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Summary of the pathways and compartmentalization of betaine metabolism within mammalian hepatocytes. Transporters are listed numerically and enzymatic steps are designated by letters. Betaine can be synthesized from choline, obtained from the diet, or via lipid (including phospholipid) metabolism. Choline enters the mitochondrion via the choline transporter (1), which has been identified but not characterized or studied in detail (6,7). Once in the mitochondrial matrix, choline is metabolized to betaine by 2 sequential and physiologically irreversible enzymatic dehydrogenation steps, first by the FAD-linked choline dehydrogenase (A; EC 1.1.99.1), which is associated with the inner mitochondrial membrane, followed by the NAD-linked matrix enzyme betaine aldehyde dehydrogenase (B; EC 1.2.1.8) (8). Betaine cannot be further metabolized within the mitochondrion and requires transport out to the cytosol. It has been suggested this is via passive diffusion (28); however, this transport step has not been studied in detail. As such, a ''?'' has been included with step 2. Betaine can also enter the hepatocyte from the extracellular fluid via 2 routes (5), the betaine:g-aminobutyrate transporter (3) or amino acid transport system A (4). Betaine in the cytosol can be metabolized to dimethyglycine (DMG) via betaine:homeocysteine methyltransferase (C; EC 2.1.1.5), producing methionine in the process (8). The DMG is rapidly oxidized in mitochondria, but the transporter(s) of DMG into the mitochondrion (5) are not well understood; thus an ''?'' is included on this step as well.
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The time course of betaine accumulation and activities of enzymes involved in betaine metabolism were studied in developing rats. In study 1, pups weaned on a nonpurified diet had a transient increase in liver and kidney betaine content followed by a decline after approximately 42-56 d. In study 2, dams and, following weaning, pups were fed an AIN-...
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... uses, including the treatment of mild hyperhomocysteinemia (1), nonalcoholic steatohepatitis (2), and alcohol-induced liver damage (3). Betaine is also important to renal function, because it is an intracellular osmolyte in the mammalian kidney (4). Betaine's potential use as a therapeutic agent relates either directly to betaine metab- olism ( Fig. 1) or is facilitated by indirect effects thereof. Betaine can be obtained through the diet and enter cells, including hepatocytes, either via the g-aminobutyric acid/betaine trans- porter or the amino acid transport system A (5). Endogenous synthesis of betaine occurs following entry of choline into the mitochondrion (6,7) by the 2-step ...
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Citations
... Betaine levels are primarily controlled by the liver metabolism and only to a small extent by urinary excretion. Specifically, it is converted to N, Ndimethylglycine and methionine by cytosolic betaine-homocysteine methyltransferase (BHMT) [9,10]. ...
Hypertension leads to water-electrolyte disturbances and end-organ damage. Betaine is an osmolyte protecting cells against electrolyte imbalance and osmotic stress, particularly in the kidneys. This study aimed to evaluate tissue levels and hemodynamic and renal effects of betaine in normotensive and hypertensive rats. Betaine levels were assessed using high-performance liquid chromatography-mass spectrometry (HPLC-MS) in normotensive rats (Wistar-Kyoto, WKYs) and Spontaneously Hypertensive rats (SHRs), a model of genetic hypertension. Acute effects of IV betaine on blood pressure, heart rate, and minute diuresis were evaluated. Gene and protein expression of chosen kidney betaine transporters (SLC6a12 and SLC6a20) were assessed using real-time PCR and Western blot. Compared to normotensive rats, SHRs showed significantly lower concentration of betaine in blood serum, the lungs, liver, and renal medulla. These changes were associated with higher urinary excretion of betaine in SHRs (0.20 ± 0.04 vs. 0.09 ± 0.02 mg/ 24h/ 100g b.w., p = 0.036). In acute experiments, betaine increased diuresis without significantly affecting arterial blood pressure. The diuretic response was greater in SHRs than in WKYs. There were no significant differences in renal expression of betaine transporters between WKYs and SHRs. Increased renal excretion of betaine contributes to decreased concentration of the protective osmolyte in tissues of hypertensive rats. These findings pave the way for studies evaluating a causal relation between depleted betaine and hypertensive organ damage, including kidney injury.
