Homocysteine and MTHFR weight problems

Homocysteine and MTHFR weight problems

Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Jamie Hope - Founder of Methyl-Life

Medical Reviewer:

Jamie Hope - Founder of Methyl-Life
Kari Asadorian - Bachelor of Science in Nursing

Edited By:

Kari Asadorian - Bachelor of Science in Nursing

Updated On:

March 25, 2025

Table of Contents

    Homocysteine and MTHFR weight problems

    If there’s any one health issue that affects nearly all of us at some point in our lives, it’s weight. Whether you’re male, female, young, middle-aged, or a little older, it’s quite likely that there’s been a stage that you’ve been dissatisfied with how much you weigh, and perhaps tried to shed a few pounds.


    Unfortunately, trying to lose weight can seem like a never-ending battle with calories in, calories out. We attempt extreme diets and sign up for grueling exercise regimes, and we might lose a little - but it all piles back on when we return to our ‘normal’ lifestyles.


    Globally, the prevalence of metabolic syndrome and obesity is increasing, largely due to poor diets and sedentary lifestyles.


    Research shows that impaired glucose tolerance and diabetes mellitus occurs in nearly 20% of adults age 55–65 years, and high blood glucose is globally the third leading cause of premature mortality.


    There are dozens of reasons for our weight issues - and it’s not just about diet.


    One of the biggest obstacles to losing weight is actually your genes. One gene in particular: MTHFR.


    But what is this MTHFR? How do you know if you’re affected? What does it have to do with weight gain? 

    What is MTHFR?

    To understand MTHFR, you first need to understand methylation. Methylation is a metabolic process crucial to every cell and organ in your body.


    It’s like billions of little switches turning on and off every second, controlling everything from your metabolism and your stress response to brain chemistry and detoxification. In short, methylation is life: you would not exist without it. 

    Some of the processes that methylation is required for include:

    • Cell division and renewal for healthy DNA repair
    • Proper immune cell function
    • Synthesizing and clearing adrenaline
    • Healthy liver detoxification
    • Cellular energy production for use in chemical reactions
    • Clearing out excess histamine and hormones (including estrogens)
    • Regulation of gene expression  

    This is where the MTHFR gene comes in

    We all have two well-known SNPs (single nucleotide polymorphisms) on the MTHFR gene (methylenetetrahydrofolate reductase) which we inherit from our parents (and we get one from each of our biological parents).


    The MTHFR genes are important because they provide instructions to your body for making an enzyme called methylenetetrahydrofolate reductase. This enzyme plays many important roles in your body, including the processing of amino acids.


    Methylation is required for the conversion of a form of folate called 5,10-methylenetetrahydrofolate to a form called 5-methyltetrahydrofolate.


    This is the primary active form of folate in your blood, and it’s absolutely necessary for the conversion process of the amino acid homocysteine into methionine.


    The MTHFR gene contains the DNA code to produce the MTHFR enzyme. This enzyme converts the folate you ingest - whether through food or supplements - into the active form of folate 5-Methyltetrahydrofolate. This is the form that your body can use at the cellular level.


    However, a mutation in the MTHFR gene typically results in a malfunctioning or insufficient MTHFR enzyme.


    The MTHFR gene mutations will either affect the enzyme’s ability to function normally or it can completely inactivate it. This will in turn affect how much active folate you have available.


    Those with an MTHFR genetic mutation may experience a range of other symptoms, such as chronic fatigue, histamine intolerance, mental health issues like depression - and the inability to lose weight effectively.


    The nervous system is also known to be affected: up to 70% of people with depression are found to have a genetic variant of the methylenetetrahydrofolate reductase enzyme that compromises their ability to convert dietary folate (most particularly synthetic folic acid) into L-Methylfolate.

    What does MTHFR have to do with your weight?

    Researchers have suggested that MTHFR genetic mutations are linked to weight gain or ineffective weight loss efforts. In fact, many people have reported that their MTHFR diagnosis turns out to be a major contributor to their unexplained weight problems.


    Studies have shown that MTHFR gene polymorphisms are associated with body mass index (BMI)-defined obesity and lean mass.


