How Does MTHFR Affect Weight Gain | Methyl-Life

How Does MTHFR Affect Weight Gain | Methyl-Life

Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Dr. Conor Sheehy - PharmD, BCPS

Medical Reviewer:

Dr. Conor Sheehy - PharmD, BCPS
Kari Asadorian - Bachelor of Science in Nursing

Edited By:

Kari Asadorian - Bachelor of Science in Nursing

Updated On:

March 20, 2025

Table of Contents

    How Does MTHFR Affect Weight Gain

    Many of us have, at some stage in our lives, tried to lose weight. Not all of us are successful. For some, it’s a matter of diet and exercise; others can blame stress or medical conditions. But some people may never figure out why they can’t shed those pounds, even when they’re eating well and working out.


    For those people, genes could be to blame. Specifically, the MTHFR gene. But how can an MTHFR mutation affect weight?


    Recent research has suggested that an MTHFR mutation may affect metabolism to the point where weight loss is much more difficult.


    MTHFR genetic mutations have been linked to both weight gain or ineffective weight loss efforts. This may be due to nutritional deficiencies that result from poor methylation in the body. Methylation is required for numerous metabolic processes and has been implicated in weight gain and obesity1.


    Fortunately, many people have found that weight loss becomes easier after supporting their bodies with the nutrients their MTHFR mutation has otherwise depleted.


    This article will outline the role of the MTHFR gene in weight maintenance and how a mutated gene may lead to weight gain. We’ll also explain how estrogen affects body weight and how estrogen clearance may be affected by a MTHFR polymorphism.


    We can then look at how those with an MTHFR polymorphism can manage a healthy weight and support weight loss through diet and supplements.

    The MTHFR Gene's Role in Weight Maintenance

    The MTHFR gene instructs your body on how to make an enzyme called methylenetetrahydrofolate reductase. This enzyme plays many essential roles in your body, including converting folic acid into bioactive folate.

     

    Some polymorphisms of MTHFR can result in a reduction of the MTHFR enzyme activity2 as well as the DNA methylation process. This can significantly influence gene expression3, which in turn can influence hormone production and metabolism.

     

    DNA methylation and homocysteine metabolism also depend on folate status. Metabolic changes caused by MTHFR insufficiency have been found to increase the risk of chronic diseases, particularly cardiovascular disease. As a result, researchers have investigated the link between an MTHFR mutation and body composition and metabolism4 with regards to how folate levels may increase the risk of cardiovascular disease in obese people and even people with normal weight, but that have the metabolic profile of an obese person (De Lorenzo Syndrome).

    How the MTHFR Gene Mutation Can Affect Weight

    A mutation in the MTHFR gene can mean that the MTHFR enzyme doesn’t function as effectively as it should. The degree of inactivity varies between different MTHFR variations.

     

    The possible genotypes of the MTHFR gene include:

    ● MTHFR 677 CC (one copy of C from each parent)

    ● MTHFR 677 CT (one copy of C from one parent, one copy of T from the other parent)

    ● MTHFR 677 TT (one copy of T from each parent)


    It’s estimated that 30-40% of the American population may have the C677T mutation, and approximately 5-14% of the U.S. population is homozygous for 677TT5 (also known as a ‘double mutation’).

     

    Those who are homozygous 677TT often have significantly lower folate levels6 than heterozygous C677T. Both homozygous 677TT and compound heterozygous (C677T +A1298C) mutations are linked to higher levels of homocysteine7.

     

    Homozygous MTHFR leads to significantly reduced enzyme function8, while the homozygous MTHFR A1298C variant results in 60% of normal enzyme function9. Double heterozygous (one abnormal C677T gene and one abnormal A1298C gene) is also associated with reduced enzyme function.

     

    The link between folate metabolism and obesity has been highlighted, suggesting that folate deficiency may lead to weight gain and adiposity. A 2020 study10 showed that overweight and obese patients had 8.5% lower folate concentrations than controls. Lower folate levels also suggested a higher body fat percentage and waist circumference.

     

    Previous studies have suggested the C677T and TT genotypes may increase the prevalence of obesity by up to 20%11,although the differences in BMI between genotypes appeared to be very small. The authors concluded that their MTHFR genotype–obesity findings suggested that folate levels may be causally related to greater BMI and obesity.

     

    These authors also hypothesized that the reduced methylation caused by lower levels of folate12 might influence body mass and obesity through epigenetic control of certain genes. Epigenetic changes—including methylation—have been linked to adult obesity13 following the observation that several genes have been shown to exhibit changes in expression that correlated closely with BMI or waist to hip ratio.

