epigenetics Archives - Health Tips From The Professor

Why Is Keeping Weight Off So Hard?

March 4, 2025 by Dr. Steve Chaney

Can You Achieve Permanent Weight Loss?

Author: Dr. Stephen Chaney

Why is the dreaded yo-yo rearing its ugly head again? You tried a new diet this year, and it worked really well. The weight came off easily. But the diet is over, and the pounds are starting to creep up once again.

You are beginning to wonder if this diet was just like all the other yo-yo diets you’ve tried in the past. You are wondering whether those pounds you lost will come back and bring their friends with them. If so, you’ll be like 156 million Americans who lose weight and gain it all back each year.

And it’s so frustrating. You are trying to be good. You are still exercising and trying to eat healthily. Why isn’t it working?

Could it be that your fat cells have a memory? Could it be they like to be big and bulky with lots of stored fat? While that description is a bit fanciful, a new study (LC Hinte et al, Nature Online, 2024) suggests your fat cells may have a memory, which could explain why it is so hard to keep the weight off.

This is a highly technical study. So, before I discuss how the study was done, I should perhaps review a little bit of Biochemistry 101.

Biochemistry101: Epigenetics and Gene Activity

What Is Epigenetics? When I was a young graduate student (which is more than just a few years ago), I was taught that all genetic information resided in our DNA. During conception, we picked up some DNA from our dad and some from our mom, and that DNA was what made us a unique individual.

In recent years, the hype has centered on DNA sequencing. It seems like everyone is offering to sequence your genome and tell you what kind of diet is best for you, what foods to eat, and what supplements to take. But can DNA sequencing fulfill those promises?

The problem is that DNA sequencing only tells you what genes you have. It doesn’t tell you whether those genes are active. Simply put, it doesn’t tell you whether those genes are turned on or turned off.

This is where epigenetics comes in. Epigenetics is the science of modifications that alter gene expression. In simple terms, both DNA and the proteins that bind to DNA can be modified. This does not change the DNA sequence. But these modifications can determine whether a gene is active (turned on) or inactive (turned off).

This sounds simple enough, but here is where it really gets interesting. These modifications are affected by our diet, our lifestyle (body weight and exercise, for example), our microbiome (gut bacteria), and our environment.

And if that weren’t complicated enough, some of these epigenetic changes (DNA modifications) can be transitory and others are long-lasting.

The authors of this study hypothesized that obesity causes long-lasting epigenetic changes to certain critical genes in our fat cells that slow metabolism and promote fat accumulation, even after we have lost weight. In other words, these epigenetic changes “prime” our fat cells to regain all the weight we’ve lost.

How Do You Measure the Effect of Epigenetic Changes? As you might expect this study measured epigenetic modifications to critical genes in fat cells. But that’s only part of the story. Epigenetic modification can turn genes on, turn them off, or have no effect on gene activity.

So, the investigators also needed to monitor the activity of the genes to determine the effect of the epigenetic modifications. Fortunately, one fact you may have learned in high school or college biology is mostly unchanged by the passage of time.

It is that the genetic sequence of DNA is translated into messenger RNA and that messenger RNA is used to code for proteins. If epigenetic modifications turned on a gene, we would expect higher levels of the corresponding messenger RNA and corresponding protein in those cells. Conversely, if epigenetic modifications turned off a gene, we would expect the opposite.

It turns out that it is much easier to measure changes in messenger RNA levels than individual protein levels that correspond to specific genes. So, the investigators used cellular messenger levels to measure the effect of epigenetic modifications on gene activity.

How Was This Study Done?

The investigators measured the effect of obesity and subsequent weight loss on fat cell gene expression in a limited set of human subjects and supplemented those results with a more expansive set of experiments with mice.

I don’t normally report on animal studies or very small human studies because these studies often lead to misleading results that are not supported by subsequent long-term, large clinical studies.

However, I am making an exception for this study because it leads to an interesting paradigm shift which, if true, changes the way we think about how to keep weight off long term.

Human Study: The investigators determined messenger RNA levels for key genes in fat cells from human volunteers who were:

At a healthy weight.

Obese both before and 2 years after bariatric surgery that resulted in at least 25% weight loss.

