against oxidative damage induced by restraint stress
Stress can be defined as physical and psychological modifications that disrupt the homeostasis and the balance of organisms. Stress is known as one of the most important reasons of several diseases. In the present study, the anti-stress effect of betaine was evaluated with reference to its antioxidant property. Wistar albino rats were divided into four groups such as control, betaine, restraint stress (6 h/day for 30 days), and betaine + restraint stress. The oxidative damage was assessed by measuring the protein and corticosterone in plasma, lipid peroxidation, non-enzymic (reduced glutathione), and enzymic antioxidants (glutathione peroxidase, glutathione-S-transferase, catalase, and superoxide dismutase) in the lymphoid organs of thymus and spleen. Followed by the induction of restraint stress, the non-enzymic and enzymic antioxidants were significantly decreased with concomitant increase observed in the levels of corticosterone and lipid peroxidation. Oral pretreatment with betaine (250 mg/kg body weight daily for a period of 30 days) significantly (P < 0.001) prevented the restraint stress-induced alterations in the levels of protein and corticosterone in plasma of experimental groups of rats. It counteracted the restraint stress-induced lipid peroxidation and maintained the antioxidant defense system in the lymphoid tissues at near normal. The findings suggest that betaine possesses significant anti-stress activity, which may be due to its antioxidant property.
Ganesan, B., R. Anandan, and P.T. Lakshmanan, Studies on the protective effects of betaine against oxidative damage during experimentally induced restraint stress in Wistar albino rats. Cell Stress Chaperones, 2011. 16(6): p. 641-52
Ganesan, B., R. Anandan, and P.T. Lakshmanan, Studies on the protective effects of betaine against oxidative damage during experimentally induced restraint stress in Wistar albino rats. Cell Stress Chaperones, 2011. 16(6): p. 641-52
Monday, May 27, 2013
Betaine may serve as a neuroprotective agent in the treatment of neurodegenerative diseases
Rotenone is an inhibitor of mitochondrial complex I-induced neurotoxicity in PC12 cells and has been widely studied to elucidate the pathogenesis of Parkinson's disease. We investigated the neuroprotective effects of betaine on rotenone-induced neurotoxicity in PC12 cells. Betaine inhibited rotenone-induced apoptosis in a dose-dependent manner, with cell viability increasing from 50 % with rotenone treatment alone to 71 % with rotenone plus 100-muM betaine treatment. Flow cytometric analysis demonstrated cell death in the rotenone-treated cells to be over 50 %; the number of live cells increased with betaine pretreatment. Betaine pretreatment of PC12 cells attenuated rotenone-mediated mitochondrial dysfunction, including nuclear fragmentation, ATP depletion, mitochondrial membrane depolarization, caspase-3/7 activation, and reactive oxygen species production. Western blots demonstrated activation of caspase-3 and caspase-9, and their increased expression levels in rotenone-treated cells; betaine decreased caspase-3 and caspase-9 expression levels and suppressed their activation. Together, these results suggest that betaine may serve as a neuroprotective agent in the treatment of neurodegenerative diseases.
Im, A.R., et al., Betaine Protects Against Rotenone-Induced Neurotoxicity in PC12 Cells. Cell Mol Neurobiol, 2013
Im, A.R., et al., Betaine Protects Against Rotenone-Induced Neurotoxicity in PC12 Cells. Cell Mol Neurobiol, 2013
Betaine promotes immunobiochemical plasticity and protects against low-dose pesticide-induced oxidative stress
An experiment was conducted to evaluate the role of different lipotropes in modulating immunity and biochemical plasticity under conditions of sublethal low-dose pesticide-induced stress in fish. Labeo rohita fish fingerlings were divided in two sets with one set of fish continuously exposed to low-dose endosulfan (1/10th of 96-h LC50) for 21 days, the other was unexposed, and both sets of fish were fed with practical diets supplemented with either 2 % lecithin, 0.5 % betaine, or 0.1 % choline and compared against unsupplemented diet. Low-dose endosulfan exposure had adverse effects (P < 0.05/P < 0.01) on hematological profile (erythrocyte count, hemoglobin, and hematocrit), serum protein (total protein, albumin, and globulin) and lipid profile (cholesterol and triglyceride), anti-oxidative status (ascorbic acid content of muscle, liver, brain, and kidney and activity of anti-oxidative enzymes: catalase and superoxide dismutase), neurotransmission (acetylcholinesterase activity in muscle and brain), immunological attributes (WBC count, albumin to globulin ratio, phagocytic activity, and serum cortisol), and metabolic plasticity as revealed from enzyme activities (muscle lactate dehydrogenase, liver and kidney glucose-6-phosphatase dehydrogenase-G6PDH activity). Dietary lipotropes prevented these effects completely or partially and the effects were lipotrope dependent. Kinetics (maximum velocity value V max, catalytic efficiency and Michaelis constant K m) of G6PDH enzyme from crude extracts of liver and kidney indicated inhibition due to endosulfan but lipotropes could protect enzyme and showed a stabilizing effect. The supplements also helped maintain integrity of histoarchitecture of the hepatocytes in endosulfan-exposed fish to a great extent. Feeding lipotropes to fish reared in endosulfan-free water also improved hematological and serum protein and lipid profiles and were immunostimulatory. In conclusion, dietary lipotropes, especially betaine and lecithin at the levels used, improve erythropoiesis, serum protein and lipid profile, anti-oxidant status, immunocompetence, neurotransmission, and protect the livers of L. rohita fingerlings even when continuously exposed to low-dose endosulfan.