    BMI and lean mass have actually been linked to the specific chromosome (chromosome 1p36) which is also where the MTHFR gene is located.

    Storing unmetabolized folic acid

    As MTHFR variations cause the body to not be able to process folic acid into the active and usable form of methylfolate, your body will end up storing unmetabolized folic acid. This accumulation has been linked to weight gain or the inability to lose weight.


    A study published in the Nutrients Open access journal examined the effects of folic acid on rats that were fed a high-fat diet. The results showed that excess levels of folic acid caused increased lipid storage and weight gain.

    Homocysteine and MTHFR

    As mentioned above, methylation is required for the conversion of folate into 5-methyltetrahydrofolate, which is also necessary for the conversion process of the amino acid homocysteine into methionine.


    Homocysteine is a naturally-occurring amino acid that’s created when your body breaks down the essential amino acid methionine.


    Methionine is broken down into homocysteine, and then homocysteine is ‘recycled’ back to become methionine again. Methionine is a sulfur-containing amino acid involved in building proteins and producing certain substances in the body, including the antioxidant glutathione and the molecule SAMe.


    There are two pathways through which the methylation cycle can convert homocysteine to methionine:

    1. The cobalamin (vitamin B12) and folate-dependent re-methylation pathway that regenerates methionine. This is ‘“long way” around the cycle via the MTR and MTRR enzymes that require B12 and the forward reaction of the MTHFR (where the C677T and/or A1298C impairs the activity) for function.
    2. The second is a “shortcut” through the middle of the cycle that bypasses MTR, MTRR, and MTHFR via the BHMT enzyme.


    If you think of this portion of the cycle as a clock, the BHMT enzyme can use phosphatidylserine, phosphatidylcholine, and TMG as substrates to go directly from homocysteine at 6:00 to methionine at 12:00 skipping 7:00 through 11:00.


    The use of phosphatidylcholine, phosphatidylserine, and TMG may therefore help to bypass these mutations.


    When this happens properly, there should be very little homocysteine left in your bloodstream.


    However, a double mutation of the MTHFR gene (677TT, 1298CC - also called homozygous or C677T / A1298C - referred to as compound heterozygous) often results in an increase of homocysteine. High levels of homocysteine that cannot be converted into methionine can lead to a multitude of serious conditions due to lack of methylation, lack of enzymes, or an abundance of metabolic intermediates.


    High homocysteine affects the way cells use oxygen, resulting in a build-up of damaging free radicals. Oxidation has already been linked to the onset of numerous diseases of the heart, brain, and immune system. Reactive chemical forms such as free radicals can oxidize low-density lipoproteins, which result in the buildup of harmful oxidized fats and proteins within the arteries and, in turn, arterial plaques. 

    What is considered high homocysteine?

    A normal level of homocysteine in the blood is less than 15 micromoles per liter (mcmol/L) of blood. Higher levels of homocysteine are split into three main categories:


    Ideal: 5-9 mcmol/L

    Moderate: 15-30 mcmol/L

    High: 30-100 mcmol/L

    SEVERE: greater than 100 mcmol/L


    The problem with hyperhomocysteinemia is that it typically doesn’t produce any noticeable symptoms (much like high blood sugar - you can’t feel it, but it’s still causing lots of harm inside the body).


    Most people will only have their homocysteine levels tested if they appear to have symptoms of a vitamin deficiency (and a practitioner is well-versed enough to consider it typically only some naturopaths). Anything outside of an ‘ideal’ homocysteine range should be supplemented for reduction.

    How is high homocysteine linked to MTHFR and weight problems?

    Although homocysteine concentrations naturally increase with age, other causes include low intake or deficiencies of B vitamins, genetic defects, genetic polymorphisms of enzymes involved in homocysteine metabolism (such as MTHFR), impaired renal function, and lifestyle factors such as smoking, high coffee intake, lack of exercise and some drugs (like warfarin and metformin).


    Studies involving rat models have also shown that insulin alters the activity of metabolic enzymes involved in the clearing of homocysteine.


