Dietary factors associated with adiponectin

In this epidemiological study, dietary betaine and choline intake were not correlated with plasma HMW adiponectin levels.

Yannakoulia et al (2008). "Dietary factors associated with plasma high molecular weight and total adiponectin levels in apparently healthy women." Eur J Endocrinol 159(4): R5-10.

Dietary patterns, food groups, and nutrients as predictors of plasma choline and betaine

Higher plasma betaine was predicted by consumption of high-fiber bread, complex carbohydrates, fiber, folate, thiamine and total energy. Lower plasma betaine was correlated with high-fat dairy products and western dietary pattern (with a high loading for meat, pizza, sugar, and fat). Higher plasma choline was predicted by egg consumption and cholesterol intake.

Konstantinova et al (2008). "Dietary patterns, food groups, and nutrients as predictors of plasma choline and betaine in middle-aged and elderly men and women." Am J Clin Nutr 88(6): 1663-1669.

Molecular Mechanisms of Alcoholic Fatty Liver

This paper reviews several mechanisms, including that betaine may attenuate fatty liver by down-regulating SREBP-1 (sterol regulatory element-binding protein-1) activity. Alcohol may increase SREBP-1 activity by decreasing the activities of AMP-activated protein kinase and sirtuin-1. Tumor necrosis factor-α (TNF-α) produced in response to alcohol exposure may cause fatty liver by up-regulating SREBP-1 activity

Purohit et al (2008). "Molecular Mechanisms of Alcoholic Fatty Liver." Alcoholism: Clinical and Experimental Research Nov 19;. [Epub ahead of print]

Improved Body Weight and Biochemistry

Lu et al (2008). "Effects of betaine on body weight and biochemical index of obese rats fed high-fat diet." Acta Nutr Sinica 30(3): 311-5.

This study, published in Chinese, compared rats fed for 8 weeks on these diets:

- control
- high fat (HF)
- HF plus low betaine (15 mg/kg bwt) (HF/LB)
- HF plus medium betaine (30 mg/kg bwt) (HF/MB)
- HF plus high betaine (60 mg/kg bwt) (HF/HB)

Results for weight compared to control showed:

- HF diet led to greatest weight gain (i.e. 14% greater body weight at 8 weeks)
- HF/HB diet led to slowest weight gain (i.e. 7% greater body weight at 8 weeks)

Results for blood markers showed:

HF diet compared to control led to:

- higher fasting glucose and insulin
- higher malonaldehyde (MDA - marker of oxidative stress) and lower total antioxidant capacity (TAOC)
- lower HDL and higher LDL cholesterol
- higher free fatty acids (FFA)
- unchanged total cholesterol and triglyerides (TG)

Compared to HF diet:

- HF/HB diet led to improved blood glucose, MDA, TG and FFA
- HF/LB diet led to improved blood insulin, MDA and TAOC

Effect of Betaine on GAA-induced homocysteinemia

Setoue et al (2008). "Hyperhomocysteinemia induced by guanidinoacetic acid is effectively suppressed by choline and betaine in rats." Biosci Biotechnol Biochem 72(7): 1696-703.

Guanidinoacetic acid (GAA), a precursor of creatine:

- raised plasma homocysteine
- raised liver homocysteine and s-adenosylhomocysteine (SAH)
- lowered liver s-adenosylmethionine (SAM)

Betaine and choline significantly suppressed these effects.

Betaine Reverses IR and NAFLD

Borgschulte et al (2008). "Betaine Treatment Reverses Insulin Resistance and Fatty Liver Disease Without Reducing Oxidative Stress or Endoplasmic Reticulum Stress in An Animal Model of NAFLD." Gastroenterology 134(4): A414.

Compared to a control diet, a high fat diet led to increased:

- body weight
- plasma insulin and homocysteine
- liver injury
- oxidative and endoplasmic reticulum stress

Addition of betaine (1.5%) to the high fat diet reduced:

- body weight
- plasma insulin and homocysteine
- liver injury

Papers 2004-7:

Erman et al (2004). "Betaine or taurine administration prevents fibrosis and lipid peroxidation induced by rat liver by ethanol plus carbon tetrachloride intoxication." Amino Acids 27(2): 199-205.