Muthappa, N.A., et al., Lipotropes promote immunobiochemical plasticity and protect fish against low-dose pesticide-induced oxidative stress. Cell Stress Chaperones, 2013
Muthappa, N.A., et al., Lipotropes promote immunobiochemical plasticity and protect fish against low-dose pesticide-induced oxidative stress. Cell Stress Chaperones, 2013
Saturday, May 18, 2013
Maternal BHMT polymorphism 742G>A is associated with decreased risk of having a Down syndrome child
Down syndrome (DS) is the most common form of mental retardation of genetic etiology. Several polymorphisms in genes involved with the folic acid cycle have been associated to the risk of bearing a DS child; however, the results are controversial. Betaine-homocysteine methyltransferase (BHMT) is a key enzyme of folate pathway, and catalyzes the remethylation of homocysteine into methionine. Recent studies suggest that the polymorphism BHMT 742G>A may be associated with a decreased risk of having a DS child. We herein investigate the association of this polymorphism with the occurrence of DS in a Brazilian population. We have genotyped 94 mothers of DS infants (DSM) and 134 control mothers (CM) for this polymorphism through PCR-RFLP, and found significant differences for both BHMT 742G>A genotype (P = 0.04) and allele (P = 0.03) frequencies between DSM and CM. The observed genotypic frequencies were GG = 0.45; GA = 0.45 and AA = 0.10 in CM, and GG = 0.54; GA = 0.38 and AA = 0.02 in DSM. Allelic frequencies were G = 0.68 and A = 0.32 in CM and G = 0.78 and A = 0.22 in DSM. The presence of the mutant BHMT 742 A allele decreases 40 % the risk of bearing a DS child (OR = 0.61; 95 % CI: 0.40-0.93; P = 0.03), and the risk is diminished up to >80 % in association with the homozygous genotype (OR = 0.17; 95 % CI: 0.04-0.80; P = 0.01). Our results indicate that women harboring the single nucleotide polymorphism BHMT 742G>A have a decreased risk of a DS pregnancy, and further studies are necessary to confirm this protective effect.
Amorim, M.R., et al., Betaine-homocysteine methyltransferase 742G>A polymorphism and risk of down syndrome offspring in a Brazilian population. Mol Biol Rep, 2013
Amorim, M.R., et al., Betaine-homocysteine methyltransferase 742G>A polymorphism and risk of down syndrome offspring in a Brazilian population. Mol Biol Rep, 2013
Wednesday, May 8, 2013
Plant-based foods as a source of lipotropes for human nutrition: a survey of in vivo studies
Increased consumption of plant products is associated with lower chronic disease prevalence. This is attributed to the great diversity of healthy phytochemicals present in these foods. The most investigated physiological effects have been their antioxidant, anti-carcinogenic, hypolipidemic, and hypoglycemic properties. Although less studied in humans, some compounds were very early on shown to be lipotropic in animals, i.e., the capacity to hasten the removal of fat from liver and/or reduce hepatic lipid synthesis or deposits by mainly increasing phospholipid synthesis via the transmethylation pathway for triglyceride-rich lipoprotein exportation from the liver and enhanced fatty acid beta-oxidation and/or down- and up-regulation of genes involved in lipogenic and fatty acid oxidation enzyme synthesis, respectively. The main plant lipotropes are choline, betaine, myo-inositol, methionine, and carnitine. Magnesium, niacin, pantothenate, and folates also indirectly support the overall lipotropic effect. The exhaustive review of rat studies investigating phytochemical effect on hepatic lipid metabolism suggests that some fatty acids, acetic acid, melatonin, phytic acid, some fiber compounds, oligofructose, resistant starch, some phenolic acids, flavonoids, lignans, stilbenes, curcumin, saponins, coumarin, some plant extracts, and some solid foods may be lipotropic. However, this remains to be confirmed in humans, for whom intervention studies are practically non-existent.
Fardet, A. and J.M. Chardigny, Plant-based foods as a source of lipotropes for human nutrition: a survey of in vivo studies. Crit Rev Food Sci Nutr, 2013. 53(6): p. 535-90
Fardet, A. and J.M. Chardigny, Plant-based foods as a source of lipotropes for human nutrition: a survey of in vivo studies. Crit Rev Food Sci Nutr, 2013. 53(6): p. 535-90
Betaine may be used as a methyl-donor during fetal life
OBJECTIVE: Methylation metabolism is essential for fetus development. However, normative data for amniotic fluid (AF) concentrations of methylation metabolites at different gestational ages are lacking. We aimed to determine in AF reference values of 14 intermediates involved in methylation.
METHODS: 268 AFs sampled between 14 and 39 weeks of gestation (WG) were retrospectively selected in our AF bank. Next, we measured methionine-cycle intermediates (S-adenosyl-methionine (AdoMet), S-adenosyl-homocysteine (AdoHcy), total homocysteine, methionine, methyl malonic acid) and methyldonors and methylacceptors (betaine, dimethylglycine, sarcosine, free and total choline, free and total ethanolamine, creatine, guanidinoacetate) by liquid chromatography coupled with tandem mass spectrometry.
RESULTS: Reference ranges according to gestational age were determined for each parameter. Strong correlations between metabolites directly connected in their metabolic pathway and between total homocysteine and betaine were observed.
CONCLUSION: Methionine, an essential amino-acid required for protein synthesis is the only parameter that dramatically decreases with gestational age. The AdoMet/AdoHcy ratio exponentially increases from 25 WG, which could reflect increasing methylation capacities. The negative correlation between betaine and total homocysteine together with a constant betaine to dimethylglycine ratio during gestation suggest that betaine may be used as a methyl-donor during fetal life.
Imbard, A., et al., Methylation metabolites in amniotic fluid depend on gestational age. Prenat Diagn, 2013
METHODS: 268 AFs sampled between 14 and 39 weeks of gestation (WG) were retrospectively selected in our AF bank. Next, we measured methionine-cycle intermediates (S-adenosyl-methionine (AdoMet), S-adenosyl-homocysteine (AdoHcy), total homocysteine, methionine, methyl malonic acid) and methyldonors and methylacceptors (betaine, dimethylglycine, sarcosine, free and total choline, free and total ethanolamine, creatine, guanidinoacetate) by liquid chromatography coupled with tandem mass spectrometry.
RESULTS: Reference ranges according to gestational age were determined for each parameter. Strong correlations between metabolites directly connected in their metabolic pathway and between total homocysteine and betaine were observed.
CONCLUSION: Methionine, an essential amino-acid required for protein synthesis is the only parameter that dramatically decreases with gestational age. The AdoMet/AdoHcy ratio exponentially increases from 25 WG, which could reflect increasing methylation capacities. The negative correlation between betaine and total homocysteine together with a constant betaine to dimethylglycine ratio during gestation suggest that betaine may be used as a methyl-donor during fetal life.