     

    Another study found that MTHFR 677 TT+CT both resulted in a significantly greater risk for obesity compared with the CC genotype14. The MTHFR 677T allele was significantly associated with elevated homocysteine, with the mean homocysteine level in obese patients significantly higher than in those without obesity.

    Estrogen and Weight Maintenance

    Estrogen is one of the most important female reproductive hormones. It gives women female sex characteristics, regulates menstruation, and tells the body to store excess fat reserves in the hips and thighs. It is also involved with cholesterol production in the liver and many other processes.


    Estrogen promotes the storage of fat in the hips and thighs during the reproductive years. After menopause, a decrease in estrogen levels often leads to a loss of subcutaneous fat and an increase in visceral fat (the fat around the abdominal organs). This type of fat produces hormones that can increase insulin resistance15, reducing the body’s ability to use insulin effectively. This can, in turn, lead to high blood sugar and weight gain.

    The Impact MTHFR has on Estrogen Production

    Methylation is involved in many major biochemical processes, including gene expression, DNA and RNA synthesis, detoxification, hormone production, mitochondrial metabolism, and phospholipid synthesis. Methylation is essential for the inactivation and detoxification16 of a number of hormones, particularly estrogen.


    Phase II detoxification depends upon proper methylation17, sulfation, and glucuronidation to make the estrogens water-soluble so that they can be excreted in urine or feces.


    Phase II methylation of estrogen is also governed by the COMT enzyme18 (catechol oxygen methyltransferase). This methyltransferase must be made with a methyl group supplied by SAMe (the body’s methyl donor). To make SAMe, the body requires methylfolate, vitamin B12, B6, methionine, and zinc19, along with optimal levels of homocysteine (below 10 to 12µmol/L).

    How the MTHFR Gene Mutation and its Variants Impact Estrogen Production

    Problems with methylation can have a significant impact on hormone-related issues, particularly estrogen clearance.


    Depending on the variant, the MTHFR polymorphism can result in reduced levels of folate, B12, or B620. This same situation can result in higher levels of homocysteine due to the lack of methionine. As a result, the body’s ability to create the COMT enzyme—which is required for phase II methylation of estrogen—may be compromised21.


    SAM is also required to inactivate estrogen through methylation. Methyl groups for DNA methylation originate from SAMe, which is synthesized in the methionine cycle22 by methionine, folate, choline, betaine, and the B2, B6, and B12 vitamins. Each of these nutrients enters the methionine cycle at different sites in the making of SAMe.


    However, deficiencies in these nutrients may result in changes in the SAMe pool, which can also influence DNMT activity(the measure of DNA methyltransferase activity) and DNA methylation. Methylation depends on these nutritional factors23, which suggests supplementation may help correct metabolic processes.

    Weight Loss Treatments with MTHFR

    Discovering you have an MTHFR polymorphism can provide a pathway to rebalancing your genetic strengths and weaknesses, particularly in terms of nutritional deficiencies. This can help in losing weight.


    Weight loss through diet and lifestyle changes has been associated with specific methylation signatures24. Understanding these methylation differences in specific genes may help in successful weight-loss treatments, especially for patients struggling with weight gain and unsuccessful weight loss.


    As with any weight loss program, someone with MTHFR should begin with restoring the integrity of the digestive system and gut microflora. This can help to reduce inflammation, improve nutritional uptake, and help optimize methylation25.


    Supplementing your diet with an active form of folate such as methylfolate can help to restore folate levels, which can then support methylation involved in estrogen clearance and the conversion of homocysteine to methionine.


    Boosting SAM-e is also recommended, as low levels of SAMe are associated with an MTHFR mutation26. One study found that supplementing obese rats with SAMe reduced insulin resistance and weight gain27.

    How to Manage Weight Gain with MTHFR

    Research suggests that modulating DNA methylation through diet28 and environment may be a means of preventing and treating certain metabolic diseases.


    Lower folate intake and serum levels have been linked to higher body weight29 and body fat percentage in people aged 20–40, and those with an MTHFR mutation often have significantly reduced folate levels, but a causal link has not been verified at this time.


    Folate is also required for the synthesis of SAMe, which is involved in methylation and estrogen clearance.


    This suggests that supplementing with L-methylfolate should be one of the first steps in restoring nutritional imbalances caused by an MTHFR mutation. L-methylfolate is the primary active form of folate in your body required for healthy methylation.


    Some of the best methylfolate supplements for those with MTHFR mutations can be found in the Methyl-Life® product range. These include B-Methylated II, Methylated Multivitamin, Methylfolate 7.5+ or Methylfolate 15+. The Methyl-Life® range has been created by a team of natural health experts and contains the purest, most stable, and most potent of four of the world’s industry-leading patented L-methylfolate products. It is also suitable for vegans and those with cardiovascular risks.