... In between the first and final visits, subjects continuously consumed 3 g/twice daily (6 g total per day; separated by~12 h) either betaine anhydrous (BET; Vital Pharmaceuticals [VPX] inc., Weston, FL, USA) for 14 days to allow for skeletal muscle saturation or cellulose placebo (PLA; NutriCology, South Salt Lake, UT, USA) in matched doses and times [34][35][36]. Supplement preparation and distribution was done so in a double-blind and counterbalanced manner (9 subjects assigned to BET and 9 assigned to PLA), whereby both conditions were identically encapsulated (fine white powder in transparent gelatin capsules). ...
The purpose of this investigation was to compare the impacts of a potential blood flow restriction (BFR)-betaine synergy on one-leg press performance, lactate concentrations, and exercise- associated biomarkers. Eighteen recreationally trained males (25 ± 5 y) were randomized to supple- ment 6 g/day of either betaine anhydrous (BET) or cellulose placebo (PLA) for 14 days. Subsequently, subjects performed four standardized sets of one-leg press and two additional sets to muscular failure on both legs (BFR [LL-BFR; 20% 1RM at 80% arterial occlusion pressure] and high-load [HL; 70% 1RM]). Toe-tip lactate concentrations were sampled before (PRE), as well as immediately (POST0), 30 min (POST30M), and 3 h (POST3H) post-exercise. Serum homocysteine (HCY), growth hormone (GH) and insulin-like growth factor-1 concentrations were additionally assessed at PRE and POST30M. Analysis failed to detect any significant between-supplement differences for total repetitions completed. Baseline lactate changes (∆) were significantly elevated from POST0 to POST30 and from POST30 to POST3H (p < 0.05), whereby HL additionally demonstrated significantly higher ∆Lactate versus LL-BFR (p < 0.001) at POST3H. Although serum ∆GH was not significantly impacted by supplement or condition, serum ∆IGF-1 was significantly (p = 0.042) higher in BET versus PLA and serum ∆HCY was greater in HL relative to LL-BFR (p = 0.044). Although these data fail to support a BFR-betaine synergy, they otherwise support betaine’s anabolic potential.
... Multiple doses did not significantly affect time to maximum plasma concentrations (i.e., T max ; average~1 h), but did increase peak serum concentrations (i.e., C max ) from an average of 0.939 to 1.456 mmol/L. Interestingly, the evidence regarding tissue-specific saturation is sparse; however, a past rodent model demonstrates peak skeletal muscle concentrations occur at approximately 10 days with levels slowly increasing up to 56 days following betaine administration [21]. While serum concentrations do not necessarily reflect tissue concentrations, there appears to be a strong correlation between serum and skeletal muscle concentrations that are not mirrored in many other tissue types [22]. ...
... This loading regimen was chosen to represent the highest betaine dose administered in the performance literature [9]. Furthermore, the present supplementation timeframe was selected to ostensibly ensure peak skeletal muscle betaine concentrations, predicated on prior rodent pharmacokinetic data [21]. To assess the lasting impact of betaine loading on various serum and hydration-associated parameters, participants additionally visited the laboratory the day following their supplementation period (POST0), as well as 4,7,10,13,16,19,22,25, and 28 days post-supplementation (POST-4,-7,-10,-13,-16,-19,-22,-25 and -28, respectively). ...
... Several prior performance-oriented crossover investigations have previously implemented a range of betaine supplementation washout periods, utilizing limited pharmacokinetic data and without confirming full intervention reversibility [10,11,[19][20][21]27]. The present pilot investigation sought to elucidate whether a 28 day period was sufficient to return serum betaine, total body water parameters, hematocrit, as well as serum GH, IGF-1, and HCY to baseline following 14 days of betaine supplementation. ...