Balkan et al (2004). "The effect of betaine treatment on triglyceride levels and oxidative stress in the liver of ethanol-treated guinea pigs." Exp Toxicol Pathol 55(6): 505-9.

Balkan et al (2005). "The effect of taurine or betaine pretreatment on hepatotoxicity and prooxidant status induced by lipopolysaccharide treatment in the liver of rats." Eur J Gastroenterol Hepatol 17(9): 917-21.

Kharbanda et al (2005). "A Comparison of the Effects of Betaine and S-Adenosylmethionine on Ethanol-Induced Changes in Methionine Metabolism and Steatosis in Rat Hepatocytes." J. Nutr. 135(3): 519-524.

Kharbanda et al (2005). "Role of elevated S-adenosylhomocysteine in rat hepatocyte apoptosis: Protection by betaine." Biochem Pharmacol 70: 1883-90.

Kim et al (2005). "Effect of betaine supplementation on changes in hepatic metabolism of sulfur-containing amino acids and experimental cholestasis induced by alpha-naphthylisothiocyanate." Food Chem Toxicol 43(5): 663-70.

Trappoliere et al (2005). "The treatment of NAFLD." Eur Rev Med Pharmacol Sci 9(5): 299-304.

Samara et al (2006). "Betaine resolves severe alcohol-induced hepatitis and steatosis following liver transplantation." Dig Dis Sci 51(7): 1226-9.

Duong et al (2006). "S-Adenosylmethionine and betaine correct hepatitis C virus induced inhibition of interferon signaling in vitro." Hepatology 43(4): 796-806.

Hanje et al (2006). "The use of selected nutrition supplements and complementary and alternative medicine in liver disease." Nutr Clin Pract 21(3): 255-72.

Kaplowitz and Ji (2006). "Unfolding new mechanisms of alcoholic liver disease in the endoplasmic reticulum." J Gastroenterol Hepatol 21 Suppl 3: S7-9.

Liu et al (2006). "Betaine modulates high carbohydrate diet-induced fatty liver in mice." Faseb J 20(4): A183.

Sparks et al (2006). "Hepatic very-low-density lipoprotein and apolipoprotein B production are increased following in vivo induction of betaine-homocysteine S-methyltransferase." Biochem J 395(2): 363-71.

Chang et al (2006). "Therapy of NAFLD: Antioxidants and Cytoprotective Agents." J Clin Gastroenterol 40 Suppl 1: S51-60.

Kaplowitz et al (2007). "Endoplasmic reticulum stress and liver injury." Semin Liver Dis 27(4): 367-77.

Kharbanda et al (2007). "Betaine attenuates alcoholic steatosis by restoring phosphatidylcholine generation via the phosphatidylethanolamine methyltransferase pathway." J Hepatol 46(2): 314-21.

Purohit et al (2007). "Role of S-adenosylmethionine, folate, and betaine in the treatment of alcoholic liver disease: summary of a symposium." Am J Clin Nutr 86(1): 14-24.

Song et al (2007). "Involvement of AMP-activated protein kinase in beneficial effects of betaine on high-sucrose diet-induced hepatic steatosis." Am J Physiol Gastrointest Liver Physiol 293(4): G894-902.

Song et al (2008). "Inhibition of adiponectin production by homocysteine: a potential mechanism for alcoholic liver disease." Hepatology 47(3): 867-79.

Ji (2008). "Dissection of endoplasmic reticulum stress signaling in alcoholic and non-alcoholic liver injury." J Gastroenterol Hepatol 23 Suppl 1: S16-24.

Kim et al (2008). "Alleviation of acute ethanol-induced liver injury and impaired metabolomics of S-containing substances by betaine supplementation." Biochemical and Biophysical Research Communications 368(4): 893-898.

Mato et al (2008). "Methionine Metabolism and Liver Disease." Annual Review of Nutrition 28: 273-93.

Strength and Power

Maresh et al (2007). "The Effects of Betaine Supplementation on Strength and Power Performance" Med Sci Sports Exerc 39(5 Suppl): S101.

This study found that ingestion of betaine over 2 weeks led to increased power, force and maintenance as measured in:

- vertical jump power
- isometric squat force
- isometric bench press
- bench throw power

There were no differences in bench press repetitions, number of squat repetitions, and jump squat power.