Imbard, A., et al., Methylation metabolites in amniotic fluid depend on gestational age. Prenat Diagn, 2013
Dietary Choline and Betaine Intakes Vary in an Adult Multiethnic Population
Choline and betaine are important nutrients for human health, but reference food composition databases for these nutrients became available only recently. We tested the feasibility of using these databases to estimate dietary choline and betaine intakes among ethnically diverse adults who participated in the Multiethnic Cohort (MEC) Study. Of the food items (n = 965) used to quantify intakes for the MEC FFQ, 189 items were exactly matched with items in the USDA Database for the Choline Content of Common Foods for total choline, choline-containing compounds, and betaine, and 547 items were matched to the USDA National Nutrient Database for Standard Reference for total choline (n = 547) and 148 for betaine. When a match was not found, choline and betaine values were imputed based on the same food with a different form (124 food items for choline, 300 for choline compounds, 236 for betaine), a similar food (n = 98, 284, and 227, respectively) or the closest item in the same food category (n = 6, 191, and 157, respectively), or the values were assumed to be zero (n = 1, 1, and 8, respectively). The resulting mean intake estimates for choline and betaine among 188,147 MEC participants (aged 45-75) varied by sex (372 and 154 mg/d in men, 304 and 128 mg/d in women, respectively; P-heterogeneity < 0.0001) and by race/ethnicity among Caucasians, African Americans, Japanese Americans, Latinos, and Native Hawaiians (P-heterogeneity < 0.0001), largely due to the variation in energy intake. Our findings demonstrate the feasibility of assessing choline and betaine intake and characterize the variation in intake that exists in a multiethnic population.
Yonemori, K.M., et al., Dietary Choline and Betaine Intakes Vary in an Adult Multiethnic Population. J Nutr, 2013
Yonemori, K.M., et al., Dietary Choline and Betaine Intakes Vary in an Adult Multiethnic Population. J Nutr, 2013
Estimation of usual intake and food sources of choline and betaine in New Zealand reproductive age women
Recently, choline has been associated with neurodevelopment, cognitive function and neural tube defect incidence. However, data on usual intakes are limited, and estimates of dietary intakes of choline and its metabolite betaine, are not available for New Zealanders. The objective of the present study was to determine usual intake and food sources of choline and betaine in a group of New Zealand reproductive age women. Dietary intake data were collected from a sample of 125 women, aged 18-40 years, by means of a 3-day weighed food record, and usual choline and betaine intake distributions were determined. The mean (SD) daily intakes of choline and betaine were 316 (66) mg and 178 (66) mg, respectively. The total choline intake relative to energy intake and body weight was 0.18 mg/kcal and 5.1 mg/kg, respectively. Only 16% of participants met or exceeded the Adeuate Intake (AI) for adult women of 425 mg of choline. The top five major food contributors of choline were eggs, red meat, milk, bread and chicken; and of betaine were bread, breakfast cereal, pasta, grains and root vegetables (carrots, parsnips, beetroot, swedes). Our findings contribute towards the recent emergence of published reports on the range of dietary choline and betaine intakes consumed by free-living populations. In our sample of New Zealand women, few participants were meeting or exceeding the AI level. Given recent epidemiological evidence suggesting health benefits of increased choline and betaine intakes, recommendations should be made to encourage the consumption of choline and betaine-rich foods.
Mygind, V.L., et al., Estimation of usual intake and food sources of choline and betaine in New Zealand reproductive age women. Asia Pac J Clin Nutr, 2013. 22(2): p. 319-24
Mygind, V.L., et al., Estimation of usual intake and food sources of choline and betaine in New Zealand reproductive age women. Asia Pac J Clin Nutr, 2013. 22(2): p. 319-24
Tuesday, April 30, 2013
Betaine supplementation reduced subjective measures of fatigue to an exercise protocol
Effect of 15 days of betaine ingestion on concentric and eccentric force outputs
during isokinetic exercise. J Strength Cond Res 25(8): 2235-2241,
2011—The purpose of this study was to examine the efficacy of 15 days of betaine
supplementation on peak concentric (CON) and eccentric (ECC) force during
isokinetic exercise in active college-aged men. Eleven men volunteered for this
study (21.7 ± 5.1 years; height: 178.5 ± 6.4 cm; body mass: 79.8 ± 10.3 kg).
Subjects were randomly assigned to either a supplement (BET) or placebo (PL)
group. Supplementation occurred for 15 days. Subjects reported to the Human
Performance Laboratory on 5 occasions during this period, separated by 72 hours,
for a testing and exercise session on an isokinetic chest press device. After
each exercise protocol, subjects rated their fatigue and muscle soreness on a
15-cm visual analog scale. Subjects then consumed no daily BET for 4 weeks but
maintained familiarity with the exercise device once per week. After the washout
period, subjects resumed the BET protocol using the opposite drink and repeated
the same 15-day protocol. No differences were noted in maximum CON force output
between pre (335.9 ± 78.3 and 321.6 ± 63.6 N) and post (330.3 ± 74.8 and 330.2 ±
71.6 N) workouts in both BET and PL, respectively. In addition, no differences
were noted in maximum ECC force output between pre (352.0 ± 90.6 and 324.4 ±
85.2 N) and post (353.2 ± 98.2 and 366.9 ± 128.5 N) workouts in BET and PL,
respectively. No differences in subjective measures of soreness and fatigue were
seen, but a significant reduction in Δ fatigue was observed in BET compared to
PL. In conclusion, 15 days of betaine supplementation did not increase peak CON
or ECC force outputs during an isokinetic chest press but did appear to reduce
subjective measures of fatigue to the exercise protocol.
Hoffman, J.R., et al., Effect of 15 Days of Betaine Ingestion on Concentric and Eccentric Force Outputs During Isokinetic Exercise. The Journal of Strength & Conditioning Research, 2011. 25(8): p. 2235-2241.
Betaine ingestion improves cycling sprint power in recreationally active males and females
ABSTRACT: Purpose To examine the effect of betaine supplementation on cycling sprint performance. METHODS: Sixteen recreationally active subjects (7 females and 9 males) completed three sprint tests, each consisting of four 12 sec efforts against a resistance equal to 5.5% of body weight; efforts were separated by 2.5 min of cycling at zero resistance. Test one established baseline; test two and three were preceded by seven days of daily consumption of 591 ml of a carbohydrate-electrolyte beverage as a placebo or a carbohydrate-electrolyte beverage containing 0.42% betaine (approximately 2.5 grams of betaine a day); half the beverage was consumed in the morning and the other half in the afternoon. We used a double blind random order cross-over design; there was a 3 wk washout between trials two and three. Average and maximum peak and mean power were analyzed with one-way repeated measures ANOVA and, where indicated, a Student Newman-Keuls.
