s-adenosylhomocysteine and Weight-Gain

Gamma-hydroxybutyrate (GHB) was originally introduced as an anesthetic but was first abused by bodybuilders and then became a recreational or club drug.1 Sodium salt of GHB is currently used for the treatment of cataplexy in patients with narcolepsy. The mode of action and metabolism of GHB is not well understood. GHB stimulates growth hormone release in humans and induces weight loss in treated patients, suggesting an unexplored metabolic effect. In different experiments the effect of GHB administration on central (cerebral cortex) and peripheral (liver) biochemical processes involved in the metabolism of the drug, as well as the effects of the drug on metabolism, were evaluated in mice.. C57BL/6J, gamma-aminobutyric acid B (GABAB) knockout and obese (ob/ob) mice were acutely or chronically treated with GHB at 300 mg/kg.. Respiratory ratio decreased under GHB treatment, independent of food intake, suggesting a shift in energy substrate from carbohydrates to lipids. GHB-treated C57BL/6J and GABAB null mice but not ob/ob mice gained less weight than matched controls. GHB dramatically increased the corticosterone level but did not affect growth hormone or prolactin. Metabolome profiling showed that an acute high dose of GHB did not increase the brain GABA level. In the brain and the liver, GHB was metabolized into succinic semialdehyde by hydroxyacid-oxoacid transhydrogenase. Chronic administration decreased glutamate, s-adenosylhomocysteine, and oxidized gluthathione, and increased omega-3 fatty acids.. Our findings indicate large central and peripheral metabolic changes induced by GHB with important relevance to its therapeutic use.

Topics: Alcohol Oxidoreductases; Animals; Body Composition; Cell Respiration; Cerebral Cortex; Corticosterone; Fatty Acids, Omega-3; gamma-Aminobutyric Acid; Glutamic Acid; Glutathione Disulfide; Growth Hormone; Hydroxybutyrates; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Mitochondrial Proteins; Oxidation-Reduction; Prolactin; S-Adenosylhomocysteine; Weight Gain

To elucidate the mechanism by which moderate and high protein diets fail to increase plasma homocysteine concentration despite dietary methionine levels being higher, rats were fed diets with graded levels (10, 30, and 50%) of casein or low casein diets supplemented with methionine at levels of 0.5 and 1.0% together with or without glycine+serine, which corresponded to moderate and high casein diets with respect to these amino acids, for 14 d. The plasma homocysteine concentration significantly decreased with an increase in dietary casein level, whereas it significantly increased with an increase in dietary methionine level when the low casein diet was supplemented with methionine. Supplementation with glycine+serine significantly suppressed the elevation of plasma homocysteine concentration due to methionine supplementation, but it could not decrease plasma homocysteine concentration to the levels in rats fed corresponding casein diets. Increased concentrations of hepatic S-adenosylhomocysteine and homocysteine due to methionine supplementation were also significantly suppressed by glycine+serine. The activity of hepatic cystathionine beta-synthase (CBS) did not increase in response to methionine supplementation, while it significantly increased with an increase in dietary casein level. In contrast, the activity of hepatic betaine-homocysteine S-methyltransferase (BHMT) significantly increased with increase in both dietary casein level and dietary methionine level. Hepatic levels of mRNA for CBS and BHMT were parallel to the enzyme activities. The results suggest that, in contrast to methionine-supplemented low casein diets, moderate and high casein diets avoid increasing plasma homocysteine concentration through dual mechanisms, greater supply of glycine+serine and an increase in CBS activity.

Topics: Animals; Betaine-Homocysteine S-Methyltransferase; Caseins; Cystathionine beta-Synthase; Cysteine; Dietary Proteins; Dietary Supplements; Dose-Response Relationship, Drug; Energy Intake; Glycine; Homocysteine; Liver; Male; Methionine; Organ Size; Rats; Rats, Wistar; RNA, Messenger; S-Adenosylhomocysteine; S-Adenosylmethionine; Serine; Weight Gain