    Previous studies in humans have shown a positive association between serum insulin and homocysteine levels.


    More recently, it’s been found that body weight is also a significant influence in plasma concentrations of total homocysteine levels.


    It appears that there is an inverse association between weight gain and changes in homocysteine levels, even when vitamin status, smoking, coffee consumption and medicines are accounted for.

    Overcoming MTHFR and weight gain

    The first step is to ascertain whether in fact you are affected by a MTHFR gene mutation. Identifying a MTHFR gene defect will provide information about your genetic strengths and weaknesses and allow you to address any issues you may have relating to weight management and other health concerns.


    Speak to your doctor or healthcare practitioner about a comprehensive gene test.


    A functional health practitioner will then be able to interpret your genetic data and guide you in designing a health regime according to your unique genetic make-up.


    If an MTHFR genetic mutation is identified, monitoring homocysteine levels regularly is also crucial.

    Dietary intervention for those with MTHFR gene mutation

    A diet plan is an important part of weight management. This should include:

    • Digestive repair and restoration 


    Repairing the digestive system and optimizing gut flora is the first step in treating methylation deficiency. This includes rebalancing healthy microbes in and providing essential nutrients to repair the gut lining. 


    Consider spore-based probiotics to be an important tool in your arsenal for this important task (I have yet to come across any probiotic product that can do some of the profound things for the gut which spore-based strains can - so do some research here).


    A recent study showed that the C677T MTHFR polymorphism may play a significant role in the body and metabolic factors changes of those with metabolic syndrome. 


    The study involved 44 obese women who followed a low-calorie diet for 12 weeks. The participants in the study all experienced weight loss, along with reduced blood pressure, a decrease in fasting glucose, and reduced triglycerides. 


    As a result, the researchers were able to establish that MTHFR genetic variations analysis can be an important tool in nutritional assessment, particularly when it comes to personalized dietary recommendations based on someone's genetic makeup and nutritional status.

    Methylation support with supplementation

    Homocysteine levels can often be reduced by supplementing with methylfolate, B6, and an active form of vitamin B12. That’s why the next step is to take the right supplements to restore your body’s required levels of the nutrients required for optimal homocysteine metabolism.


    Your first priority is a high daily dose of activated folate such as methylfolate - NOT folic acid. Those with an MTHFR mutation will not be able to process folic acid.


    Instead, the folic acid will accumulate in your tissues and can end up blocking folate receptor sites. It’s also important to avoid processed or fortified foods that contain synthetic folic acid. These include most commercial cereals, grains, bread, and snacks.


    Food sources of folate include dark leafy greens like spinach, kale, bok choy, and Swiss chard. Try to include at least one cup or more of dark greens in your diet every day.


    Specific nutrients to supplement with include:


    • Vitamin B6 (P-5-P)


    The active form of vitamin B6 is known as pyridoxal-5-phosphate (P5P). This nutrient serves as a cofactor for more than 150 enzymes in the body, including those involved in the synthesis of dopamine, serotonin, gamma-aminobutyric acid (GABA), and histamine. Most importantly, vitamin B6 is required for the metabolism of homocysteine and tryptophan.


    Research indicates that around 70-80% of vitamin B6 in your plasma is in the form of P-5-P. The higher your levels of P-5-P, the lower your inflammatory markers - and vice versa. Inflammation increases the uptake of P-5-P into the tissues, which reduces the amount available in your plasma and liver. 


    P-5-P is necessary for the function of two enzymes, cystathione ß-synthase (CBS) and cystathione γ-lyase (CSE) in the breakdown of homocysteine to cysteine. 


    This is involved in reducing homocysteine levels and also in overall detoxification, as up to 50% of the cysteine produced through this pathway is used to create glutathione. 


    This means those with increased homocysteine levels almost certainly require additional P-5-P.


    Be aware that another complicating factor can sneak in here - not everyone tolerates high levels of P-5-P as genetics in another area of the body can play a role in its toxic build up. 


    So if you begin supplementing with it and find you’re getting headaches that stop when you quit taking the P-5-P, you may be one of the ‘special people’ who should consider only taking lower amounts of P-5-P when you supplement (and stop when you are having headaches).