The groups were small (10-16 total), in part because obtaining fat cell samples is an invasive and painful procedure.

Mouse study: The investigators determined both messenger RNA levels and epigenic modifications for key genes in fat cells from 6-week-old male mice who were:

Fed either a low-fat or high-fat chow diet for 25 weeks. As expected, the mice fed the low-fat diet remained lean and the mice fed the high-fat diet became obese.

Subsequently, the obese mice were put on low-fat chow for 8 weeks during which time their weight returned to normal.

Finally, both the ‘always lean’ and ‘formerly obese’ mice were put on high-fat chow to compare how rapidly they gained weight.

What Happens To Fat Cells During Obesity And Weight Loss?

This study is best viewed as a story of what happens to fat cells during obesity and subsequent weight loss. There are two parts – what happens to human fat cells and what happens to mouse fat cells:

Human Fat Cells: When obese individuals were compared to lean individuals:

Genes coding for fat storage and inflammation (which is known to be associated with obesity) were more active.

Fat-burning genes were less active.

These changes in gene expression were retained even after the obese individuals lost substantial weight through bariatric surgery.

[Note: The measurements of gene expression were based on the amount of messenger RNA produced by those genes.]

The human study had a couple of important limitations, which is why the investigators also did a similar study with mice.

#1: Because the study did not include a habitually lean group who became obese after going on a high-fat diet (no clinical review board would approve such a study), it could not determine whether the differences in gene expression were caused by the onset of obesity or whether they caused obesity.

Simply put, we know some individuals are genetically predisposed to obesity. The differences in gene expression between lean and obese individuals could have simply represented a genetic predisposition to obesity.

The mouse experiments did not suffer from that limitation because it was possible to put lean mice on a high fat diet until they became obese.

#2: The study did not measure epigenetic changes that may have caused the changes in gene expression. That is because humans are genetically heterogeneous. Consequently, you need population studies with hundreds of individuals to reliably determine epigenetic differences between groups.

The mouse experiments did not suffer from that limitation because laboratory mice are genetically homogeneous.

Mouse Fat Cells:

When the investigators looked at the physical effects of obesity:

When mice became obese on a high-fat diet:

- Blood glucose levels rose.

- Insulin levels rose, indicating the mice had become insulin resistant.

- Fat accumulated in their livers.

When the obese mice lost the excess weight on a low-fat diet all these parameters returned to normal.

When the ‘always lean’ and ‘previously obese’ mice were put back on a high fat diet at the end of the study, the previously obese mice gained weight more quickly than the always lean mice.

In other words, mice responded to obesity in the same way that humans do except none of these effects could be explained by genetics. This strain of mice was genetically homogeneous.

When the investigators compared gene expression (as measured by messenger RNA levels) in mice who had become obese to ‘always lean’ mice:

Genes coding for fat storage and inflammation were more active.

Fat-burning genes were less active.

These changes in gene expression were retained even after the obese mice lost weight.

In other words, mice responded to obesity in the same ways as humans with respect to gene expression. However, in this case it was clear that obesity caused the changes in gene expression.

When the investigators looked at epigenetic modifications:

They identified epigenetic modifications to the regulatory regions of genes whose activity was increased or decreased when the mice became obese.

These epigenetic modifications were retained even after the mice lost weight.

These data suggest, but do not prove, that the epigenetic modifications were responsible for the changes in gene activity.

The authors concluded, “We show that both human and mouse adipose tissues retain transcriptional changes after appreciable weight loss.

Furthermore, we find persistent obesity induced alterations in the epigenome of mouse adipocytes that negatively affect their function and response to metabolic stimuli. Mice carrying this obesogenic memory show accelerated rebound weight gain…in response to high-fat diet feeding.

In summary, our findings indicate the existence of an obesogenic memory, largely on the basis of stable epigenetic changes, in mouse adipocytes and probably other cell types. These changes seem to prime cells for pathological response [weight gain] in an obesogenic environment, contributing to the problematic ‘yo-yo’ effect often seen with dieting.”

More simply put, the investigators concluded that obesity causes epigenetic modifications to the DNA of fat cells that prime them to regain their fat stores. They said that this may contribute to the ‘yo-yo’ effect often seen with dieting and explain why keeping weight off is so hard.

