Explaining the Science: MTHFR, COMT, POMC, and PPARG in Lipedema

It all starts in the DNA….
Here’s where it gets really exciting—epigenetics. We do not have to be afraid of our genes. We just have to OPTIMIZE them!!!

I ABSOLUTELY LOVE THE BIOCHEMICAL PATHOPHYSIOLOGICAL PATHWAYS in the body. This chemical leads to this chemical, etc. It is the same with EPIGENETICS!!
Epigenetics is the study of how lifestyle (stress, diet, exercise and movement) and environmental factors (toxins, mold) can influence our genes, and therefore our chemical pathways.

And the beautiful thing about epigenetics is that we’re not stuck with the genetic cards we’re dealt. We do not have to accept the status quo we wake up with every day. We can change our MIND!

Even if you have mutations in genes like MTHFR, POMC, COMT or PPARG, we can use epigenetic tools to improve how these genes function and reduce the impact they have on our health.
It is OUR choice!

There are many polymorphisms and genes that affect how we detoxify estrogen and/or the way we store or burn fat. These can be directly or indirectly related to LIPEDEMA.

You’ve already heard me mention MTHFR—a gene essential for methylation and detoxification.
When MTHFR isn’t functioning optimally, it impairs the body’s ability to detoxify estrogen, resulting in buildup of estrogen metabolites, particularly 16-hydroxy estrone (16-OH)—a metabolite linked to fat accumulation, fibrosis, and inflammation, which are key features of lipedema (Yager & Davidson, 2006). Leafy greens and limited processed foods can optimize MTHFR. Processed foods contain folic acid, which can build up in the body due to the lack of the MTHFR enzyme in the liver to methylate folic acid. The right supplements help tremendously!

MTHFR can also cause low dopamine, which affects mood, motivation, and the permeability of our blood vessels. MTHFR has also been linked to ADHD, autism, Asberger's, and coronary artery disease, due to high homocysteine and increased risk of clotting.

But there’s another gene in this detox pathway we can’t ignore: COMT—catechol-O-methyltransferase.

COMT acts like the final "bouncer" at the estrogen party—if it’s sluggish, the rowdy guests (harmful metabolites) hang around too long, causing chaos in the form of inflammation, tissue damage, and possibly contributing to lipedema, fibroids, and even mood disorders.

COMT’s job is to methylate and deactivate harmful estrogen metabolites, especially 2-OH and 4-OH estrone.
When COMT is slow or under-functioning—either due to genetic mutations or low methylation capacity—those metabolites linger, increasing oxidative stress, DNA damage, and tissue inflammation (Liu et al., 2022).

In lipedema, where tissue fibrosis, pain, and hormonal sensitivity are already present, inefficient COMT function may amplify symptoms by allowing pro-inflammatory estrogen metabolites to accumulate in fat and connective tissue.

And because COMT also breaks down dopamine and norepinephrine, women with COMT variants often experience greater sensitivity to stress—which can worsen cortisol dysregulation, insulin resistance, and fat storage.

Then there’s POMC—a gene that influences appetite, fat storage, and pain perception.
POMC mutations or dysregulation are linked to abnormal fat distribution and chronic pain syndromes, both of which mirror the symptoms of lipedema (Krude et al., 1998).

PPARG—often called the “fat regulator gene.”
This gene influences how adipocytes (fat cells) grow and respond to inflammation. Exercise, especially strength training and cardiovascular workouts can can activate this gene in a way that it encourages and promotes fat burning instead of storage, while also reducing inflammation.

In lipedema, PPARG activity may be upregulated in early stages, driving excessive fat accumulation, and dysregulated in later stages, promoting fibrosis and lymphatic congestion (Al-Ghadban et al., 2020).

CYP19A1 plays an essential role in estrogen biosynthesis, as it encodes for the aromatase enzyme. This leads to aromatization of testosterone into estrogen (Poojari). More estrogen can lead to less detoxification.

Finally, AKR1C1 interferes with the normal breakdown of Progesterone. This one is very rare. Progesterone is normally anti-proliferative, anti-inflammatory, anti-estrogenic, protecting agains Estrogen Dominance. However, when VERY high, such as higher than luteal levels, it can cause weight gain.

All of these genes—MTHFR, COMT, POMC, PPARG, and AKR1C1—interact with estrogen, inflammation, and metabolism.
When they don’t function well, the result is a perfect storm: estrogen and/or progesterone buildup, impaired fat breakdown, chronic inflammation, disproportionate fat storage that resists diet and exercise.

Epigenetics: Rewriting the Genetic Story

But get EXCITED!!! Things are about to change!! We can OPTIMIZE THESE.

Genetics load the gun, but our decisions every day pull the trigger!!

The genes are like light switches in our body. But we do not have to turn them on.

By our choices, the light switches are turned on or off.

This is EPIGENETICS!!

By optimizing and balancing with Bio Identical Hormone Therapy (BHRT), metabolite detox, nutrition, the right supplements for our genetics, exercise, and stress management, we can help these genes work better, improve estrogen detoxification, reduce inflammation, and decrease fat storage.

We are no longer prisoners to our genetic makeup.
With epigenetics, we can change the way our bodies respond to these genetic pathways, and start the healing process.

We are in charge of our health—and that’s a message worth hearing.

Genomic Insight Testing can identify polymorphisms that can affect your health. By Artificial Intelligence, foods and supplements are recommended to optimize and prevent these conditions.

The Dried Urine Test for Comprehensive Hormones (DUTCH) Test can reveal hormones, metabolites that genetics might have affected and/or that are just naturally off-balance. We know how to correct these!

I can tell you from personal experience, having two copies of MTHFR—within two weeks of treating MTHFR, I felt like a completely different person.

I felt a clarity in my brain that I had never felt before. That simple change in my diet didn’t just help me metabolize estrogen better;
it gave me back my energy

I knew I had a problem at the age of 8-9, when I couldn't hold my head up in class, I fell asleep every time I sat down. I still do. In a 12 hour shift, day or night, I never sit down. MTHFR and low dopamine can cause ADHD, which can be hyperactive of hypoactive. However, I found out I absolutely loved to read!! (obviously, now I know I was raising my dopamine).

I learned that exercise made me feel so much better at 13 and I have exercised ever since. Again, raising the Dopamine. When possible, early AM in the sunlight. The sunlight optimizes all hormone's neurotransmitters for a great, productive day!

Also in my teens, I researched what would give me energy and found Vitamin B12. Unknowingly, this was addressing the deficiencies caused by the MTHFR.

At 29, there was the breast cancer. All of these are related to the MTHFR. In mt 30s I found SAM-E, another supplement tha, unbeknownst to me was addressing my MTHFR. I was innately reaching for the cure to my problem.

The nutrition method I learned in the 90s taught me to balance glucagon and insulin for optimal mood and energy. and has proven to be the best, both professionally and personally.

It is not a choice for me. I learned to OPTIMIZE at a very young age.

With Dr. June Stevens, I was diagnosed with the MTHFR that had prevented me from breaking down estrogen sufficiently. She optimized this with the proper supplement. She advised the proper supplements to detox the harmful metabolites off estrogen. . She also prescribed BioIdentical Hormone Therapy (BHRT). In other words, She OPTIMIZED me. This changed my life. This was also the minute that I decided I wanted to do this with others

I HACK MY HORMONES AND THE BIOCHEMICAL PATHWAYS IN THE BODY EVERY DAY!!

Let's hack yours!!

Let’s PERSONALIZE your care!!

OPTIMIZE!!! Hormones, LIPEDEMA, and Weight With me,
Carla Whorton, NP