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    References

    1. Andrea Maugeri; "The Effects of Dietary Interventions on DNA Methylation: Implications for Obesity Management"; International Journal of Molecular Sciences; 2020 Nov

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698434/

    2. Lin Wan, Yuhong Li, Zhengrong Zhang, Zuoli Sun, Yi He, Rena Li; "Methylenetetrahydrofolate reductase and psychiatric diseases"; Open Access; 2018 Nov

      https://www.nature.com/articles/s41398-018-0276-6

    3. Phillips, T; "The role of methylation in gene expression."; Nature Education 1(1):116; 2008

      https://www.nature.com/scitable/topicpage/the-role-of-methylation-in-gene-expression-1070/

    4. L. DI RENZO, M. BIGIONI, F.G. BOTTINI, V. DEL GOBBO, M.G. PREMROV, R. CIANCI, A. DE LORENZO; "Normal Weight Obese syndrome: role of single nucleotide polymorphism of IL-15Rα and MTHFR 677C→T genes in the relationship between body composition and resting metabolic rate"; European Review for Medical and Pharmacological Sciences; 2006

      https://www.europeanreview.org/wp/wp-content/uploads/397.pdf

    5. TESTING.COM; "MTHFR Mutation"; MTHFR DNA Testing; 2021 Nov

      https://labtestsonline.org/tests/mthfr-mutation

    6. The American Journal of Clinical Nutrition

      https://academic.oup.com/ajcn/article/77/3/687/4689724

    7. Lakhdar Ghazouani, Nesrine Abboud, Nabil Mtiraoui, Walid Zammiti, Faouzi Addad, Haitham Amin, Wassim Y Almawi, Touhami Mahjoub; "Homocysteine and methylenetetrahydrofolate reductase C677T and A1298C polymorphisms in Tunisian patients with severe coronary artery disease"; Journal of thrombosis and thrombolysis; 2009 Feb

      https://pubmed.ncbi.nlm.nih.gov/18204887/

    8. Stephan Moll, Elizabeth A. Varga; "Homocysteine and MTHFR Mutations"; Circulation; 2015 Jul

      https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.114.013311

    9. Stephan Moll, Elizabeth A. Varga; "Homocysteine and MTHFR Mutations"; Circulation; 2015 Jul

      https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.114.013311

    10. Monika A. Mlodzik-Czyzewska, Anna M. Malinowska, Agata Chmurzynska; "Low folate intake and serum levels are associated with higher body mass index and abdominal fat accumulation: a case control study"; Nutrition Journal; 2020 Jun

      https://nutritionj.biomedcentral.com/articles/10.1186/s12937-020-00572-6

    11. Sarah J Lewis, Debbie A Lawlor, Børge G Nordestgaard, Anne Tybjærg-Hansen, Shah Ebrahim, Jeppe Zacho, Andy Ness, Sam Leary, George Davey Smith; "The methylenetetrahydrofolate reductase C677T genotype and the risk of obesity in three large population-based cohorts."; European Journal of Endocrinology; 2008 Jul

      https://eje.bioscientifica.com/view/journals/eje/159/1/35.xml#bib8

    12. Simonetta Friso, Sang-Woon Choi, Domenico Girelli, Joel B Mason, Gregory G Dolnikowski, Pamela J Bagley, Oliviero Olivieri, Paul F Jacques, Irwin H Rosenberg, Roberto Corrocher, Jacob Selhub; "A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status"; Proceedings of the National Academy of Sciences of the United States of America; 2002 Apr

      https://pubmed.ncbi.nlm.nih.gov/11929966/

    13. Stephane Gesta, Matthias Blüher, Yuji Yamamoto, Andrew W. Norris, Janin Berndt, Susan Kralisch, Jeremie Boucher, Choy Lewis, C. Ronald Kahn; "Evidence for a role of developmental genes in the origin of obesity and body fat distribution"; Biological Sciences; 2006 Apr

      https://www.pnas.org/content/103/17/6676.short

    14. Liwan Fu, Ya-nan Li, Dongmei Luo, Shufang Deng, Yue-Qing Hu; "Plausible relationship between homocysteine and obesity risk via MTHFR gene: a meta-analysis of 38,317 individuals implementing Mendelian randomization"; Diabetes, metabolic syndrome and obesity: targets and therapy; 2019 Jul

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662519/

    15. Olga T Hardy, Michael P Czech, Silvia Corvera; "What causes the insulin resistance underlying obesity?"; Current opinion in endocrinology, diabetes, and obesity; 2012 Apr