Why Is Keeping Weight Off So Hard?

You are not alone. You are like millions of other Americans. You lose weight effectively, but you struggle to keep it off. You just look at a donut and the fat jumps from the donut to your hips. You try to eat right, but the pounds keep creeping back on.

Experts have told us for years that our fat cells (and perhaps other cells in our body) are the culprit. Those cells have switched from a fat burning mode to a fat storage mode. There have been lots of attempts to explain that phenomenon, but my favorite is one that hypothesizes that our metabolism was designed for paleolithic times when it was either feast or famine.

Simply put, the theory is that our bodies were designed to store energy reserves in times of plenty and hold on to those energy reserves as long as possible in times of famine. Holding on to energy reserves was essential for prehistoric man to survive cold winters when food was hard to come by. And our number one energy reserve is, you guessed it, fat.

That is an appealing hypothesis, but it doesn’t tell us how our bodies manage to do that.

That’s what makes this study so intriguing. It may be wrong. It needs to be substantiated by large scale clinical trials. But the idea that epigenic changes occur during obesity and persist after substantial weight loss is novel. More importantly, it may explain the “feast or famine” response and why it is so hard to keep weight off after substantial weight loss.

Can You Achieve Permanent Weight Loss?

By now you may be thinking, “I thought my weight loss woes were due to my genetics. Now you’re telling me that they could be due to my epigenetics. Am I doubly cursed? Is there nothing I can do to keep my weight off?”

I can tell you science doesn’t have a simple answer, but there are two big clues that offer hope.

#1: Slow and steady wins the race. Obesity experts have known for years that slow weight loss often results in permanent weight loss.

If you are counting calories, that means a reduction of around 500 calories per week (That’s 71 calories per day, which is equivalent to one small apple, one hard-boiled egg, or 1.5 ounces of chicken breast). And a 500-calorie deficit maintained each week for a year can lead to a 20-25 pound weight loss.

If you are thinking of diets, it could amount to switching to a diet of unprocessed or minimally processed foods consisting of fruits, vegetables, whole grains, and primarily plant-based proteins without worrying about calories or serving sizes. Again, clinical studies show that switching from the typical American diet to this kind of diet can lead to substantial weight loss over a period of years.

Neither approach is popular in the weight loss world, but they work. Why do they work? It could be because the daily reduction in calories is so small that it never triggers the famine response.

If we look at the two parts of the study I reported on above:

In the human study weight loss was achieved through bariatric surgery which causes a huge reduction in caloric intake and rapid weight loss.

In the mouse study going from high-fat chow to low-fat chow represented a large decrease in calories. And again, weight loss was very rapid. It took the mice 25 weeks to become obese and only 4-8 weeks to lose the weight they had gained.

When viewed from this perspective, the epigenetic modifications observed after weight loss in this study may have been due to the famine response rather than a retention of the modifications observed during obesity.

And when you think about it, most popular diets feature major restrictions (calories, fats, carbs, forbidden foods, time of eating) and cause rapid weight loss. They are likely to trigger a famine response as well.

#2: The secrets of the National Weight Control Registry. There are some people who manage to keep their weight off and avoid the yo-yo effect. They don’t have any genetic or epigenetic advantage over the rest of us. They have lost weight on every diet imaginable – including rapid weight loss fad diets.

Yet they have managed to keep the weight off. What are their secrets? How did they avoid regaining their weight? How did they avoid the yo-yo diet effect?

An organization called the National Weight Control Registry was established to answer that question. It has enrolled more than 10,000 people who have lost weight and kept it off. On average people in this group have lost 66 pounds and kept it off for at least 5 years.

The National Weight Control Registry kept track of what they did to keep the weight off. Everyone’s approach was a little different, but the National Weight Control Registry summarized the ones that were most frequently mentioned. Here is what they do that you may not be doing:

#1: They consume a reduced calorie, whole food diet.

#2: They get lots of exercise (around 1 hour/day).

#3: They have internalized their eating patterns. In short, this is no longer a diet. It has become a permanent part of their lifestyle. This is the way they eat without even thinking about it.

#4: They monitor their weight regularly. When they gain a few pounds, they modify their diet until they are back at their target weight.