Several previous investigations have employed betaine supplementation in randomized controlled crossover designs to assess its ostensible ergogenic potential. Nevertheless, prior method- ology is predicated on limited pharmacokinetic data and an appropriate betaine-specific washout period is hitherto undescribed. The purpose of the present pilot investigation was therein to de- termine whether a 28 day washout period was sufficient to return serum betaine concentrations to baseline following a supplementation protocol. Five resistance-trained men (26 ± 6 y) supplemented with 6 g/day betaine anhydrous for 14 days and subsequently visited the lab 10 additional times during a 28 day washout period. Participants underwent venipuncture to assess serum betaine and several other parameters before (PRE) and periodically throughout the washout timeframe (POST0, -4, -7, -10, -13, -16, -19, -22, -25 and -28). All analyses were performed at a significance level of p < 0.05. While analyses failed to detect any differences in any other serum biomarker (p > 0.05), serum be- taine was significantly elevated from PRE-to-POST0 (p = 0.047; 2.31 ± 1.05 to 11.1 ± 4.91 μg·mL−1) and was statistically indistinguishable from baseline at POST4 (p = 1.00). Nevertheless, visual data assessment and an inability to assess skeletal muscle concentrations would otherwise suggest that a more conservative 7 day washout period is sufficient to truly return both serum-and-skeletal muscle betaine content to pre-supplementation levels.
... 23 In young mice (21 to 56 days of age), betaine accumulation in skeletal muscle seems to be most rapid dur-ing the first 10 days of supplementation, but will continue to slowly rise for up to 6 weeks or longer. 24 Based upon this data and the ergogenic results reported in sub-chronic supplementation studies, 7 it would appear that at least 10 days of supplementation is necessary to reach muscle tissue concentrations whereby betaine can exert an ergogenic effect. ...
Objective: To analyse the acute effect of betaine supplementation on muscular endurance in weight training practitioners. Design: An experimental, crossover, randomized and double-blind study. Methods: The sample composed of 10 male subjects practicing resistance training (age: 23.71 ± 4.23 years old). Participants performed 2 sessions (i.e., Betaine x Placebo) with 3 sets of repetitions until failure with 70% of 1RM. The participants were provided 3 minutes of recovery between sets and 48 hours between sessions. The 24H food recall was evaluated before each exercise session. Results: There were no significant differences in carbohydrates (p = 0.732), protein (p = 0.684), fat (p = 0.271), or in total energy consumption (p = 0.865). A time effect occurred for the training session (F (2,18) = 54.626, p < 0.0001, η² = 0.859), with a linear reduction in the number of repetitions performed throughout the series for both conditions (1set > 2set > 3set). However, there was no interaction (F (2,18) = 0.625, p= 0.546, η² = 0.065) or condition effect (F(1,9) = 0.045, p = 0.837, η² = 0.005). Conclusion: Acute betaine supplementation had no effect on muscular endurance performance in the bench press.
... Due to its chemical structure, betaine has a number of different functions both at the gastrointestinal and metabolic level (EKLUND et al., 2005). Betaine is involved in cellular fluid balance and electrolyte concentration of the small intestine, thereby increasing water holding capacity and promoting structural changes in the intestinal epithelium (KETTUNEN et al., 2001;CLOW et al., 2008). This beneficial effect has been seen in improved villus integrity and mucosal structure (KLASING et al., 2002). ...
