The genetic obesity risk and why methylation matters

Obesity is complex and multifactorial. And unlikely to be driven by just one factor for most.   So understanding your methylation efficiency combined with your genetic obesity risk is important. 

You see, research shows that your genetics lay the foundation, but the interplay between methylation, inflammation, glucose & insulin regulation, detoxification, gut bacteria and hormones contribute to one’s difficulty in managing a healthy weight.  And unfortunately, healthcare often oversimplifies the problem by focusing on an ineffective calories in calories out model.  Often through a lens of weight bias with dismissive practitioners.  

Now, there has been a delayed scientific understanding that your genes are not your destiny.  In fact, until recently the role of genetics, epigenetics and the gut microbiome were not fully understood.  And in the last couple of years I’ve taken a few genetic courses and have come to realize that many may have been misguided in their weight management approaches.   

Although I still believe in using surgery & medication as a tool.  I know first hand that obesity is a multifaceted disease, as someone who has been in the weight loss industry for >25 years.  As a matter of fact, there are over 25 genes that influence weight loss, gain & maintenance and certain gene variations that can make it harder to lose weight or maintain a healthy weight.  This is why a one-size-fits-all approach doesn’t work. 

For example, your genes can affect how much and how frequently you eat, as well as how you experience hunger and fullness.  However, having obesity genes does not necessarily mean you’ll develop obesity.  In fact, some genes are protective and can improve your ability to fight against disease.  Therefore, understanding a gene’s impact is crucial for effective weight management. 

In fact, genetic impact is sorted out as 

• Protective
• No impact
• Low impact
• Medium impact
• High impact
• Very high impact

For example, what if out of the 25 weight and appetite regulation genes, 19 were either protective, no impact or low impact?  This could mean there are only 6 genes that are influencing your ability to regulate your weight and appetite.  Six. 

Now, let’s go broader.  Yes, these 6 genes influence how well you can manage a healthy weight.  And would interact with other higher impact genes.  But what if your genetic roadmap showed that inflammation, glucose & insulin regulation had the highest impact?

So if you had these 6 genes that influence weight & appetite regulation and were seeking weight loss.  Focusing on lowering your inflammation, blood sugar and insulin would be more impactful than the standard protocol of counting calories & following a restrictive diet while exercising more. 

So as you can see, those who are overweight or obese may or may not have impactful weight & appetite regulating genes causing their issue.  This is why knowing your genetic roadmap can be your guide to turn off disease & obesity causing genes.

So over the next several weeks we’re going to break down the genetic pathways that are influential in contributing to weight & appetite regulation that lead to obesity.  And this week we’ll uncover the genetic obesity risk and why methylation matters. 

As a matter of fact, recent studies have emphasized the role of epigenetic modifications in weight control. The epigenetic process involves changes in gene expression without altering the DNA sequence. And one of the most studied epigenetic modifications is DNA methylation.  

The Methylation Pathway

Methylation is a biochemical process that ensures that all cells within your body function optimally. Methylation performs many functions, including repairing genetic material, making energy, dealing with stress, handling inflammation, detoxifying cells, and regulating brain chemistry. It is also essential for turning genes on or off, which is critical for maintaining proper cell function.

The Role of Methylation in Obesity: 

Methylation is crucial to the regulation of energy homeostasis and body weight. Several studies have reported differences in methylation patterns between lean and obese individuals, suggesting a link between epigenetic modifications and weight regulation. 

In a study, researchers found that obese individuals had significantly higher levels of DNA methylation of the leptin gene than lean individuals. Adipose tissue produces leptin, a hormone that regulates appetite and energy expenditure. Low leptin expression and increased appetite may be associated with high levels of methylation of the leptin gene. 

Another study found that DNA methylation levels of the insulin receptor substrate 1 (IRS1) gene was significantly lower in obese individuals compared to lean individuals. In addition to its role in insulin signaling, IRS1 is also an important regulator of glucose metabolism. It has been shown that lower methylation levels of the IRS1 gene are associated with increased expression and insulin sensitivity, which may protect against obesity and type 2 diabetes. These studies suggest that DNA methylation is crucial to regulating genes involved in energy homeostasis and body weight regulation. An altered level of DNA methylation may contribute to obesity by altering gene expression. 