Glycine N-methyltransferase (GNMT) regulates S-adenosylmethionine (SAM) levels and the ratio of SAM:S-adenosylhomocysteine (SAH). In liver, methionine availability, both from the diet and via the folate-dependent one-carbon pool, modulates GNMT activity to maintain an optimal SAM:SAH ratio. The regulation of GNMT activity is accomplished via posttranslational and allosteric mechanisms. We more closely examined GNMT regulation in various tissues as a function of excess dietary methyl groups. Sprague Dawley rats were fed either a control diet (10% casein plus 0.3% L-methionine) or the control diet supplemented with graded levels (0.5-2%) of L-methionine. Pair-fed control groups of rats were included due to the toxicity associated with high methionine consumption. As expected, the hepatic activity of GNMT was significantly elevated in a dose-dependent fashion after 10 d of feeding the diets containing excess methionine. Moreover, the abundance of hepatic GNMT protein was similarly increased. The kidney had a significant increase in GNMT as a function of dietary methionine, but to a much lesser extent than in the liver. For pancreatic tissue, neither the activity of GNMT nor the abundance of the protein was responsive to excess dietary methionine. These data suggest that additional mechanisms contribute to regulation of GNMT such that synthesis of the protein is greater than its degradation. In addition, methionine-induced regulation of GNMT is dose dependent and appears to be tissue specific, the latter suggesting that the role it plays in the kidney and pancreas may in part differ from its hepatic function.

Topics: Animals; Dietary Proteins; Dose-Response Relationship, Drug; Glycine N-Methyltransferase; Kidney; Liver; Male; Methionine; Methyltransferases; Pancreas; Random Allocation; Rats; Rats, Sprague-Dawley; S-Adenosylhomocysteine; S-Adenosylmethionine; Up-Regulation; Weight Gain

Phenytoin (PHT) has long been known to cause folate depletion with chronic use. In animal models PHT has been shown to interfere with folate-dependent one-carbon metabolism. Folic acid supplementation in humans has been shown to restore blood levels of folates to normal, but the effects of folic acid supplementation on the PHT-induced effects on one-carbon metabolism have not been addressed. In the present study rats were treated for 8 wk with 1) PHT, 2) folic acid, 3) PHT plus folic acid or 4) vehicle (propylene glycol). Phenytoin treatment caused a decrease in weight gain over the 8 wk of treatment. This effect on weight gain was reversed by folic acid supplementation, but the decrease in brain folate concentration caused by PHT was not reversed by folic acid supplementation, which by itself apparently caused a decrease in brain folate concentration. Phenytoin treatment tended to increase methylation capacity (S-adenosylmethionine:S-adenosylhomocysteine ratio) in the brain and decrease methylation capacity in the liver. Folate supplementation by itself increased methylation capacity in the liver but had no effect in the brain. Folic acid and PHT apparently had independent but opposite effects in the liver, leading to a normalization of methylation capacity. These data suggest that folic acid supplementation in PHT therapy may be effective in reversing the peripheral effects of chronic PHT treatment on one-carbon metabolism but not the central effects.

Topics: Animals; Brain; Drug Interactions; Folic Acid; Liver; Male; Methylation; Methylenetetrahydrofolate Reductase (NADPH2); Oxidoreductases Acting on CH-NH Group Donors; Phenytoin; Rats; Rats, Inbred Strains; S-Adenosylhomocysteine; S-Adenosylmethionine; Weight Gain

Amino acid-defined diets deficient in methyl groups have been shown to result in a very high incidence of hepatocellular carcinoma. It has been suggested that this is a result of decreased levels of S-adenosylmethionine and the undermethylation of DNA. Accordingly, the enzyme glycine N-methyltransferase (GNMT, EC 2.1.1.20) may play a major role in maintaining the levels of S-adenosylmethionine in liver in response to changes in dietary methionine. The effect of methyl-deficient, amino acid-defined diets on GNMT activity and S-adenosylmethionine levels in rat liver was therefore investigated. When rats were fed a defined amino acid diet containing no choline in which homocysteine was substituted for the methionine of the control diet at an equimolar level, there was a rapid and marked decrease in growth rate in spite of the fact that the rats consumed 85% of the food eaten by control rats fed a nutritionally adequate, defined amino acid diet. The GNMT activity in livers of methyl-deficient rats decreased rapidly, but there was no difference in amount of GNMT protein as measured immunologically. In methyl-deficient rats, the levels of S-adenosylmethionine were maintained but the levels of S-adenosylhomocysteine were rapidly elevated compared to control values. These changes are consistent with the postulated role of GNMT in regulating methyl group metabolism.

Topics: Amino Acids; Animals; Carbon; Choline Deficiency; Diet; Glycine N-Methyltransferase; Liver; Male; Methionine; Methylation; Methyltransferases; Organ Size; Rats; Rats, Inbred F344; S-Adenosylhomocysteine; S-Adenosylmethionine; Weight Gain