#5: They eat breakfast on a regular basis.

#6: They watch less than 10 hours of TV/week.

#7: They are consistent (no planned cheat days).

The good news is that participants in the National Weight Control Registry reported that while maintaining weight loss was difficult at first, it became easy after 2 years.

Of course, we don’t know whether is due to epigenic modifications being reset to “lean” by these behaviors or whether the new behaviors became automatic and overrode epigenetics.

It doesn’t matter. It means you can end the ‘yo-yo’ cycle forever. You can keep weight off, and you know how to do it.

The Bottom Line

A recent study in both humans and mice suggests that epigenetic modifications to key genes in your fat cells make it hard to keep weight off. These epigenetic changes may explain why so many people struggle with yo-yo dieting.

For more details on this study and how you may be able to override these epigenetic modifications and prevent weight regain read the article above.

These statements have not been evaluated by the Food and Drug Administration. This information is not intended to diagnose, treat, cure or prevent any disease.

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My posts and “Health Tips From the Professor” articles carefully avoid claims about any brand of supplement or manufacturer of supplements. However, I am often asked by representatives of supplement companies if they can share them with their customers.

My answer is, “Yes, as long as you share only the article without any additions or alterations. In particular, you should avoid adding any mention of your company or your company’s products. If you were to do that, you could be making what the FTC and FDA consider a “misleading health claim” that could result in legal action against you and the company you represent.

For more detail about FTC regulations for health claims, see this link.

https://www.ftc.gov/business-guidance/resources/health-products-compliance-guidance

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About The Author

Dr. Chaney has a BS in Chemistry from Duke University and a PhD in Biochemistry from UCLA. He is Professor Emeritus from the University of North Carolina where he taught biochemistry and nutrition to medical and dental students for 40 years.

Dr. Chaney won numerous teaching awards at UNC, including the Academy of Educators “Excellence in Teaching Lifetime Achievement Award”.

Dr Chaney also ran an active cancer research program at UNC and published over 100 scientific articles and reviews in peer-reviewed scientific journals. In addition, he authored two chapters on nutrition in one of the leading biochemistry text books for medical students.

Since retiring from the University of North Carolina, he has been writing a weekly health blog called “Health Tips From the Professor”. He has also written two best-selling books, “Slaying the Food Myths” and “Slaying the Supplement Myths”. And most recently he has created an online lifestyle change course, “Create Your Personal Health Zone”. For more information visit https://chaneyhealth.com.

For the past 45 years Dr. Chaney and his wife Suzanne have been helping people improve their health holistically through a combination of good diet, exercise, weight control and appropriate supplementation.

Is DNA Testing Valuable?

October 5, 2021 by Dr. Steve Chaney

What Is The True Value Of DNA Tests?

Author: Dr. Stephen Chaney

DNA testing is hot! DNA testing companies claim they can tell you your disease risk and personalize your diet and supplement program – all based on the sequence of your DNA.

On the other hand, most reputable medical sources say these DNA testing companies overpromise and underdeliver. They tell you that diet, lifestyle, and supplement recommendations based only on your DNA sequence are often inaccurate.

So, what should you believe? At this point you are probably wondering:

Is DNA testing valuable or is it a waste of money?

Is there a way to make DNA testing more accurate?

What is the true value of DNA testing to you, the consumer?

I will consider these 3 questions in my article below. But first let me share two stories about DNA testing, one true and the other fictional.

Perspectives on DNA Testing

When the human genome was first sequenced in 2003, it took 13 years and cost millions of dollars. That was an exciting time. Many of us in the scientific community thought we were on the verge of a revolution in human health and longevity. We would soon be able to tell individuals their risk of developing various diseases.

Even better, we would be able to tell them the kind of diet and supplementation they needed to avoid those diseases. We would be able to personalize our nutritional recommendation for every individual based on their genome – something we called nutrigenomics.

How naive we were! It has turned out to be much more complicated to design personalized nutrition recommendations based on someone’s genome than we ever imagined.

Today an analysis of your genome requires hours and costs less than $200. That represents a tremendous advance in technology. However, we are no closer to being able to make personal nutrition recommendations based on our DNA sequence today than we were 18 years ago.