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038351/

    16. Rebecca Raftogianis, Cyrus Creveling, Richard Weinshilboum, Judith Weisz; "Chapter 6: Estrogen Metabolism by Conjugation"; JNCI Monographs, Vol. 2000, Iss. 27; 2000 Jul

      https://academic.oup.com/jncimono/article/2000/27/113/934445

    17. Science Direct; "Estrogen Metabolism"; Medicine and Dentistry; 2018

      https://www.sciencedirect.com/topics/medicine-and-dentistry/estrogen-metabolism

    18. Rebecca Raftogianis, Cyrus Creveling, Richard Weinshilboum, Judith Weisz; "Chapter 6: Estrogen Metabolism by Conjugation"; JNCI Monographs, Vol. 2000, Iss. 27; 2000 Jul

      https://academic.oup.com/jncimono/article/2000/27/113/934445

    19. Science Direct; "Methionine Synthase"; Agricultural and Biological Sciences; 2017

      https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/methionine-synthase

    20. Juan Ni, Ling Zhang, Tao Zhou, Wei-Jiang Xu, Jing-Lun Xue, Neng Cao, Xu Wang; "Association between the MTHFR C677T polymorphism, blood folate and vitamin B12 deficiency, and elevated serum total homocysteine in healthy individuals in Yunnan Province, China"; Journal of the Chinese Medical Association Vol. 80, Iss. 3, Pg. 147-153; 2017 Mar

      https://www.sciencedirect.com/science/article/pii/S1726490116302179

    21. Micaela Almeida, Mafalda Soares, José Fonseca-Moutinho, Ana Cristina Ramalhinho, Luiza Breitenfeld; "Influence of Estrogenic Metabolic Pathway Genes Polymorphisms on Postmenopausal Breast Cancer Risk"; Pharmaceuticals (Basel); 2021 Jan

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910923/

    22. Science Direct; "S-Adenosyl Methionine"; Biochemistry, Genetics and Molecular Biology; 2011

      https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/s-adenosyl-methionine

    23. Luca Parrillo, Rosa Spinelli, Antonella Nicolò, Michele Longo, Paola Mirra, Gregory Alexander Raciti, Claudia Miele, Francesco Beguinot; "Nutritional Factors, DNA Methylation, and Risk of Type 2 Diabetes and Obesity: Perspectives and Challenges"; International Journal of Molecular Science; 2019 Jun

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627657/

    24. Maria Keller, Anat Yaskolka Meir, Stephan H. Bernhart, Yftach Gepner, Ilan Shelef, Dan Schwarzfuchs, Gal Tsaban, Hila Zelicha, Lydia Hopp, Luise Müller, Kerstin Rohde, Yvonne Böttcher, Peter F. Stadler, Michael Stumvoll, Matthias Blüher, Peter Kovacs, Iris Shai; "DNA methylation signature in blood mirrors successful weight-loss during lifestyle interventions: the CENTRAL trial"; Open Access; 2020 Nov

      https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-020-00794-7

    25. Manvi Sharma, Yuanyuan Li, Matthew L Stoll, Trygve O Tollefsbol; "The Epigenetic Connection Between the Gut Microbiome in Obesity and Diabetes"; Frontiers in Genetics; 2020 Jan

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974692/

    26. Science Direct; "Methylenetetrahydrofolate Reductase"; Medicine and Dentistry; 2016

      https://www.sciencedirect.com/topics/medicine-and-dentistry/methylenetetrahydrofolate-reductase

    27. Cheng Ji Jin, Hyeong Kyu Park, Young Min Cho, Youngmi Kim Pak, Ki-Up Lee, Min Seon Kim, Simonetta Friso, Sang-Woon Choi, Kyong Soo Park, Hong Kyu Lee; "S-adenosyl-L-methionine increases skeletal muscle mitochondrial DNA density and whole body insulin sensitivity in OLETF rats"; The Journal of nutrition; 2007 Feb

      https://pubmed.ncbi.nlm.nih.gov/17237308/

    28. Karyn M Frick, Zaorui Zhao, Lu Fan; "The epigenetics of estrogen"; Epigenetics; 2011 Jun

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360196/

    29. Monika A. Mlodzik-Czyzewska, Anna M. Malinowska, Agata Chmurzynska; "Low folate intake and serum levels are associated with higher body mass index and abdominal fat accumulation: a case control study"; Open Access; 2020 Jun

      https://nutritionj.biomedcentral.com/articles/10.1186/s12937-020-00572-6

    30. Banner Image Designed by FreePik

      https://www.freepik.com/

    Katie Stone - Naturopath

    About the Author

    Katie is a qualified Naturopath (BNatMed) and freelance writer from New Zealand. She specializes in all things health and wellness, particularly dietary supplements and nutrition. Katie is also a dedicated runner and has completed more half-marathons than she can count!

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