RESULTS: Compared to baseline, betaine ingestion increased average peak power (6.4%; p < 0.001), maximum peak power (5.7%; p < 0.001), average mean power (5.4%; p = 0.004), and maximum mean power (4.4%; p = 0.004) for all subjects combined. Compared to placebo, betaine ingestion significantly increased average peak power (3.4%; p = 0.026), maximum peak power max (3.8%; p = 0.007), average mean power (3.3%; p = 0.034), and maximum mean power (3.5%; p = 0.011) for all subjects combined. There were no differences between the placebo and baseline trials.
CONCLUSIONS: One week of betaine ingestion improved cycling sprint power in recreationally active males and females.
Pryor, J.L., S.A. Craig, and T. Swensen, Effect of betaine supplementation on cycling sprint performance. J Int Soc Sports Nutr, 2012. 9(1): p. 12-18.
RESULTS: Compared to baseline, betaine ingestion increased average peak power (6.4%; p < 0.001), maximum peak power (5.7%; p < 0.001), average mean power (5.4%; p = 0.004), and maximum mean power (4.4%; p = 0.004) for all subjects combined. Compared to placebo, betaine ingestion significantly increased average peak power (3.4%; p = 0.026), maximum peak power max (3.8%; p = 0.007), average mean power (3.3%; p = 0.034), and maximum mean power (3.5%; p = 0.011) for all subjects combined. There were no differences between the placebo and baseline trials.
CONCLUSIONS: One week of betaine ingestion improved cycling sprint power in recreationally active males and females.
Betaine supplementation enhances anabolic endocrine and Akt signaling in response to acute bouts of exercise
Our aim was to examine the effect of betaine supplementation on selected circulating hormonal measures and Akt muscle signaling proteins after an acute exercise session. Twelve trained men (age 19.7 +/- 1.23 years) underwent 2 weeks of supplementation with either betaine (B) (1.25 g BID) or placebo (P). Following a 2-week washout period, subjects underwent supplementation with the other treatment (B or P). Before and after each 2-week period, subjects performed an acute exercise session (AES). Circulating GH, IGF-1, cortisol, and insulin were measured. Vastus lateralis samples were analyzed for signaling proteins (Akt, p70 S6k, AMPK). B (vs. P) supplementation approached a significant increase in GH (mean +/- SD (Area under the curve, AUC), B: 40.72 +/- 6.14, P: 38.28 +/- 5.54, p = 0.060) and significantly increased IGF-1 (mean +/- SD (AUC), B: 106.19 +/- 13.45, P: 95.10 +/- 14.23, p = 0.010), but significantly decreased cortisol (mean +/- SD (AUC), B: 1,079.18 +/- 110.02, P: 1,228.53 +/- 130.32, p = 0.007). There was no difference in insulin (AUC). B increased resting Total muscle Akt (p = 0.003). B potentiated phosphorylation (relative to P) of Akt (Ser(473)) and p70 S6 k (Thr(389)) (p = 0.016 and p = 0.005, respectively). Phosphorylation of AMPK (Thr(172)) decreased during both treatments (both p = 0.001). Betaine (vs. placebo) supplementation enhanced both the anabolic endocrine profile and the corresponding anabolic signaling environment, suggesting increased protein synthesis.
Apicella, J.M., et al., Betaine supplementation enhances anabolic endocrine and Akt signaling in response to acute bouts of exercise. Eur J Appl Physiol, 2013. 113(3): p. 793-802
Apicella, J.M., et al., Betaine supplementation enhances anabolic endocrine and Akt signaling in response to acute bouts of exercise. Eur J Appl Physiol, 2013. 113(3): p. 793-802
Sunday, April 28, 2013
Low folate status enhances pregnancy changes in plasma betaine and dimethylglycine concentrations and the association between betaine and homocysteine
BACKGROUND: Folate, choline, and betaine participate in
homocysteine metabolism. It is not known whether they interact during
pregnancy. OBJECTIVE: The objective was to investigate how folate status
affects choline, betaine, and dimethylglycine during pregnancy.
DESIGN: Fasting
plasma folate, cobalamin, free choline, betaine, dimethylglycine, and total
homocysteine (tHcy) were measured longitudinally at >12, 15, 24-27, and 34
gestational weeks (GW); at labor (nonfasting); and in the cord in participants
(n = 522) from the Reus-Tarragona Birth Cohort (NUTricio i Creixement
Intrauteri Retardat phase). Timing, dose, and duration of folic acid supplement
use were recorded. Folate status was classified as below (low) or above (high)
median plasma folate at baseline (27.6 nmol/L) and at 24-27 GW (11.4 nmol/L).
Associations between folate or betaine with tHcy were investigated by using
multiple linear regression analysis.
RESULTS: Plasma betaine decreased by 34.8%
(1.0%) throughout pregnancy, and dimethylglycine increased by 39.7% (2.7%)
between 24-27 GW and labor (all P < 0.001). Low folate status was associated
with a higher dimethylglycine/betaine ratio from 15 GW and with lower plasma
betaine and higher dimethylglycine from 24 to 27 GW, for the rest of pregnancy,
compared with high status. Regression analysis showed that by 24-27 GW, both
plasma folate and betaine were inversely associated with tHcy when folate
status was low and that the association between betaine and tHcy depended on
folate status at 24-27 and 34 GW (interaction terms: P < 0.001 and P <
0.01). Betaine was inversely associated with tHcy at labor regardless of folate
status.
CONCLUSION: Low folate status enhances the reduction in betaine and the
increase in dimethylglycine during pregnancy and strengthens the association
between betaine and tHcy. This trial was registered at clinicaltrials.gov as
NCT01778205.
Fernandez-Roig, S., et al., Low folate status enhances pregnancy changes in plasma betaine and dimethylglycine concentrations and the association between betaine and homocysteine. Am J Clin Nutr, 2013
Thursday, April 18, 2013
Lower seasonal maternal dietary betaine intake and resultant lower blood levels correlates with previously reported reduced DNA methylation in offspring
BACKGROUND: Animal models show that periconceptional supplementation with folic acid, vitamin B-12, choline, and betaine can induce differences in offspring phenotype mediated by epigenetic changes in DNA. In humans, altered DNA methylation patterns have been observed in offspring whose mothers were exposed to famine or who conceived in the Gambian rainy season.