Why is that? Let me share a fictional story because it provides a clue. In 1997, when I was still a relatively young scientist, I saw a film called GAATACA. [If you are looking for an entertaining film to watch, it is still available on some streaming services.]

This film envisioned a future society in which parents had their sperm and eggs sequenced so that their children would be genetically perfect. In that society the term “love child” had been redefined as a child who had been conceived without prior DNA sequencing.

The hero of this film was, of course, a love child. He was born with a genetic predisposition for heart disease. He was considered inferior, a second-class citizen of this future world.

Without giving away the plot of the film (I don’t want to spoil the enjoyment for you if you are thinking of watching it), he overcame his genetic inferiority. With a strict regimen of diet and physical fitness he became stronger and healthier than many of his genetically perfect peers.

This is when I first began to realize that our DNA does not have to be our destiny. We have the power to overcome bad genetics. We also have the power to undermine good genetics.

You might be wondering, “How can this be? Why doesn’t our DNA determine our destiny” I will answer that question in two parts.

First, I will share what experts say about the value of DNA testing.

Then I will put on my professor hat and discuss “Genetics 101 – What we didn’t know in 2003” (When the genome was first sequenced).

Is DNA Testing Valuable?

As I said above, most scientists are skeptical about the ability of DNA testing to predict our ideal diet and supplementation regimens. For example, here are two recent reviews on the current status of DNA testing. [Note: These scientists are using “science speak”. Don’t worry if you don’t understand all the terms. I will explain their message in simpler terms in the next section.]

One review (C Murgia and MM Adamski, Nutrients, 366, 2017) published in 2017 concluded: “The potential applications to nutrition of this invaluable tool [DNA sequencing] were apparent since the genome was mapped…However, fifteen years and hundreds of publications later, the gap between genome mapping and health practice is not yet closed.”

“The discovery of other levels of control, including epigenetics [modifications of DNA that affect gene expression] and the intestinal microbiome complicate the interpretation of genetic data. While the science of nutritional genomics remains promising, the complex nature of gene, nutrition and health interactions provides a challenge for healthcare professionals to analyze, interpret and apply to patient recommendations.”

Another review (M Gaussch-Ferre et al, Advances in Nutrition, 9: 128-135, 2018) published in 2018 concluded: “Overall, the scientific evidence supporting the dissemination of genomic information for nutrigenomic purposes [predicting ideal diet and supplement regimens] remains sparse. Therefore, additional knowledge needs to be generated…”

In short, the experts are saying we still don’t know enough to predict the best diet or the best supplements based on genetic information alone.

Genetics 101 – What We Didn’t Know In 2003

In simple terms the experts who published those reviews are both saying that the linkage between our DNA sequence and either diet or supplementation is much more complex than we thought in 2003 when the genome was first sequenced.

That is because our understanding of genetics has been transformed by two new areas of research, epigenetics and our microbiome. Let me explain.

Epigenetics has an important influence on gene expression. When I was a graduate student, we believed our genetic destiny was solely determined by our DNA sequence. That was still the prevailing viewpoint when the human genome project was initiated. As I said above, we thought that once we had our complete DNA sequence, we would know everything we needed to know about our genetic destiny.

It turns out that our DNA can be modified in multiple ways. These modifications do not change the DNA sequence, but they can have major effects on gene expression. They can turn genes on or turn them off. More importantly, we have come to learn that these DNA modifications can be influenced by our diet and lifestyle.

This is the science we call epigenetics. We have gone from believing we have a genome (DNA sequence) that is invariant and controls our genetic destiny to understanding that we also have an “epigenome” (modifications to our DNA) that is strongly influenced by our diet and lifestyle and can change day-to-day.

2) Our microbiome also has an important influence on our health and nutritional status. Simply put, the term microbiome refers to our intestinal microbes. Our intestinal bacteria are incredibly diverse. Each of us has about 1,000 distinct species of bacteria in our intestines.

Current evidence suggests these intestinal bacteria influence our immune system, inflammation and auto-immune diseases, brain function and mood, and our predisposition to gain weight – and this may just be the tip of the iceberg.

More importantly, our microbiome is also influenced by our diet and lifestyle, and environment. For example, vegetarians and meat eaters have entirely different microbiomes.

