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MTHFR and Weight Issues: Is There a Link?

Article at a Glance
  • MTHFR mutations have been linked with an increased risk of obesity and weight gain. Studies have shown that people with MTHFR mutations are more likely to have higher levels of homocysteine and suggest that MTHFR mutations may contribute to obesity by affecting the metabolism of folate.
  • While some research does point to a higher likelihood of weight gain with MTHFR variants, the SNPs are common and more research is needed.
Genes Mentioned

Despite best efforts to maintain a healthy lifestyle, weight management can be a challenging task for many of us. While lifestyle choices do play a significant role in weight control, genetic factors also play a role. Genetic variants can influence the metabolism of food, the release of hormones related to appetite, and the way fat is stored in the body. Understanding the role of genetics in weight management is crucial to creating a personalized approach that considers the individual’s unique genetic makeup.

MTHFR genes regulate folate metabolism

MTHFR genes are important in folate metabolism. Folate is a nutrient that is found in leafy green vegetables, legumes, and nuts. The body needs to maintain adequate levels of folate, as it is involved in the production of red blood cells and the metabolism of DNA.

It is also important for the metabolism of homocysteine. The MTHFR gene provides instructions for making an enzyme called methylenetetrahydrofolate reductase. This enzyme is involved in the conversion of folate to its active form, methylfolate, which your body recognizes and absorbs.

See also: Does MTHFR affect the metabolism of all B vitamins?

Common MTHFR variants

Variations in the MTHFR gene have been linked with folate metabolism and obesity. But what is the link?

First, let’s look at the most studied MTHFR variation:

  • 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 has been estimated that 30-40% of the American population may have the C677T mutation and that approximately 5-14% of the U.S. population is homozygous for 677TT ( ‘double mutation’).1

Individuals who are homozygous 677TT often have significantly lower folate levels than those who are heterozygous C677T. Interestingly, both homozygous 677TT and compound heterozygous (C677T +A1298C) mutations are linked to higher levels of homocysteine.

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

MTHFR mutations have been linked with an increased risk of obesity and weight gain. Studies have shown that people with MTHFR mutations are more likely to have higher levels of homocysteine and suggest that MTHFR mutations may contribute to obesity by affecting the metabolism of folate.

What is the link between MTHFR and weight gain?

The link between the MTHFR gene and weight gain was first suggested when it was observed that people who were obese were more likely to have a specific variation of the MTHFR gene. Interest in this topic gathered momentum but studies reached different conclusions.

A recent study has suggested the C677T and TT genotypes may increase the risk of obesity by up to 20% although the differences in BMI between genotypes were very small. The authors concluded that their MTHFR genotype–obesity findings shed light on the fact that folate levels may cause higher BMIs and therefore, obesity.1

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

A recent meta-analysis that looked at 8,622 cases and 29,695 controls found that MTHFR C677T is associated with an increased risk of obesity and increased homocysteine levels in the blood and agreed with the consensus that MTHFR variations could cause weight gain. 2

Although the link is now generally accepted, the question remains as to how this genetic variation causes weight gain.

How do MTHFR mutations contribute to weight gain or weight loss?

  1.       Fat accumulation

As discussed previously, people with MTHFR mutations cannot properly metabolize folic acid, which can lead to the accumulation of folic acid in the blood. In a study published in Nutrients, scientists examined the effects of folic acid on rats that were fed a high-fat diet.  Results concluded that excess levels of folic acid caused increased lipid storage and weight gain, i.e. higher fat accumulation. 3

  1.       Appetite and mood

Research has found that MTHFR mutations can play a role in various mood disorders as folate is a requirement for the synthesis of neurotransmitters such as serotonin and dopamine. Serotonin is the body’s natural appetite suppressant, so a lack of serotonin (caused by a lack of folate) can result in increased cravings and appetite. 4, 5

  1.       Metabolism

Vitamin B9 (A.K.A. folate) and other B vitamins are also cofactors that play a central role in energy metabolism. Vitamin B5 is involved in the synthesis of fats, cholesterol, and neurotransmitters, and vitamin B6 functions to release glucose from glycogen. Vitamin B1 is crucial for glucose metabolism as well as ATP energy synthesis, whereas vitamins B2, B3, and B7 are important in carbohydrate, lipid, and protein metabolism.  B12 is necessary for the breakdown of fat and protein. Studies suggest that deficiencies in these B vitamins affect your metabolism which can therefore lead to weight gain.6

  1.       Hormones

Research has found that MTHFR mutations are linked to estrogen dominance with high estrogen concentration cycles. This is because the body needs to be able to methylate estrogen to clear it/break it down efficiently. Without this methylation due to MTHFR mutations, you may experience hormone weight. Additionally, folate is crucial to prevent pregnancy complications and miscarriages. High homocysteine levels caused by low B vitamin intake and poor methylation can also impact insulin levels, which can contribute to insulin resistance and PCOS (polycystic ovarian syndrome).7

Weight Loss Treatments with MTHFR

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

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

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 S-adenosyl-L-methionine (SAM-e) is also a good option, as low levels of SAMe are associated with MTHFR mutations. One study found that supplementing obese rats with SAMe reduced insulin resistance and weight gain.8


Individuals with a genetic predisposition to weight gain may need to adopt a more targeted approach, focusing on specific dietary interventions and exercise strategies that support their body’s natural tendencies and folate requirements. While genes do play a significant role in weight management, lifestyle choices remain essential in achieving sustainable weight loss and overall health. By understanding the role of genetics in weight management, you can develop a personalized approach that supports your unique needs and genetic makeup.

Dr. Gina Leisching

Dr. Gina Leisching holds a BSc in Functional Human Biology, and Honours degree in Physiological Sciences, as well as a doctorate in human physiology from Stellenbosch University, South Africa. At Gene Food, Dr. Gina uses her expertise to provide evidence-pieces that readers may find helpful and informative.

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