Obesity, high fat diet, and urine metabolites

To investigate metabolic changes in the urine of a rat model of obesity induced by a high-fat diet (HFD), rats were divided into the following four groups based on the diet type and degree of weight gain: normal-diet (ND) low gainers, ND high gainers, HFD low gainers, and HFD high gainers. Biochemical analyses of visceral fat-pad weight, plasma, and liver tissues were performed.

It was observed that the metabolic profile of urine obtained by 1H-NMR-spectroscopy-based metabolomic analysis differed between ND low gainers and ND high gainers even though these animals consumed the same normal diet. Several key metabolites in urine, such as betaine, taurine, acetone/acetoacetate, phenylacetylglycine, pyruvate, lactate, and citrate contributed to the classification of these two groups. The metabolic profile of urine also differed between ND low gainers and HFD high gainers, which consumed the different diet and showed a different weight gain.

In short, these key metabolites, including betaine, were at higher concentrations in urine for high gainers vs low gainers.

This study has identified features of urine metabolites in various groups and demonstrated the reliability of an NMR-based metabolomics approach to investigate the effects of the diet and the physical constitution on obesity.

Kim et al (2009). "(1)H-nuclear magnetic resonance spectroscopy-based metabolic assessment in a rat model of obesity induced by a high-fat diet." Anal Bioanal Chem. Epub August

Ovarian cancer risk

The authors prospectively examined the relationship between the intake of choline/betaine and ovarian cancer risk among participants from the Nurses' Health Study (NHS) and NHSII. There were no associations between total choline, betaine, as well as choline plus betaine intake and ovarian cancer risk. Results did not vary by alcohol consumption, folate intake or after the exclusion of cases diagnosed during the 4-year period after dietary assessment.

Kotsopoulos et al (2010). "Dietary betaine and choline intake are not associated with risk of epithelial ovarian cancer." Eur J Clin Nutr 64(1): 111-114.

Fibrates may cause abnormal urinary betaine loss

Abnormal urinary loss of betaine is common in patients with the metabolic syndrome or diabetes mellitus. These patients are often treated with fibrates which alter renal function and raise plasma homocysteine concentrations.

- patients taking bezafibrate had higher betaine excretion than patients not taking fibrates
- of 32 patients taking bezafibrate, 20 had abnormal (>97.5 %-ile) betaine excretion
- plasma homocysteine correlated positively with betaine excretion in male patients with lipid disorders who were not taking fibrate, but the relationship was stronger if patients taking bezafibrate were included
- in elderly (>65 years) subjects with hypertension there was a similar correlation, which was stronger when a subject taking bezafibrate was included

Abnormal betaine excretion is common in patients treated with bezafibrate. Bezafibrate appears to exacerbate betaine loss, which will cause a rise in plasma homocysteine. Betaine supplementation could be considered in conjunction with fibrate therapy.

Lever et al (2009). "Fibrates may Cause an Abnormal Urinary Betaine Loss Which is Associated with Elevations in Plasma Homocysteine." Cardiovasc Drugs Ther. Epub Aug 4

Prevention of amyloid β-peptide formation

S-Adenosylhomocysteine (SAH) has been implicated as a risk factor for neurodegenerative diseases such as Alzheimer's disease. SAH is a potent inhibitor of all cellular methyltransferases and this study showed that SAH increased amyloid β-peptide (Aβ) formation in a concentration-dependent manner (10–500 nM), and this effect of SAH was accompanied by significantly increased expression of APP and PS1 proteins.

Pre-incubation of cells with betaine (1.0 mM), 30 min followed by incubation with SAH (500 nM) or 5′-azc (20 μM) for 24 h markedly prevented the expression of Aβ protein (by 50%, P < 0.05) and the gene promoter hypomethylation of APP and PS1.

Lin et al (2009). "S-Adenosylhomocysteine increases beta-amyloid formation in BV-2 microglial cells by increased expressions of beta-amyloid precursor protein and presenilin 1 and by hypomethylation of these gene promoters." Neurotoxicology 30(4): 622-7.

Protective effect in liver cancer

Four groups of rats were given diethylinitrosamine (DEN) and fed with AIN-93G diets supplemented with 0, 10, 20 or 40 g betaine/kg (model, 1%, 2%, and 4% betaine, respectively), while the control group, received no DEN, fed with AIN-93G diet. Eight or 15 weeks later, the expression of p16 and c-myc mRNA was examined by Real-time PCR (Q-PCR). The DNA methylation status within the p16 and c-myc promoter was analyzed using methylation-specific PCR.

Compared with the model group, numbers and areas of glutathione S-transferase placental form (GST-p)-positive foci were decreased in the livers of the rats treated with betaine (P < 0.05). Although the frequency of p16 promoter methylation in livers of the four DEN-fed groups appeared to increase, there is no difference among these groups after 8 or 15 weeks (P > 0.05). Betaine supplementation attenuated the down-regulation of p16 and inhibited the up-regulation of c-myc induced by DEN in a dose-dependent manner (P < 0.01). Meanwhile, increases in levels of malondialdehyde (MDA) and glutathione S-transferase (GST) in model, 2% and 4% betaine groups were observed (P < 0.05). Finally, enhanced antioxidative capacity (T-AOC) was observed in both the 2% and 4% betaine groups.

The data suggest that betaine attenuates DEN-induced damage in rat liver and reverses DEN-induced changes in mRNA levels.

Du et al (2009). "Assessment of the effect of betaine on p16 and c-myc DNA methylation and mRNA expression in a chemical induced rat liver cancer model." BMC Cancer 9(1): 261.

Reduced breast cancer risk and mortality

The authors investigated the associations of dietary intakes of choline and betaine and breast cancer risk and mortality in the population-based Long Island Breast Cancer Study Project.

- there was an indication that a higher intake of free choline was associated with reduced risk of breast cancer
- higher intakes of betaine, phosphocholine, and free choline were associated with reduced all-cause as well as breast cancer-specific mortality in a dose-dependent fashion
- the betaine-homocysteine methyltransferase gene (BHMT) rs3733890 polymorphism was associated with reduced breast cancer-specific mortality

The study suggests that high intake of betaine and choline may be a promising strategy to prevent the development of breast cancer and to reduce its mortality.

Xu et al (2009). "High intakes of choline and betaine reduce breast cancer mortality in a population-based study". FASEB J., epub July 27.