Impaired development and weight loss (WL) in chicks are common phenomena in commercial poultry production. In this study in ovo application of betaine hydrochloride (BH) to reduce these effects was investigated. On day (d) 18 of incubation, prior to in ovo feeding, 10 fertile eggs each of Arbor Acre (AA) and Marshall (MS) genotypes (GN) were
broken-out and the embryos were dissected. Organs were weighed and examined. Residual yolk sac moisture (RYSM), and liver and pectoral muscle glycogen were determined and morphometric evaluation of the duodenum and ileum was carried out. On d 18, 1 ml of BH solution was injected into the amniotic sac of fertile broiler breeder eggs (n = 210; 105 each of AA and MS) in quantities of 0 mg, (BH0), 5 mg (BH5) and 10 mg/egg (BH10). At day of hatch (d 21), a part of the chicks (n = 48) was killed, dissected and assessments were carried out as on d 18 of incubation. The remaining chicks were fasted for 24 h and WL was calculated. Prior to in ovo injection, breast weight (P=0.048) and RYSM (P=0.001) were higher in AA than in MS. Ileal villus height (VH; P< 0.01), crypt depth (CD; P< 0.05) and thickness of Tunica muscularis (TM; P< 0.001) were greater in MS than in AA, while villus width (VW) was greater in AA (P< 0.05) compared with MS. On d 21, no BH×GN interaction on organ weight and biochemical indices was determined. Liver glycogen tended to increase with BH (P=0.068), while GN influenced carcass moisture (P=0.002). Significant BH×GN interaction was observed for duodenal VW (P< 0.001), TM (P< 0.001), and ileal VH (P< 0.001), VW (P< 0.01) and TM (P< 0.05). WL was lower in the BH5 group compared with other treatments (P< 0.001), and higher in AA than MS (P< 0.001). In conclusion, feeding BH in ovo improved intestinal morphology of broiler chicks. This effect was influenced by the genotype of the broiler chicken. In 1-d-old fasted chicks in ovo BHapplication (5 mg/egg) also significantly reduced weight loss (about 35%) compared to un-supplemented chicks.
... It is widely found in common food, including shellfish, flour, grains, and some vegetables [1][2][3]. Betaine in mammals is mainly absorbed from food and the synthesis of choline in vivo, while dietary betaine leads to a transient increase in tissue [4]. Betaine mainly functions as an osmotic regulator and methyl donor in the body. ...
It is widely reported how betaine addition regulates lipid metabolism but how betaine affects cholesterol metabolism is still unknown. This study aimed to investigate the role of betaine in hepatic cholesterol metabolism of Sprague-Dawley rats. Rats were randomly allocated to four groups and fed with a basal diet or a high-fat diet with or without 1% betaine. The experiment lasted 28 days. The results showed that dietary betaine supplementation reduced the feed intake of rats with final weight unchanged. Serum low-density-lipoprotein cholesterol was increased with the high-fat diet. The high-fat diet promoted cholesterol synthesis and excretion by enhancing the HMG-CoA reductase and ABCG5/G8, respectively, which lead to a balance of hepatic cholesterol. Rats in betaine groups showed a higher level of hepatic total cholesterol. Dietary betaine addition enhanced cholesterol synthesis as well as conversion of bile acid from cholesterol by increasing the levels of HMGCR and CYP7A1. The high-fat diet decreased the level of bile salt export pump, while dietary betaine addition inhibited this decrease and promoted bile acid efflux and increased total bile acid levels in the intestine. In summary, dietary betaine addition promoted hepatic cholesterol metabolism, including cholesterol synthesis, conversion of bile acids, and bile acid export.
... Betaine may stimulate the protection of the intestinal epithelium against osmotic disturbances, thereby improving digestion, absorption and nutrient utilization in broiler chickens (Mahmoudnia & Madani, 2012). According to Clow, Treberg, Brosnan, and Brosnan (2008), dietary betaine enhances the betaine concentration in the intestinal epithelium. It is involved in the osmoregulation of the duodenal epithelium of broiler chickens and affects the movement of water across the small intestinal epithelium in vitro . ...