Athletic Performance in the Heat

Armstrong et al (2008). "Influence of betaine consumption on strenuous running and sprinting in a hot environment." J Strength Cond Res 22(3): 851-60.

Investigators found a trend towards longer sprint time until exhaustion when betaine was present in either a sports beverage or in flavored water compared to placebo.

Papers 2004-7:

Millard-Stafford et al (2005). "Fluid replacement in the heat - effects of betaine." Med Sci Sports Exerc 37(5): S28.

Cancer Treatment Hypothesis

Jellinek (2008). "The need for a multi-level biochemical approach to defeat cancer that will also support the host." Medical Hypotheses 71(4): 515-526.

The author suggests a multi-level, simultaneous biochemical approach to treating key elements of cancer (metastasis, tumor growth and immunity) and that betaine should be a component to help prevent tumor growth. For studies to confirm the proposal, the overall expected result is that a combined administration of all agents cited here will outperform any single agent considered so far for anticancer treatment.

Papers 2004-7:

Cho et al (2007). "Dietary Choline and Betaine and the Risk of Distal Colorectal Adenoma in Women." J. Natl. Cancer Inst.: 1224-31.

Cho et al (2007). "Nutrients involved in one-carbon metabolism and risk of breast cancer among premenopausal women." Cancer Epidemiol Biomarkers Prev 16(12): 2787-90.

Ziegler and Lim (2007). "One-Carbon Metabolism, Colorectal Carcinogenesis, Chemoprevention with Caution." J. Natl. Cancer Inst. 99(16): 1214-5.

Xu et al (2007). "A functional 19-base pair deletion polymorphism of dihydrofolate reductase (DHFR) and risk of breast cancer in multivitamin users." Am J Clin Nutr 85(4): 1098-102.

Xu et al (2008). "Choline metabolism and risk of breast cancer in a population-based study." Faseb J 22(6): 2045-52.

Betaine Metabolism and Distribution

A couple of studies investigating the intake and distribution of betaine in tissues:

Clow et al (2008) "Elevated tissue betaine content in developing rats are due to dietary betaine, not synthesis"

Increase in tissue betaine reflects high dietary betaine and not a change in endogenous betaine synthesis.

Slow et al (2008) "Plasma Dependent and Independent Accumulation of Betaine in Male and Female Rat Tissues"

The authors measured the betaine concentration of plasma and various tissues (brain, heart, lungs, liver, kidney, spleen, intestine, reproductive tissues, skeletal muscle and skin) in male and female rats. Some of the findings were:

- betaine was highest in the liver and kidney
- plasma betaine concentrations were significantly lower than tissue levels except in the brain and skeletal muscle
- there was significant plasma-related accumulation of betaine in the heart, skin and skeletal muscle, while the lung, liver, kidney, spleen, and intestine showed significant plasma-related and plasma-independent accumulations of betaine.

Metabolic Syndrome, CVD Risk & Related Epidemiological Studies

Konstantinova et al (2008) "Divergent Associations of Plasma Choline and Betaine with Components of Metabolic Syndrome in Middle Age and Elderly Men and Women"

This epidemiological study found that high serum betaine was associated with low:

- serum non-HDL cholesterol
- triglycerides
- BMI
- percent body fat
- waist circumference
- systolic and diastolic blood pressure
- smoking

and associated with high:

- HDL cholesterol
- physical activity

Thus favorable cardiovascular and metabolic syndrome risk factors were associated with high betaine concentrations.

Papers 2004-7:

Shaw et al (2004) "Periconceptional dietary intake of choline and betaine and neural tube defects in offspring."

Yagisawa et al (2004). "Effects of intravenous betaine on methionine-loading-induced plasma homocysteine elevation in rats." J Nutr Biochem 15(11): 666-71.

Schwahn et al (2005) "Betaine is a determinant of plasma lipids in men."

Melse-Boonstra et al (2005). "Betaine concentration as a determinant of fasting total homocysteine concentrations and the effect of folic acid supplementation on betaine concentrations." Am J Clin Nutr 81(6): 1378-1382.

Ueland et al (2005). "Betaine: a key modulator of one-carbon metabolism and homocysteine status." Clin Chem Lab Med 43(10): 1069-75.