    • DMG and/or TMG


    TMG (trimethylglycine) and DMG (dimethylglycine) are closely related but each serve different purposes and use different pathways. Both TMG and DMG are integral parts of the one-carbon cycle, and they both play critical roles in methylation pathways.


    TMG transfers its methyl group directly to homocysteine, while DMG uses the folate (methylfolate) pathway. When this works properly, both TMG and DMG send methyl groups into the methyl pool to produce SAM-e (S-Adenosyl methionine) from homocysteine.


    If your body can use two pathways, methylation is much more efficient. The fact that each pathway uses different systems to donate to the methyl pool also means that TMG might work better for some and DMG for others.

    Recommended methylfolate and homocysteine-reducing supplements

    Some of the best-selling methylfolate supplements for reducing homocysteine are in the Methyl-Life™ product range, including B-Methylated II, MTHFR Beginner's Bundle, General Health Bundle and Methylfolate 7.5+.


    Each product is designed to support the body’s requirements for energy production, detoxification, balanced homocysteine levels (therefore cardiovascular, nerve and pregnancy health) as well as neurotransmitter synthesis, while also restoring healthy levels of folate.


    Methyl-Life’s™ Methylfolate 15 best-selling product contains a high dose (15 mg) of internationally-patented Magnafolate® PRO [(6S)-5-methyltetrahydrofolate acid, Calcium salt, Type C Crystalline molecule (L-Methylfolate)]. This best-selling product is formulated especially for people with a heightened need for bioavailable folate due to genetic (MTHFR) defects, dietary deficiencies or drug-induced need (i.e. taking warfarin, coumadin, metformin, etc.).


    This product is particularly targeted at raising serotonin levels which can aid in depression and mood-related challenges.


    This unique and internationally-patented L-5-Methylfolate ingredient is crystalline calcium salt-based for superior stability and absorption. A recent study has revealed that this proprietary form of methylfolate is three times purer than any other L-Methylfolate competing in the market today. Methylfolate is often known or labeled as L-MTHF, L-5-Methylfolate, L-5-MTHF, and (6S)-5-Methylfolate.


    As with taking any supplement, it is strongly advised that you consult with a qualified healthcare practitioner before beginning any treatment.

    Common signs that your weight gain is linked to a MTHFR genetic mutation include:

    • Icon Fat accumulation around your abdominal area:
      If you have a higher BMI (body mass index) and a larger hip to waist ratio, you’re likely to also have more fat around your waistline
    • Icon Fatty liver:
      Many people who test positive for MTHFR genetic mutations have a fatty liver, which also predisposes them to further weight gain.
      Dietary fats and cholesterol are processed by your liver, which packages them into low-density lipo-proteins that can be delivered through your bloodstream to all the tissues that require them.
      However, the MTHFR gene mutation prevents these fats from being metabolized properly. The lack of the MTHFR enzyme means the liver can’t keep up with the processing of the fats so they end up being trapped in the liver and accumulating. This leads to fatty liver, a serious condition that can be fatal. Other signs include high blood pressure, a lack of results despite dieting and exercise, a family history of weight problems, and sluggish metabolism. MTHFR mutations may cause lowered ATP production, which in turn can lead to chronic fatigue syndrome.

    Product Recommendations

    MTHFR Actives - L-Methylfolate + Hydroxy B12 Sublingual - Methyl-Life® Supplements

    MTHFR Actives - L-Methylfolate + Hydroxy B12 Sublingual
    (2)

    $58.00

    • Easy Starting Dosage Levels for MTHFR Newbies
    • Bioidentical L-Methylfolate for Immediate Absorption & Use
    • Bioactive Vitamin B12 Sublingual, Hydroxy Form
    • 3rd-Party Tested for Purity & Safety, Vegan & Non-GMO

    References

    1. --

    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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    MTHFR Actives - L-Methylfolate + Hydroxy B12 Sublingual - Methyl-Life® Supplements

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    2 MAIN ACTIVE NUTRIENTS DESIGNED TO SUPPORT MTHFR