OBJECTIVE:The objective was to understand the seasonality of DNA methylation patterns in rural Gambian women. We studied natural variations in dietary intake of nutrients involved in methyl-donor pathways and their effect on the respective metabolic biomarkers.
DESIGN:In 30 women of reproductive age (18-45 y), we monitored diets monthly for 1 y by using 48-h weighed records to measure intakes of choline, betaine, folate, methionine, riboflavin, and vitamins B-6 and B-12. Blood biomarkers of these nutrients, S-adenosylhomocysteine (SAH), S-adenosylmethionine (SAM), homocysteine, cysteine, and dimethylglycine were also assessed monthly.
RESULTS:Dietary intakes of riboflavin, folate, choline, and betaine varied significantly by season; the most dramatic variation was seen for betaine. All metabolic biomarkers showed significant seasonality, and vitamin B-6 and folate had the highest fluctuations. Correlations between dietary intakes and blood biomarkers were found for riboflavin, vitamin B-6, active vitamin B-12 (holotranscobalamin), and betaine. We observed a seasonal switch between the betaine and folate pathways and a probable limiting role of riboflavin in these processes and a higher SAM/SAH ratio during the rainy season.
CONCLUSIONS:Naturally occurring seasonal variations in food-consumption patterns have a profound effect on methyl-donor biomarker status. The direction of these changes was consistent with previously reported differences in methylation of metastable epialleles. This trial was registered at www.clinicaltrials.gov as NCT01811641.
Tuesday, March 26, 2013
Betaine alleviated hepatic triglyceride accumulation and improved antioxidant capacity by decreasing PPAR alpha promoter methylation and upregulating PPAR alpha and its target genes mRNA expression
BACKGROUND: Betaine is a methyl donor and has been considered a lipotropic effect substance. But its mechanism remains unclear. Hepatic steatosis is associated with abnormal expression of genes involved in hepatic lipid metabolism. DNA methylation contributes to the disregulation of gene expression. Here we hypothesized that betaine supplement and subsequent DNA methylation modifications alter the expression of genes that are involved in hepatic lipid metabolism and hence alleviate hepatic triglyceride accumulation. METHODS: Male wild-type (WT) C57BL/6 mice (n = 6) were fed with the AIN-93 G diet. ApoE-/- mice (n = 12), weight-matched with the WT mice, were divided into two groups (n = 6 per group), and fed with the AIN-93 G diet and AIN-93 G supplemented with 2% betaine/100 g diet. Seven weeks after the intervention, mice were sacrificed. Liver betaine, choline, homocysteine concentration were measured by HPLC. Liver oxidants activity and triglyceride level were assessed by ultraviolet spectrophotometry. Finally, hepatic PPAR alpha gene and its target gene expression levels and the methylation status of the PPAR alpha gene were determined.
RESULTS: ApoE-/- mice had higher hepatic triglyceride and lower GSH-Px activity when compared with the WT mice. Betaine intervention reversed triglyceride deposit, enhanced SOD and GSH-Px activity in the liver. Interestingly, mice fed on betaine-supplemented diet showed a dramatic increase of hepatic choline concentration and a decrease of betaine and homocysteine concentration relative to the WT mice and the ApoE-/- mice absent with betaine intervention. Expression of PPAR alpha and CPT1 were decreased and expression of FAS was markedly increased in ApoE-/- mice. In parallel, PPAR alpha promoter methylation level were slightly decreased in ApoE-/- mice though without significance. Betaine supplement upregulated expression of PPAR alpha and its target genes (CPT1, CYP2E1) and reversed hypermethylation of PPAR alpha promoter of ApoE-/- mice. Furthermore, PPAR alpha methylation was positively correlated with hepatic betaine concentration.
CONCLUSIONS: Our findings indicate that betaine supplement could alleviate hepatic triglyceride accumulation and improve antioxidant capacity by decreasing PPAR alpha promoter methylation and upregulating PPAR alpha and its target genes mRNA expression.
Wang, L., et al., Betaine supplement alleviates hepatic triglyceride accumulation of apolipoprotein E deficient mice via reducing methylation of peroxisomal proliferator-activated receptor alpha promoter. Lipids Health Dis, 2013. 12(1): p. 34
RESULTS: ApoE-/- mice had higher hepatic triglyceride and lower GSH-Px activity when compared with the WT mice. Betaine intervention reversed triglyceride deposit, enhanced SOD and GSH-Px activity in the liver. Interestingly, mice fed on betaine-supplemented diet showed a dramatic increase of hepatic choline concentration and a decrease of betaine and homocysteine concentration relative to the WT mice and the ApoE-/- mice absent with betaine intervention. Expression of PPAR alpha and CPT1 were decreased and expression of FAS was markedly increased in ApoE-/- mice. In parallel, PPAR alpha promoter methylation level were slightly decreased in ApoE-/- mice though without significance. Betaine supplement upregulated expression of PPAR alpha and its target genes (CPT1, CYP2E1) and reversed hypermethylation of PPAR alpha promoter of ApoE-/- mice. Furthermore, PPAR alpha methylation was positively correlated with hepatic betaine concentration.
CONCLUSIONS: Our findings indicate that betaine supplement could alleviate hepatic triglyceride accumulation and improve antioxidant capacity by decreasing PPAR alpha promoter methylation and upregulating PPAR alpha and its target genes mRNA expression.
Wang, L., et al., Betaine supplement alleviates hepatic triglyceride accumulation of apolipoprotein E deficient mice via reducing methylation of peroxisomal proliferator-activated receptor alpha promoter. Lipids Health Dis, 2013. 12(1): p. 34
Increased risk of low birth weight with increased umbilical choline and betaine in venous UC blood
Background: Low birth weight (LBW) is associated with increased morbidity and mortality for the newborn and risk of chronic disease in adulthood. Choline plays an essential role in the integrity of cell membranes, methylation reactions and memory development. We examined whether choline, betaine and dimethylglycine (DMG) concentrations were associated with LBW in Dutch women.
Methods: Blood was sampled from umbilical cords (UC) at delivery in singleton pregnancies (n=1126). Maternal blood was sampled at 30-34 weeks of gestational age (n=366). We calculated birth weights standardized for gestational age (SBW) and defined LBW as SBW </= 2500 grams.