Olthof et al (2005) "Effect of homocysteine-lowering nutrients on blood lipids: results from four randomised, placebo-controlled studies in healthy humans."

Velzing-Aarts et al (2005). "Plasma choline and betaine and their relation to plasma homocysteine in normal pregnancy." Am J Clin Nutr 81(6): 1383-1389.

Verhoef and de Groot (2005). "Dietary determinants of plasma homocysteine concentrations." Semin Vasc Med 5(2): 110-23.

Olthof and Verhoef (2005) "Effects of betaine intake on plasma homocysteine concentrations and consequences for health."

Olthof et al (2006) "Effect of folic acid and betaine supplementation on flow-mediated dilation: a randomized, controlled study in healthy volunteers."

Olthof et al (2006) "Acute effect of folic acid, betaine, and serine supplements on flow-mediated dilation after methionine loading: a randomized trial."

Iqbal et al (2006) "Betaine, a novel antithrombotic agent for effective management of peripheral arterial occlusive diseases."

Iqbal et al (2006) "Betaine induced release of tissue factor pathway inhibitor and nitric oxide: implications in the management of cardiovascular disease."

Schwab et al (2006) "Orally Administered Betaine Has an Acute and Dose-Dependent Effect on Serum Betaine and Plasma Homocysteine Concentrations in Healthy Humans."

Cho et al (2006) "Dietary choline and betaine assessed by food-frequency questionnaire in relation to plasma total homocysteine concentration in the Framingham Offspring Study."

Francois H. T. Duong (2006). "S-adenosylmethionine and betaine correct hepatitis C virus induced inhibition of interferon signaling in vitro." Hepatology 43(4): 796-806.

Zeisel (2006). "Betaine supplementation and blood lipids: fact or artifact?" Nutr Rev 64(2 Pt 1): 77-9.

Bidulescu et al (2007) "Usual choline and betaine dietary intake and incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study."

Schwahn et al (2007) "Betaine supplementation improves the atherogenic risk factor profile in a transgenic mouse model of hyperhomocysteinemia."

Chiuve et al (2007). "The association between betaine and choline intakes and the plasma concentrations of homocysteine in women."

Dalmeijer et al (2007). "Prospective study on dietary intakes of folate, betaine, and choline and cardiovascular disease risk in women."

Wallace et al (2008) "Homocysteine concentration, related B vitamins, and betaine in pregnant women recruited to the Seychelles Child Development Study."

Antioxidants, Cereals and Betaine

Fardet (2008) "Fardet et al (2008). "Is the in vitro antioxidant potential of whole-grain cereals and cereal products well reflected in vivo?" Journal of Cereal Science 48(2): 258-76."

This paper suggests that betaine has long been neglected as a source of antioxidant from cereals.

Papers 2004-7:

Fardet et al (2007). "Whole-Grain and Refined Wheat Flours Show Distinct Metabolic Profiles in Rats as Assessed by a 1H NMR-Based Metabonomic Approach." J Nutr 137(4): 923-29.

Likes et al (2007). "The betaine and choline content of a whole wheat flour compared to other mill streams." J. Cereal Sci. 46(1): 93-5.

Price et al (2007). "Plasma uptake of methyl donors from wheat fractions." Proc Nutr Soc 66(S1): 114A.

Betaine and Inflammation

An article by Detopoulou et al (2008). "Dietary choline and betaine intakes in relation to concentrations of inflammatory markers in healthy adults: the ATTICA study." showed that participants who consumed >360 mg/d of betaine had, on average:

- 10% lower concentrations of homocysteine
- 19% lower concentrations of C-reactive protein
- 12% lower concentrations of tumor necrosis factor

than did those who consumed <260 mg/d.

This was accompanied by an Editorial by Zeisel "Is there a new component of the Mediterranean diet that reduces inflammation?" and a letter to the editor of AJCN by Slow et al, entitled "Dietary betaine and inflammation". Zeisel draws the correlation between betaine/choline intake and the Mediterranean diet, whilst Slow et al stress the importance of the osmolyte function in addition to the methylation role of betaine. The reply to Slow et al is here.

Papers 2004-7:

Go et al (2005). "Betaine Suppresses Proinflammatory Signaling During Aging: The Involvement of Nuclear Factor-{kappa}B via Nuclear Factor-Inducing Kinase/I{kappa}B Kinase and Mitogen-Activated Protein Kinases."