Furthermore, the effect of diet and lifestyle on our microbiome also changes day to day. If you change your diet, the species of bacteria in your microbiome will completely change in a few days.

If you are wondering how that could be, let me [over]simplify it for you:

- What we call fiber, our gut bacteria call food.

- Different gut bacteria thrive on different kinds of fiber.

- Different plant foods provide different kinds of fiber.

- Whenever we change the amount or type of fiber in our diet, some gut bacteria will thrive, and others will starve.

- Bacteria grow and die very rapidly. Thus, the species of bacteria that thrive on a particular diet quickly become the predominant species in our gut.

- And when we change our diet, those gut bacteria will die off and other species will predominate.

Finally, our microbiome also influences our nutritional requirements. For example, some species of intestinal bacteria are the major source of biotin and vitamin K2 for all of us and the major source of vitamin B12 for vegans. Other intestinal bacteria inactivate and/or remove some vitamins from the intestine for their own use. Thus, the species of bacteria that populate our intestines can influence our nutritional requirements.

Now that you know the complexity of gene interactions you understand why we are not ready to rely on DNA tests alone. That science is at least 10-20 years in the future. Companies that tell you otherwise are lying to you.

What Is The True Value Of DNA Tests?

By now you are probably thinking that my message is that DNA tests are worthless. Actually, my message is a bit different. What I, and most experts, are saying is that DNA tests are of little value by themselves.

To understand the true value of DNA tests, let me start with defining a couple of terms you may vaguely remember from high school biology – genotype and phenotype.

Genotype is your genes.

Phenotype is you – your health, your weight, and your nutritional needs. Your phenotype is determined by your genes plus your diet and your lifestyle.

With that in mind, let’s review the take-home messages from earlier sections of this article.

The take-home message from the two stories in “Perspectives on DNA Testing” is that our DNA does not have to be our destiny. We have the power to overcome bad genetics. We also have the power to undermine good genetics.

The take-home message from “Genetics 101” is that while the genes we inherit do not change, the expression of those genes is controlled in part by:

- Epigenetic modifications to the DNA. And those epigenetic modifications are controlled by our diet and our lifestyle.

- Our microbiome (gut bacteria). And our microbiome is controlled by our diet and our lifestyle.

Now we are ready to answer the question, “What is the true value of DNA testing?” There are actually two answers to this question. You have probably guessed the first answer by now, but you will be surprised by the second.

DNA testing can only indicate the potential for obesity, the potential for nutritional deficiencies, and the potential for disease. But whether that potential is realized depends on our diet and lifestyle. Therefore, the true value of DNA testing comes from adding a comprehensive analysis of diet and lifestyle to the DNA test results. That includes:

- Questionnaires that assess diet, lifestyle, health goals, and health concerns.

For example, your genetics may indicate an increased need for vitamin D. This is a concern if your vitamin D intake is marginal but may not be a concern if you are getting plenty of vitamin D from your diet, supplementation, and sun exposure.

- Direct measurements of obesity such as height and weight (from which BMI can be calculated) and waist circumference (belly fat is more dangerous to our health than fat stored elsewhere in our body).

For example, most Americans have a genetic predisposition to obesity, but not everyone is obese. If you are overweight or obese, your nutrition and lifestyle recommendations should include approaches to reduce your weight. If not, these recommendations are not needed, even if you have a genetic predisposition to obesity.

- Blood pressure and blood markers of disease risk (cholesterol, triglycerides, and blood sugar).

For example, you may have genetic predisposition to high blood pressure or high cholesterol. If either of these are high, your recommendations should include nutrition and lifestyle approaches to lower them. However, if you are already keeping them under control through diet and lifestyle, no further changes may be necessary.

2) While the scientific community now knows the limitations of DNA testing, this information has not filtered down to the general public. This brings me to the second value of DNA testing. Several recent studies have shown that people are much more likely to follow recommendations based on DNA testing than recommendations based on dietary questionnaires, blood markers of disease, or even recommendations from their physician.

The Bottom Line

DNA testing is hot! DNA testing companies claim they can tell you your disease risk and personalize your diet and supplement program – all based on the sequence of your DNA.