Genes Involved in DNA Methylation and Obesity: 

Several genes have been linked to the regulation of DNA methylation and the development of obesity. One of the most studied genes is the peroxisome proliferator-activated receptor gamma (PPARγ) gene. This gene plays an important role in adipocyte differentiation and lipid metabolism.

A study found that DNA methylation levels of the PPARγ gene were significantly higher in adipose tissue from obese people than in lean individuals. Higher methylation levels were associate with lower PPARγ expression and impaired lipid metabolism, resulting in obesity and metabolic disorders. The melanocortin four receptor (MC4R) gene has also been link to DNA methylation and obesity. It plays a critical role in appetite control and energy homeostasis. 

A study found that DNA methylation levels of the MC4R gene were significantly lower in obese individuals compared to lean individuals. A decreased methylation level was associated with increased MC4R expression and energy expenditure, which may contribute to obesity prevention. 

These studies suggest that DNA methylation of key genes involved in energy homeostasis and body weight regulation could contribute to the development of obesity. 

DNA methylation and adiposity 

Adiposity and fat distribution are also associate with DNA methylation. A person’s adiposity refers to how much fat they have, while fat distribution refers to how it is distribute on their body. 

The DNA methylation patterns of lean and obese individuals differ, suggesting a link between epigenetic modifications and obesity. A study found that obese individuals had significantly higher levels of DNA methylation of the leptin gene, which regulates appetite and energy expenditure in adipose tissue. Higher methylation levels were associated with lower leptin expression and increased appetite, which could contribute to the development of obesity. Moreover, studies have also investigated the relationship between DNA methylation and fat distribution. According to a study, visceral adiposity, the accumulation of fat around the internal organs, is associate with DNA methylation levels of the adiponectin gene, which regulates glucose and lipid metabolism. 

In the presence of higher methylation levels of the adiponectin gene, there was lower adiponectin expression and increased visceral obesity, which increases the risk of metabolic diseases like type 2 diabetes. According to these studies, DNA methylation regulates adiposity and fat distribution genes. Dysregulation of DNA methylation patterns could alter gene expression and contribute to obesity and related metabolic disorders. 

Genetic Variations and Methylation 

Genetic variations, or mutations, in genes involved in the methylation pathway, can affect methylation patterns and, consequently, metabolic function.

MTHFR Gene and Folate Metabolism 

The MTHFR gene is one of the genetic variations that affect methylation. It encodes an enzyme that is essential for folate metabolism. The B-vitamin folate is crucial for DNA methylation, and mutations in the MTHFR gene can impair folate metabolism and alter methylation patterns. This, in turn, can lead to metabolic disorders, such as obesity. 

MTHFR mutations are associate with obesity, insulin resistance, and other metabolic disorders in individuals. According to a study, individuals with a particular mutation in the MTHFR gene (C677T) had a higher risk of developing obesity and insulin resistance than those without the mutation. 

Other Genetic Variations and Methylation 

In addition to the MTHFR gene, several other genetic variations have been associate with altered methylation patterns and an increase in risk of metabolic disorders. 

These include: 

BHMT

The betaine-homocysteine methyltransferase (BHMT) enzyme is involve in the metabolism of homocysteine. According to a study, methylation levels of the BHMT gene were associate with elevated body mass index (BMI) in children, indicating that epigenetic modifications may contribute to obesity. 

CBS 

CBS (cystathionine beta-synthase) is an enzyme that plays a role in methionine metabolism. According to a study, children with higher levels of DNA methylation of the CBS gene had greater BMIs. Suggesting epigenetic modifications to this gene contribute to obesity. 

COMT 

The enzyme COMT (catechol-O-methyltransferase) plays a role in the metabolism of catecholamines, such as dopamine, epinephrine, and norepinephrine. A study published in Molecular Psychiatry found that DNA methylation levels of the COMT gene were associates with BMI and body fat percentage in women. Higher methylation levels were associate with increased BMI and body fat percentage. 