Go et al (2007). "Betaine modulates age-related NF-kappaB by thiol-enhancing action."

Betaine and Muscle

This paper helps explain the positive effects seen on muscle by betaine.

Ortiz-Costa et al (2008) "Betaine protects urea-induced denaturation of myosin subfragment-1."

Myosin belongs to a family of motor proteins that transform the chemical energy of ATP into mechanical work.

Urea, a waste-product of protein metabolism, can increase due to exercise. Urea alters the structure of skeletal muscle myosin subfragment-1 (the catalytic domain), thereby inhibiting ATPase activity and reducing energy production.

Betaine, acting as a 'counteracting' osmolyte, was able to protect against these changes in structure, thereby preserving the enzyme’s catalytic activity.

Papers 2003-7:

Brigotti et al (2003). "Effects of osmolarity, ions and compatible osmolytes on cell-free protein synthesis." Biochem. J. 369(2): 369-374.

Animal Studies on Body Composition

A couple of new studies add to the body of evidence that betaine increases muscle and decreases fat mass:

Huang et al (2008) "Effect of dietary betaine supplementation on lipogenic enzyme activities and fatty acid synthase mRNA expression in finishing pigs."

Betaine supplementation led to:

- increased lean muscle mass
- decreased body fat proportion
- decreased lipogenic enzyme activity in adipose tissue (acetyl-CoA carboxylase, malic acid and FAS (including mRNA expression))

Reduction in adipose tissue with betaine might result from diminished rates of lipogenesis as a consequence of decreased activities and gene expression of lipogenic enzymes.

Jahanian and Rahmani (2008) "The Effect of Dietary Fat Level on the Response of Broiler Chicks to Betaine and Choline Supplements"

Dietary betaine inclusion instead of choline resulted in:

- increased lean muscle mass
- reduced abdominal fat proportion
- improved blood lipids (decreased triglycerides and VLDL, increased HDL)


Fernandez-Figares et al (2008). "Synergistic effects of betaine and conjugated linoleic acid on the growth and carcass composition of growing Iberian pigs." J. Anim Sci. 86(1): 102-111.

Dietary supplementation of betaine + CLA increased:

- average daily gain
- protein
- water
- lean deposition

There appears to be a synergistic action.

Papers 2004-7:


Sillence (2004) "Technologies for the control of fat and lean deposition in livestock."

Eklund et al (2005) "Potential nutritional and physiological functions of betaine in livestock."

Eklund et al (2006) "Effects of betaine and condensed molasses solubles on nitrogen balance and nutrient digestibility in piglets fed diets deficient in methionine and low in compatible osmolytes."

Zhan et al (2006) "Effects of methionine and betaine supplementation on growth performance, carcase composition and metabolism of lipids in male broilers."

Huang et al (2006)" Changes in hormones, growth factor and lipid metabolism in finishing pigs fed betaine."

Huang et al (2007) "Effect of betaine on growth hormone pulsatile secretion and serum metabolites in finishing pigs."

FASEB Summer Research Conference

Recently returned from this conference in Lucca, Italy. Here is the link

There were several interesting talks and posters on betaine, including:

Betaine: An important methyl donor in the liver
Kusum Kharbanda, Omaha VA Medical Center / UNMC, USA

Dietary glycine betaine vs supplementation: chronic effects on betaine and homocysteine concentrations in healthy male subjects
Jane Elmslie, Canterbury Health Laboratories, NZ

The quantification and effect of diet on tissue betaine accumulation - the major store of one-carbon units
Sandy Slow, Canterbury Health Laboratories, NZ

Dietary patterns, food groups and nutrients as predictors of plasma choline and betaine in middle age and elderly men and women: the Horlander Health Study
Svetlana Konstantinova, University of Bergen, Norway

Metabolism and fate of betaine methyl groups in rat hepatocytes
Jason Treberg, Memorial University of Newfoundland, Canada

The Betaine Buzz!

There's a growing body of research on the benefits of betaine, so I've decided to start this blog to help sort it all out! I'll provide a brief summary and a link to new papers I find when they are published. I'll also try to add links to papers that have been published since the 2004 AJCN review.