So, what is the true value of DNA testing? To answer that question, we need to know two things:

1) Our DNA is not our destiny. We have the power to overcome bad genetics. We also have the power to undermine good genetics.

2) While the genes we inherit do not change, the expression of these genes is controlled in part by:

- Epigenetic modifications to the DNA. And those epigenetic modifications are controlled by our diet and our lifestyle.

- Our microbiome (gut bacteria). And our microbiome is controlled by our diet and our lifestyle.

With this information in mind, we are ready to answer the question, “What is the true value of DNA testing?” The true value of DNA testing is tw0-fold:

1) It comes from adding a comprehensive analysis of diet and lifestyle to the DNA test results. This includes:

- Questionnaires that assess diet, lifestyle, health goals, and health concerns.

- Direct measurements of obesity such as height and weight (from which BMI can be calculated) and waist circumference (belly fat is more dangerous to our health than fat stored elsewhere in our body).

- Blood pressure and blood markers of disease risk (cholesterol, triglycerides, and blood sugar).

2) In addition, several recent studies have shown that people are much more likely to follow recommendations based on DNA testing than recommendations based on dietary questionnaires, blood markers of disease, or even recommendations from their physician.

For more details and explanations of the statements in “The Bottom Line”, read the article above.

These statements have not been evaluated by the Food and Drug Administration. This information is not intended to diagnose, treat, cure, or prevent any disease.

Do Low Fat Diets Reduce The Risk Of Diabetes?

May 4, 2021 by Dr. Steve Chaney

Why Is Nutrition So Confusing?

Author: Dr. Stephen Chaney

Sometimes the professor likes to introduce you to the frontiers of nutrition. Epigenetics is such a frontier. In recent years, the hype has centered on DNA sequencing. It seems like everyone is offering to sequence your genome and tell you what kind of diet is best for you, what foods to eat, and what supplements to take. But can DNA sequencing fulfill those promises?

This sounds simple enough, but here is where it really gets interesting. These modifications are affected by our diet, our lifestyle (BMI and exercise), our microbiome (gut bacteria), and our environment.

In today’s “Health Tips From The Professor” I am going to share a study (CQ Lai et al, American Journal of Clinical Nutrition, 112: 1200-1211, 2020) that looks at the effect of diet (low-fat versus low-carb diets) on a particular kind of DNA modification (methylation) that affects a gene (CPT) which influences our risk for metabolic diseases (obesity, high triglycerides, low HDL, insulin resistance, pre-diabetes, and type 2 diabetes).

[Note: For simplicity I will just refer to type 2 diabetes in the rest of this article. Just be aware that whatever I say about type 2 diabetes applies to other metabolic diseases as well.]

Previous studies have shown that:

Methylation of the CPT gene is the only epigenetic change in the entire genome that is associated with decreased risk of type 2 diabetes.

CPT gene activity regulates multiple metabolic pathways that influence the risk of type 2 diabetes.

High fructose and sucrose consumption increases CPT gene methylation in rats, and high fat diets suppress that methylation.

Based on those data, the authors hypothesized that carbohydrate and fat intake affect the methylation of CPT gene, which:

Alters the activity of the CPT gene and…

Affects the risk of developing type 2 diabetes.

Since we are talking about our diet making alterations to our DNA, we could consider this as an example of, “We are what we eat”.

Biochemistry 101: Why Is Nutrition So Confusing?

Now it is time for my favorite topic, Biochemistry 101. Along the way you will discover why nutrition is so complicated – and so confusing.

The CPT gene codes for a protein called carnitine palmitoyltransferase or CPT. CPT transports fats into the mitochondria where they can be oxidized to generate energy. Simply put, without CPT we would be unable to utilize most of the fats we eat. And, as you might expect, CPT is not required for carbohydrate metabolism.

In a simple world where our DNA sequence determines our destiny, we would either have an active CPT gene or an inactive mutant version of the gene. If we had the mutant version of the CPT gene, we would be unable to use fat as an energy source.

However, we don’t live in a simple world. Epigenetic modifications alter the activity of the CPT gene. When the CPT gene is unmethylated it is fully active. Methylation inactivates the gene.