Results: Maternal concentrations were lower compared to UC concentrations and not associated with birth weight. UC choline and betaine were inversely associated with birth weight (beta= -60 (-89, -31) and beta= -65 (-94, -36)), whereas UC DMG was positively associated with birth weight (beta= 35 (6.1, 63)). Odds ratios for LBW were 4.12 (1.15, 14.78) , 5.68 (1.24, 25.91), and 0.48 (0.09, 2.65) for the highest UC choline, betaine and DMG quartile respectively compared to the lowest quartiles.
Conclusions: We observed an increased risk of low birth weight with increased umbilical choline and betaine in venous UC blood. These results might reflect a change in choline consumption or metabolism or a disturbed placental function.
Hogeveen, M., et al., Umbilical choline and related methylamines betaine and dimethylglycine in relation to birth weight. Pediatr Res, 2013
Methods: Blood was sampled from umbilical cords (UC) at delivery in singleton pregnancies (n=1126). Maternal blood was sampled at 30-34 weeks of gestational age (n=366). We calculated birth weights standardized for gestational age (SBW) and defined LBW as SBW </= 2500 grams.
Results: Maternal concentrations were lower compared to UC concentrations and not associated with birth weight. UC choline and betaine were inversely associated with birth weight (beta= -60 (-89, -31) and beta= -65 (-94, -36)), whereas UC DMG was positively associated with birth weight (beta= 35 (6.1, 63)). Odds ratios for LBW were 4.12 (1.15, 14.78) , 5.68 (1.24, 25.91), and 0.48 (0.09, 2.65) for the highest UC choline, betaine and DMG quartile respectively compared to the lowest quartiles.
Conclusions: We observed an increased risk of low birth weight with increased umbilical choline and betaine in venous UC blood. These results might reflect a change in choline consumption or metabolism or a disturbed placental function.
Hogeveen, M., et al., Umbilical choline and related methylamines betaine and dimethylglycine in relation to birth weight. Pediatr Res, 2013
Monday, March 11, 2013
High fat diet induces upregulation of BHMT to accommodate dietary fat processing and preserve methionine
Obesity is an underlying risk factor in the development of cardiovascular disease, dyslipidemia and non-alcoholic fatty liver disease (NAFLD). Increased hepatic lipid accumulation is a hallmark in the progression of NAFLD and impairments in liver phosphatidylcholine (PC) metabolism may be central to the pathogenesis. Hepatic PC biosynthesis, which is linked to the one-carbon (C1) metabolism by phosphatidylethanolamine N-methyltransferase, is known to be important for hepatic lipid export by VLDL particles. Here, we assessed the influence of a high-fat (HF) diet and NAFLD status in mice on hepatic methyl-group expenditure and C1-metabolism by analyzing changes in gene expression, protein levels, metabolite concentrations, and nuclear epigenetic processes. In livers from HF diet induced obese mice a significant downregulation of cystathionine beta-synthase (CBS) and an increased betaine-homocysteine methyltransferase (BHMT) expression were observed. Experiments , using hepatoma cells stimulated with peroxisome proliferator activated receptor alpha (PPARalpha) agonist WY14,643, revealed a significantly reduced Cbs mRNA expression. Moreover, metabolite measurements identified decreased hepatic cystathionine and L-alpha-amino-n-butyrate concentrations as part of the transsulfuration pathway and reduced hepatic betaine concentrations, but no metabolite changes in the methionine cycle in HF diet fed mice compared to controls. Furthermore, we detected diminished hepatic gene expression of DNA methyltransferase 3b but no effects on hepatic global genomic DNA methylation or hepatic DNA methylation in the Cbs promoter region upon HF diet. Our data suggest that HF diet induces a PPARalpha-mediated downregulation of key enzymes in the hepatic transsulfuration pathway and upregulates BHMT expression in mice to accommodate to enhanced dietary fat processing while preserving the essential amino acid methionine.
Dahlhoff, C., et al., Hepatic Methionine Homeostasis Is Conserved in C57BL/6N Mice on High-Fat Diet Despite Major Changes in Hepatic One-Carbon Metabolism. PLoS One, 2013. 8(3): p. e57387
Dahlhoff, C., et al., Hepatic Methionine Homeostasis Is Conserved in C57BL/6N Mice on High-Fat Diet Despite Major Changes in Hepatic One-Carbon Metabolism. PLoS One, 2013. 8(3): p. e57387
Betaine prevents vasculature remodeling and inflammatory response during vascular aging
We previously reported that lysophosphatidylcholine (LPC) is a mediator of endothelial dysfunction in expression of adhesion molecules (AMs) during aging. This study aimed at investigating the effects of betaine on LPC-related expression of AMs and the molecular modulation of nuclear factor-kappaB (NF-kappaB) activation in the aorta of aged rats and rat endothelial YPEN-1 cells. The experiment was performed on young (7months) and old (21months) rats; 2 groups of old rats were fed betaine (3 or 6mg*kg-1*day-1 for 10days). Betaine inhibited the expression of LPC-related AMs in the serum and tissue of aged rats, without affecting the elevated levels of serum LPC. Betaine also prevented the generation of reactive species, thereby maintaining the redox status via the enhancement of the thiol status during aging. Furthermore, betaine attenuated NF-kappaB activation via the dephosphorylation of IkappaB kinase (IKK) and mitogen-activated protein kinases (MAPKs) in aged aorta and LPC-treated YPEN-1 cells. Thus, betaine suppressed the LPC-related AM expression associated with NF-kappaB activation via the upregulation of IKK/MAPKs. Our findings provide insights into the prevention of vascular disorders and the development of interventions based on natural compounds, such as betaine.