This review focuses on the osmoregulatory function of betaine and its effect in terms of alleviating heat stress in poultry. Poultry appear to be particularly sensitive to temperature‐associated environmental challenges, especially heat stress. High ambient temperatures are deleterious to productive performance in poultry, including broilers, laying hens, quails and turkeys, resulting in considerable economic losses. Heat stress impairs overall poultry production by decreasing feed intake and negatively affecting intestinal development, leading to reduced nutrient digestibility. Apart from inducing a high mortality rate, heat stress is known to depress growth rate and reduce meat yield in broilers. In layers, lower feed intake impairs ovarian function, leading to decreased feed efficiency, egg production and egg quality. In addition, reduced immune functions, such as thyroid activity and antibody production, are evident in poultry exposed to heat stress. Heat stress increases the production of oxidants, causing oxidative stress and lipid peroxidation of cell membranes. Poultry respond physiologically and behaviourally when encountering the negative effects of heat stress, attempting to return the body to homeostasis. This requires energy at the expense of weight gain or egg production. Due to its zwitterionic structure, betaine has osmoprotective properties that aid in protecting intestinal cell proteins and enzymes from environmental stress, including high ambient temperature, thereby counteracting performance losses. Betaine also exerts an osmoregulatory role in cells, regulating water balance, and this results in more stable tissue metabolism. Inclusion of betaine in the diet may be beneficial for alleviating physical reactions to heat stress, as indicated by increases in nutrient digestibility. In broilers, betaine supplementation increases weight gain and breast muscle yield, while improving feed conversion. In layers, betaine supplementation improves egg production, egg quality traits and immune indices. In conclusion, due to its osmoregulatory functions, betaine plays an important role in alleviating heat stress in poultry.
... Betaine is a naturally occurring metabolite in animals, plants, and microorganisms (Craig 2004) that has attracted ample scientific attention due to a number of important roles in the organism: (1) as an intracellular osmolyte in kidney, with the role of maintaining the renal function; (2) as a methyl donor participating in the methionine cycle, primarily in liver and kidneys; (3) as a lipotropic factor, stimulating lipolysis and inhibiting lipogenesis (Cholewa et al. 2014); (4) as a dietary supplement that can improve body composition and growth performance (Eklund et al. 2005); (5) as a therapy for mild hyperhomocysteinemia, nonalcoholic steatohepatitis, and alcohol-induced liver damage (Clow et al. 2008). ...
... also named aldehyde dehydrogenase 9 family in fish (Hjelmqvist et al. 2003)] enzymes (Craig 2004). It is believed that (in rats) diet does not affect the endogenous synthesis of betaine, and that any observed alterations in betaine levels are more likely to be a result of changes in the exogenous betaine and its catabolism, rather than synthesis (Clow et al. 2008;Treberg and Driedzic 2007). Regardless, we first corroborated this in M. amblycephala by analyzing the expression levels of chodh and badh. ...
... Approximately 25% of homocysteine is remethylated to methionine by the BHMT, while betaine is converted to dimethylglycine (Clow et al. 2008). Dimethylglycine is in turn metabolized to glycine via sarcosine by dimethylglycine dehydrogenase and sarcosine dehydrogenase, which is the only known pathway for the breakdown of dimethylglycine (Magnusson et al. 2015). ...
Background
High-carbohydrate diets (HCD) are favoured by the aquaculture industry for economic reasons, but they can produce negative impacts on growth and induce hepatic steatosis. We hypothesised that the mechanism behind this is the reduction of hepatic betaine content.
Objective
We further explored this mechanism by supplementing betaine (1%) to the diet of a farmed fish Megalobrama amblycephala.
Methods
Four diet groups were designed: control (CD, 27.11% carbohydrates), high-carbohydrate (HCD, 36.75% carbohydrates), long-term betaine (LBD, 35.64% carbohydrates) and short-term betaine diet (SBD; 12 weeks HCD + 4 weeks LBD). We analysed growth performance, body composition, liver condition, and expression of genes and profiles of metabolites associated with betaine metabolism.
Results
HCD resulted in poorer growth and liver health (compared to CD), whereas LBD improved these parameters (compared to HCD). HCD induced the expression of genes associated with glucose, serine and cystathionine metabolisms, and (non-significantly, p = .20) a betaine-catabolizing enzyme betaine-homocysteine-methyltransferase; and decreased the content of betaine, methionine, S-adenosylhomocysteine and carnitine. Betaine supplementation (LBD) reversed these patterns, and elevated betaine-homocysteine-methyltransferase, S-adenosylmethionine and S-adenosylhomocysteine (all p ≤ .05).
