Mouse Betaine-Homocysteine S-Methyltransferase Deficiency Reduces Body Fat via Increasing Energy Expenditure and Impairing Lipid Synthesis and Enhancing Glucose Oxidation in White Adipose Tissue

Teng, Ya Wen; Ellis, Jessica M.; Coleman, Rosalind A.; Zeisel, Steven H.

doi:10.1074/jbc.m111.303255

Cited by 46 publications

(53 citation statements)

References 51 publications

(65 reference statements)

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“…This is to some extent in line with our data suggesting increased Hcy remethylation and improved VLDL secretion due to increased BHMT expression in obese animals [51]. Furthermore, the implication of BHMT in lipid and PL metabolism of the liver and adipose tissue was recently shown by Teng et al [52], [53]. However, the identified downregulation of CBS in our study contradicts a disturbed insulin signaling as described by others [47], [48], [50] indicating that other mechanisms may have caused the observed decrease of CBS expression.…”

Section: Discussionsupporting

confidence: 91%

Hepatic Methionine Homeostasis Is Conserved in C57BL/6N Mice on High-Fat Diet Despite Major Changes in Hepatic One-Carbon Metabolism

et al. 2013

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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 β-synthase (CBS) and an increased betaine-homocysteine methyltransferase (BHMT) expression were observed. Experiments in vitro, using hepatoma cells stimulated with peroxisome proliferator activated receptor alpha (PPARα) agonist WY14,643, revealed a significantly reduced Cbs mRNA expression. Moreover, metabolite measurements identified decreased hepatic cystathionine and L-α-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 de novo 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 PPARα-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.

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Section: Discussionsupporting

confidence: 91%

Hepatic Methionine Homeostasis Is Conserved in C57BL/6N Mice on High-Fat Diet Despite Major Changes in Hepatic One-Carbon Metabolism

et al. 2013

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“…Surprisingly, in our study, pups from the MD supplemented dams combine lower plasma leptin levels at weaning and a reduced diet-induced weight gain at adulthood. Interestingly, the phenotype we observed here on the male offspring is somehow, but to a less extent, similar to the phenotype of the Bhmt (Betaine-homocysteine methyl transferase) knock-out mice model which is characterised by an increased energy expenditure, reduced weight gain and reduced adiposity despite a normal food intake, associated with an hyperhomocysteinemia [53]. In that model, the homocysteine pathway is impaired in liver, where the Bhmt gene is normally expressed, but the whole energy metabolism is disrupted, which shows evidence of the implication of the one-carbon metabolic pathway in the control of energy homeostasis.…”

Section: Discussionmentioning

confidence: 53%

Excess of Methyl Donor in the Perinatal Period Reduces Postnatal Leptin Secretion in Rat and Interacts with the Effect of Protein Content in Diet

et al. 2013

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Methionine, folic acid, betaine and choline interact in the one-carbon metabolism which provides methyl groups for methylation reactions. An optimal intake of these nutrients during pregnancy is required for successful completion of fetal development and evidence is growing that they could be involved in metabolic long-term programming. However, the biological pathways involved in the action of these nutrients are still poorly known. This study investigated the interaction between methyl donors and protein content in maternal diet during the preconceptual, pregnancy and lactation periods and the consequences on the rat offspring in the short and long term. Methyl donor supplementation reduced leptin secretion in offspring, whereas insulin levels were mostly affected by protein restriction. The joint effect of protein restriction and methyl donor excess strongly impaired postnatal growth in both gender and long term weight gain in male offspring only, without affecting food intake. In addition, rats born from protein restricted and methyl donor supplemented dams gained less weight when fed a hypercaloric diet. Methylation of the leptin gene promoter in adipose tissue was increased in methyl donor supplemented groups but not affected by protein restriction only. These results suggest that maternal methyl donor supplementation may influence energy homeostasis in a gender-dependent manner, without affecting food intake. Moreover, we showed that macronutrients and micronutrients in maternal diet interact to influence the programming of the offspring.

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“…Protein levels of Bhmt were also correlated with the trait (Figure 3H). Previous work in Bhmt knock-out mice demonstrated that Bhmt plays a role in energy metabolism, specifically in lipid synthesis, and insulin sensitivity (Teng et al, 2012). Additional examples for associations with plasma cholesterol and total bone mineral density are describe in the Supplemental Information and Figure S6.…”

Section: Resultsmentioning

confidence: 99%

Epigenome-Wide Association of Liver Methylation Patterns and Complex Metabolic Traits in Mice

et al. 2015

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SUMMARY Heritable epigenetic factors can contribute to complex disease etiology. Here we examine the contribution of DNA methylation to complex traits that are precursors to heart disease, diabetes and osteoporosis. We profiled DNA methylation in the liver using bisulfite sequencing in 90 mouse inbred strains, genome-wide expression levels, proteomics, metabolomics and sixty-eight clinical traits, and performed epigenome-wide association studies (EWAS). We found associations with numerous clinical traits including bone density, insulin resistance, expression, protein and metabolite levels. A large proportion of associations were unique to EWAS and were not identified using GWAS. Methylation levels were regulated by genetics largely in cis, but we also found evidence of trans regulation, and we demonstrate that genetic variation in the methionine synthase reductase gene Mtrr affects methylation of hundreds of CpGs throughout the genome. Our results indicate that natural variation in methylation levels contributes to the etiology of complex clinical traits.

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Mouse Betaine-Homocysteine S-Methyltransferase Deficiency Reduces Body Fat via Increasing Energy Expenditure and Impairing Lipid Synthesis and Enhancing Glucose Oxidation in White Adipose Tissue

Cited by 46 publications

References 51 publications

Hepatic Methionine Homeostasis Is Conserved in C57BL/6N Mice on High-Fat Diet Despite Major Changes in Hepatic One-Carbon Metabolism

Hepatic Methionine Homeostasis Is Conserved in C57BL/6N Mice on High-Fat Diet Despite Major Changes in Hepatic One-Carbon Metabolism

Excess of Methyl Donor in the Perinatal Period Reduces Postnatal Leptin Secretion in Rat and Interacts with the Effect of Protein Content in Diet

Epigenome-Wide Association of Liver Methylation Patterns and Complex Metabolic Traits in Mice

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