MTHFD1 

MTHFD1 (methylenetetrahydrofolate dehydrogenase 1) is an enzyme involve in folate metabolism. According to a study, higher DNA methylation levels of the MTHFD1 gene were associate with increased BMI and adiposity in women. MTHFR 

MTHFR (methylenetetrahydrofolate reductase) also plays a role in folate metabolism. Also, Two common polymorphisms of the MTHFR gene, 1298 A>C and 677 C>T, have been linked to obesity and related metabolic disorders. Additionally, methylation patterns of the MTHFR gene have been associated with obesity and related metabolic diseases. 

MTR

Methionine synthase (MTR) is involve in methionine metabolism. A study published in the Journal of Nutrigenetics and Nutrigenomics found that DNA methylation levels of the MTR gene were associates with BMI and waist circumference in women. Higher methylation levels were associates with increased BMI and waist circumference. 

MTRR 

MTRR (methionine synthase reductase) is an enzyme that plays a role in methionine metabolism. Researchers found that MTRR DNA methylation levels in women were associate with their BMI and adiposity. 

NBPF3 

NBPF3 (neuroblastoma breakpoint family member 3) is a gene that has been implicate in neural development. A study found that higher methylation levels of the NBPF3 gene are associate with increased BMI and adiposity in children. 

NQO1 

NQO1 (NAD(P)H quinone dehydrogenase 1) is involve in detoxification. A study reported in the Journal of Clinical Endocrinology & Metabolism found that DNA methylation levels of the NQO1 gene were associated with BMI and insulin resistance in men. The study suggests that higher methylation levels were associate with increasing BMI and insulin resistance. 

OGG1 

OGG1 (8-oxo guanine DNA glycosylase 1) is an enzyme that is essential for DNA repair. Also, A study found that DNA methylation levels of the OGG1 gene were associate with BMI and adiposity in women. Researchers found that higher methylation levels were associates with increased BMI and adiposity. 

PEMT 

PEMT (phosphatidylethanolamine N-methyltransferase) plays a role in phospholipid metabolism. In a study published in the Journal of Clinical Endocrinology & Metabolism, DNA methylation levels of the PEMT gene were linked to BMI and adiposity in women. A higher methylation level was associates with a higher body mass index and adiposity. 

TCN2 

TCN2 (transcobalamin II) is a protein that plays a role in the transport of vitamin B12. In a study published in Nutrigenetics and Nutrigenomics, DNA methylation levels of the TCN2 gene are associates with BMI and waist circumference in women. It was suggest that BMI and waist circumference increases with higher methylation levels. 

Also, studies have shown that mutations in these genes can affect methylation patterns and increase the risk of metabolic disorders. Researchers found that individuals with a mutation in the MTRR gene had lower levels of DNA methylation and a higher risk of metabolic syndrome. 

Implications for the Treatment and Prevention of Obesity: 

The discovery of the role of DNA methylation in the development of obesity has significant implications for the treatment and prevention of obesity. Also, It is becoming increasingly clear that epigenetic changes are biomarkers of obesity and metabolic disorders. Methylation is the process involve in actually turning genes on or off. If we optimize our methylation, we can reduce our risk of developing certain diseases and cancers. 

According to a study, the DNA methylation levels of the FTO gene, a gene associated with obesity risk, can predict obesity and type 2 diabetes. In addition, targeting DNA methylation could provide a potential therapeutic approach for the treatment of obesity. A number of studies have examined how dietary interventions affect DNA methylation patterns in obese individuals. According to a study, a high-fiber diet can alter DNA methylation patterns in genes involved in lipid metabolism and energy homeostasis in obese individuals, potentially improving their metabolic health. 

Also, a number of potential treatments for obesity and related metabolic disorders are currently being investigates that target DNA methylation. As a matter of fact, In a study published in Diabetes, DNA methyltransferase inhibitor treatment improved insulin sensitivity and glucose metabolism in obese mice, suggesting that targeting DNA methylation could be a promising way to treat obesity. 

Conclusion: 

DNA methylation plays a critical role in the regulation of energy homeostasis and body weight. Dysregulation of DNA methylation patterns might contribute to obesity and other metabolic disorders. Increasing our understanding of the epigenetic mechanisms involved in the regulation of body weight may provide us. With new insights into the development of obesity and aid in the development of new prevention and treatment strategies. In spite of the need for more research in this field, the potential implications of DNA methylation for the prevention and treatment of obesity are promising.