Conclusion
We hypothesise that HCD reduced the content of hepatic betaine by enhancing the activity of metabolic pathways from glucose to homocysteine, reflected in increased glycolysis, serine metabolism, cystathionine metabolism and homocysteine remethylation. Long-term dietary betaine supplementation improved the negative impacts of HCD, inculding growth parameters, body composition, liver condition, and betaine metabolism. However, betaine supplementation may have caused a temporary disruption in the metabolic homeostasis.
... The applicant has referred to a study, in which the betaine concentration in tissues of developing rats was examined (Clow et al., 2008). Betaine was administered to pregnant Sprague-Dawley rats (5/group) via the diet at a level of 0% (control diet) or 0.3% from gestation day 5 to postnatal day 50. ...
Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver an opinion on betaine as a novel food (NF) pursuant to Regulation (EC) No 258/97. The information provided on the composition, the specifications, the batch-to-batch variability, stability and production process of the NF is sufficient and does not raise concerns about the safety of the NF. The NF is proposed to be used in foods intended to meet additional requirements for intense muscular effort with a maximum intake of 2.5 g/day of betaine for sports people above 10 years of age. Based on the lowest BMDL05, which was derived from a chronic toxicity study in rats in which a dose-related increase in platelet counts was observed, and the anticipated daily intake of the NF in the target population, the Margins of Exposure are 3.6 and 5, which are generally regarded as not sufficient. However, the total exposure to betaine from the diet (about 830 mg/day) is not known to be associated with adverse effects. Moreover, no adverse effects on platelet counts were noted in human intervention studies with exposure levels of 4 g/day of betaine for up to 6 months. A significant increase in total and low-density lipoprotein (LDL)-cholesterol concentrations was noted at intakes of 4 g/day of betaine in overweight subjects with metabolic syndrome but not in healthy subjects, nor at intakes of 3 g/day. Thus, considering 4 g/day of betaine as a reference point and applying an uncertainty factor of 10 to account for interindividual variability, an amount of 400 mg/day of betaine (i.e. 6 mg/kg body weight (bw) per day for adults) in addition to the background exposure is considered as safe. The Panel considers that the NF is safe to be used at maximum intake of 6 mg/kg bw per day in the target population.
... The osmolyte, glycine betaine is used to protect the osmotic integrity of the intestinal epithelial cells of monogastric animals as the intestinal lumen experiences a higher osmotic stress compared to the other tissues in these animals (Mongin 1976). A higher concentration of glycine betaine in the intestinal epithelial cells is achieved by the dilatory intake (Klasing et al. 2002;Clow et al. 2008). In broiler chickens, energy-dependent Na + -glycine betaine co-transporter is present in the duodenal and iliac regions of the intestine (Klasing et al. 2002;Kettunen et al. 2001). ...
Osmolytes are small organic molecules dissolved in cellular and extracellular fluids of all forms of living organisms to maintain the cellular volume. However, in addition to their role in volume regulation, osmolytes do play a variety of roles in biological systems including protein folding, protein disaggregation, protein-protein interaction, and protection against highly osmotic environments. Nature has preferably selected the organic osmolytes for these functions over the inorganic ions due to several reasons. The naturally occurring osmolytes belong to four chemical classes, namely, polyols, sugars, amino acids, and methylamines. In certain instances, osmolytes are used to determine the maximum depth up to which a fish can survive in the marine ecosystem. Additionally, methylamine osmolytes like trimethylamine N-oxide, glycerophosphocholine, and betaine are able to counteract the effect of denaturants under both in vivo and in vitro conditions. In fact, organisms use a large amount of different varieties of osmolytes as an adaptation to the environment where they reside. In this chapter, an up-to-date knowledge of the roles of organic osmolytes in regulating the cell volume is being discussed in detail. Future insights in this direction have also been highlighted.