Lee, E.K., et al., Betaine attenuates lysophosphatidylcholine-mediated adhesion molecules in aged rat aorta: Modulation of the nuclear factor-kappaB pathway. Exp Gerontol, 2013
Lee, E.K., et al., Betaine attenuates lysophosphatidylcholine-mediated adhesion molecules in aged rat aorta: Modulation of the nuclear factor-kappaB pathway. Exp Gerontol, 2013
Wednesday, March 6, 2013
Betaine homocysteine methyltransferase (BHMT) transcription is decreased in cancer cells due to loss of gene function
Carcinogenesis is a multi-step and multifactorial process. It includes genetic, epigenetic, nutritional and environmental factors, which are closely interconnected. Human hepatocellular carcinoma (HCC) is among the most frequent and lethal cancers. Imbalance in the S-adenosylmethionine (SAM) concentration, the main methyl group donor, strongly influences the development of HCC. Key enzymes of carbon metabolism are greatly reduced in patients with cirrhosis and HCC. These alterations play a role in genetic instability and epigenetic modifications (DNA methylation, and histone modifications), however, the molecular underlying mechanisms are still poorly understood. We aimed to investigate betaine homocysteine methyltransferase (BHMT) expression in HepG2 cells and human hepatocarcinoma tissues. Tumor and surrounding healthy tissue were compared. HepG2 cells and tumor samples showed a strong decrease in BHMT transcripts resulting from the transcription of a splicing variant that contained a frameshift mutation generating a premature termination codon and gene loss of function. This splicing variant, not detected in normal adult and fetal liver, cannot be explained by any mechanism involving the known splicing consensus sequences. BHMT activity was abolished in HepG2 cells and protein expression was detected neither in HepG2 cells nor in five of the six tumor samples investigated. Further investigation is needed to elucidate whether this abnormal BHMT transcription is part of cause or consequence of liver carcinogenesis.
Pellanda, H., Betaine homocysteine methyltransferase (BHMT)-dependent remethylation pathway in human healthy and tumoral liver. Clin Chem Lab Med, 2013. 51(3): p. 617-21
Pellanda, H., Betaine homocysteine methyltransferase (BHMT)-dependent remethylation pathway in human healthy and tumoral liver. Clin Chem Lab Med, 2013. 51(3): p. 617-21
Osmoregulation by betaine involves well-orchestrated gene expression
Betaine critically contributes to the control of hepatocellular hydration and provides protection of the liver from different kinds of stress. To investigate how the hepatocellular hydration state affects gene expression of enzymes involved in the metabolism of betaine and related organic osmolytes we used qRT-PCR gene expression studies in rat hepatoma cells as well as metabolic and gene expression profiling in primary hepatocytes of both wild-type and 5,10-methylenetetrahydrofolate reductase (MTHFR) deficient mice. Anisotonic incubation caused co-ordinated adaptive changes in the expression of various genes involved in betaine metabolism, in particular of betaine homocysteine methyltransferase (BHMT), dimethylglycine dehydrogenase (DMGDH), and sarcosine dehydrogenase (SARDH). The expression of betaine-degrading enzymes was downregulated by cell shrinking and strongly induced by an increase in cell volume under hypotonic conditions. Metabolite concentrations in the culture system changed accordingly. Expression changes were mediated through tyrosine kinases, cyclic nucleotide-dependent protein kinases and JNK-dependent signalling. Assessment of hepatic gene expression using a customised microarray chip showed that hepatic betaine depletion in Mthfr-/- mice was associated with alterations that were comparable to those induced by cell swelling in hepatocytes. In conclusion, the adaptation of hepatocytes to changes in cell volume involves the co-ordinated regulation of betaine synthesis and degradation and concomitant changes in intracellular osmolyte concentrations. The existence of such a well-orchestrated response underlines the importance of cell volume homeostasis for liver function and of methylamine osmolytes such as betaine as hepatic osmolytes.
Hoffmann, L., et al., Osmotic regulation of hepatic betaine metabolism. Am J Physiol Gastrointest Liver Physiol, 2013
Hoffmann, L., et al., Osmotic regulation of hepatic betaine metabolism. Am J Physiol Gastrointest Liver Physiol, 2013
Tuesday, February 19, 2013
Higher betaine intake may be protective against lung cancer through mitigating the adverse effect of smoking
Evidence from human and animal research indicates that choline metabolic pathways may be activated during a variety of diseases, including cancer. We report results of a case-control study of 2821 lung cancer cases and 2923 controls that assessed associations of choline and betaine dietary intakes with lung cancer. Using multivariable logistic regression analyses, we report a significant association between higher betaine intake and lower lung cancer risk that varied by smoking status. Specifically, no significant association was observed between betaine intake and lung cancer among never-smokers. However, higher betaine intake was significantly associated with reduced lung cancer risk among smokers, and the protective effect was more evident among current than former smokers: for former and current smokers, the ORs (95% CI) of lung cancer for individuals with highest as compared to lowest quartiles of intake were 0.70(0.55-0.88) and 0.51(0.39-0.66) respectively. Significant linear trend of higher betaine intake and lower lung cancer risk was observed among both former and current smokers. A similar protective effect was also observed with choline intake both in overall analysis as well as among current smokers, with p-values for chi-square tests being 0.001 and 0.004 respectively, but the effect was less evident, as no linear trend was observed. Our results suggest that choline and betaine intake, especially higher betaine intake, may be protective against lung cancer through mitigating the adverse effect of smoking.
Ying, J., et al., Associations between Dietary Intake of Choline and Betaine and Lung Cancer Risk. PLoS One, 2013. 8(2): p. e54561
Ying, J., et al., Associations between Dietary Intake of Choline and Betaine and Lung Cancer Risk. PLoS One, 2013. 8(2): p. e54561
Betaine attenuated the toxicity and oxidative stress from excess selenium intake
The present study was undertaken on male rats to elucidate the selenosis induced by sodium selenite and the role played by betaine in alleviating selenium toxicity. Rats were treated with sodium selenite (6 mg/kg body weight/day) with or without betaine (240 mg/kg body weight/day). Selenotoxicosis was evident from the elevated plasma levels of total bilirubin, transaminases, and alkaline phosphatase activities. Moreover, the total protein levels decreased, and this decrease associated with a decreased albumin level, whereas the globulin level increased in selenium-intoxicated rats. The development of selenosis corresponded well with the induction of oxidative stress evident from decrease of total thiol level and glutathione content. Furthermore, activities of glutathione reductase, glucose-6-phosphate dehydrogenase, catalase, and paraoxonase-1 were decreased in selenium-treated rats. In contrast, superoxide dismutase and glutathione peroxidase activities were increased by excess selenium administration compared with control animals. As well, malondialdehyde and protein carbonyl were elevated in rats treated with selenium. Supplementation of betaine simultaneously with selenium caused less marked alteration in the investigated parameters. Betaine attenuated the selenotoxicosis by restoring thiol levels that preserve enzymatic antioxidants activity and attenuate the oxidation of lipids and proteins.
Harisa, G.I., Oxidative Stress and Paraoxonase Activity in Experimental Selenosis: Effects of Betaine Administration. Biol Trace Elem Res, 2013
Harisa, G.I., Oxidative Stress and Paraoxonase Activity in Experimental Selenosis: Effects of Betaine Administration. Biol Trace Elem Res, 2013
Thursday, February 7, 2013
Co-administration of methyl donors (including betaine) with GAA increases serum creatine without development of hyperhomocysteinaemia
Guanidinoacetic acid (GAA) is the natural biosynthetic
precursor of creatine, in a metabolic reaction that requires only a methyl
group transfer. The use of GAA as a food additive for restoring creatine load
in human tissues is rather unexplored and data on efficacy and safety are
limited. In particular, an increase in serum homocysteine after GAA
administration can be regarded as critical and should be prevented. The present
study evaluated the effects of orally administered GAA with and without methyl
group donors on serum and urine creatine concentrations, and the occurrence of
adverse events during an intervention in healthy human subjects. A total of
twenty male and female volunteers were randomised in a double-blind design to
receive either GAA (2.4 g/d) or GAA with methyl donors (2.4 g/d of GAA and 1.6
g/d of betaine HCl, 5 mug/d of vitamin B12, 10 mg/d of vitamin B6 and 600 mug/d
of folic acid) by oral administration for 8 weeks. Serum and urine creatine
increased significantly from before to after administration in both groups
(P< 0.001). The proportion of participants who reported minor adverse events
was 33.3 % in the GAA group, and 10.0 % in the GAA with methyl donors group (P=
0.30). Hyperhomocysteinaemia was found in 55.6 % of participants supplemented
with GAA, while no participant experienced hyperhomocysteinaemia in the group
supplemented with GAA and methyl donors (P= 0.01). In summary, both
interventions strongly influenced creatine metabolism, resulting in a
significant increase in fasting serum creatine. The concomitant supplementation
of methyl donors along with GAA largely precluded the elevation of serum
homocysteine caused by GAA administration alone.
Betaine intake may be protective against lung cancer for certain genetic phenotypes
PURPOSE: Folate metabolism, with its importance to DNA
repair, provides a promising region for genetic investigation of lung cancer
risk. This project investigates genes (MTHFR, MTR, MTRR, CBS, SHMT1, TYMS),
folate metabolism related nutrients (B vitamins, methionine, choline, and
betaine) and their gene-nutrient interactions. METHODS: We analyzed 115 tag
single nucleotide polymorphisms (SNPs) and 15 nutrients from 1239 and 1692
non-Hispanic white, histologically-confirmed lung cancer cases and controls,
respectively, using stochastic search variable selection (a Bayesian model
averaging approach). Analyses were stratified by current, former, and never
smoking status. RESULTS: Rs6893114 in MTRR (odds ratio [OR] = 2.10; 95%
credible interval [CI]: 1.20-3.48) and alcohol (drinkers vs. non-drinkers, OR =
0.48; 95% CI: 0.26-0.84) were associated with lung cancer risk in current
smokers. Rs13170530 in MTRR (OR = 1.70; 95% CI: 1.10-2.87) and two SNP*nutrient
interactions [betaine*rs2658161 (OR = 0.42; 95% CI: 0.19-0.88) and
betaine*rs16948305 (OR = 0.54; 95% CI: 0.30-0.91)] were associated with lung
cancer risk in former smokers. SNPs in MTRR (rs13162612; OR = 0.25; 95% CI:
0.11-0.58; rs10512948; OR = 0.61; 95% CI: 0.41-0.90; rs2924471; OR = 3.31; 95%
CI: 1.66-6.59), and MTHFR (rs9651118; OR = 0.63; 95% CI: 0.43-0.95) and three
SNP*nutrient interactions (choline*rs10475407; OR = 1.62; 95% CI: 1.11-2.42;
choline*rs11134290; OR = 0.51; 95% CI: 0.27-0.92; and riboflavin*rs8767412; OR
= 0.40; 95% CI: 0.15-0.95) were associated with lung cancer risk in never smokers.
CONCLUSIONS: This study identified possible nutrient and genetic factors
related to folate metabolism associated with lung cancer risk, which could
potentially lead to nutritional interventions tailored by smoking status to
reduce lung cancer risk.
Tuesday, January 29, 2013
Maternal Diet Supplementation with Methyl Donors and Increased Parity Affect the Incidence of Craniofacial Defects in the Offspring of Twisted gastrulation Mutant Mice
Diets rich in methyl-donating compounds, including folate, can provide protection against neural tube defects, but their role in preventing craniofacial defects is less clear. Mice deficient in Twisted gastrulation (TWSG1), an extracellular modulator of bone morphogenetic protein signaling, manifest both midline facial defects and jaw defects, allowing study of the effects of methyl donors on various craniofacial defects in an experimentally tractable animal model. The goal of this study was to examine the effects of maternal dietary supplementation with methyl donors on the incidence and type of craniofacial defects among Twsg1(-/-) offspring. Nulliparous and primiparous female mice were fed an NIH31 standard diet (control) or a methyl donor supplemented (MDS) diet (folate, vitamin B-12, betaine, and choline). Observed defects in the pups were divided into those derived mostly from the first branchial arch (BA1) (micrognathia, agnathia, cleft palate) and midline facial defects in the holoprosencephaly spectrum (cyclopia, proboscis, and anterior truncation). In the first pregnancy, offspring of mice fed the MDS diet had lower incidence of BA1-derived defects (12.8% in MDS vs. 32.5% in control; P = 0.02) but similar incidence of midline facial defects (6.4% in MDS vs. 5.2% in control; P = 1.0). Increased maternal parity was independently associated with increased incidence of craniofacial defects after adjusting for diet (from 37.7 to 59.5% in control, P = 0.04 and from 19.1 to 45.3% in MDS, P = 0.045). In conclusion, methyl donor supplementation shows protective effects against jaw defects, but not midline facial defects, and increased parity can be a risk factor for some craniofacial defects.
Billington, C.J., Jr., et al., Maternal Diet Supplementation with Methyl Donors and Increased Parity Affect the Incidence of Craniofacial Defects in the Offspring of Twisted gastrulation Mutant Mice. J Nutr, 2013
Billington, C.J., Jr., et al., Maternal Diet Supplementation with Methyl Donors and Increased Parity Affect the Incidence of Craniofacial Defects in the Offspring of Twisted gastrulation Mutant Mice. J Nutr, 2013
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