In a simple world, a high fat diet would activate the CPT gene so our body would be able to utilize the fat in our diet. It would do that by decreasing methylation of the gene. Conversely, a high carbohydrate, low fat diet would decrease CPT gene activity by increasing methylation of the gene.

This is the one simple prediction that works exactly as expected.

In a simple world, CPT would be involved in transport of fat into our mitochondria and nothing else. In that world, the activity of the CPT gene would only affect fat metabolism.

However, we don’t live in a simple world. By mechanisms that are not completely understood, carnitine palmitoyltransferase (CPT) also influences both insulin resistance and release of insulin by our pancreas. That means the activity of the CPT gene also affects our risk of developing type 2 diabetes.

In the simplest terms, we can think of diabetes as an inability to properly regulate blood sugar levels. In a simple world, that would mean that carbohydrates are the problem, and we could reduce our risk of developing diabetes by restricting our intake of carbohydrates.

However, we don’t live in a simple world. There are short-term studies supporting the effectiveness of both low carb and low fat diets at helping to control blood sugar levels. However, longer term studies generally show that only whole food, low fat diets are associated with reduced risk of developing type 2 diabetes.

In other words, healthy carbohydrates aren’t the problem. They are the solution for reducing your risk of type 2 diabetes. This isn’t intuitive. It isn’t simple. But the weight of evidence points in this direction.

[I should add the emphasis is on “healthy” carbohydrates. I am talking about diets that emphasize whole food sources of carbohydrates (fruits, vegetables, whole grains, and legumes), not diets loaded with sugar, refined carbohydrates, and highly processed foods.]

Confused yet? Don’t worry. The authors of this study combined all this information into a single, unifying hypothesis.

They proposed that the fat and carbohydrate content of the diet influence methylation of the CPT gene, which influences the activity of the CPT gene, which influences both fat metabolism and the risk of developing type 2 diabetes. Specifically, they proposed that:

High fat diets reduce methylation of the CPT gene. This activates the CPT gene which results in more carnitine palmitoyltransferase (CPT) being produced. This improves fat metabolism, but also increases the risk of developing type 2 diabetes.

High carbohydrate, low fat diets increase methylation of the CPT gene. This inactivates the CPT gene which results in less CPT being produced. This is OK because there is little fat to be metabolized. However, it also has the advantage of reducing the risk of developing type 2 diabetes.

This can be visually represented as:

How Was This Study Done?

This study combined the results from 3,954 selected participants in three previous clinical trials:

The Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study.

The Framingham Heart Study.

The REGICORE study. This study is similar in design to the Framingham Heart Study except the participants were drawn from a region of Spain.

The participants were selected based on 4 criteria:

The study they were in measured metabolic disease outcome.

The study they were in included a detailed diet analysis.

A DNA methylation analysis was performed on blood taken from these participants so that the methylation status of the CPT gene could be determined.

mRNA levels were measured for the CPT gene (This is a measure of how active the gene is. Active genes will produce lots of mRNA. Inactive genes will produce very little mRNA).

The study then analyzed the data and looked at the associations between carbohydrate and fat intake with:

Methylation of the CPT gene.

Activity of the CPT gene (measured as the amount of CPT mRNA produced by the gene).

Type 2 diabetes and other metabolic diseases.

Do Low Fat Diets Reduce The Risk Of Diabetes?

The authors systematically tested the predictions of their unifying hypothesis (To help you understand the significance of their findings, I am repeating the visual representation of their unifying hypothesis below):

Methylation of the CPT gene was negatively associated with type 2 diabetes. Simply put, when the methylation of the of the CPT gene was high, the risk of type 2 diabetes was low. This confirmed the results of previous studies.

2) Carbohydrate and fat intake influenced methylation of the CPT gene. Specifically:

- Carbohydrate intake and the ratio of carbohydrate to fat intake were positively associated with CPT methylation. Simply put, a high carbohydrate, low fat diet resulted in increased methylation of the CPT gene.

- Fat intake was negatively associated with CPT methylation. Simply put, a high fat, low carbohydrate diet resulted in decreased methylation of the CPT gene.

3) Carbohydrate and fat intake influenced the activity of the CPT gene. Specifically:

- Carbohydrate intake and the ratio of carbohydrate to fat intake was negatively associated with CPT mRNA levels (a measure of CPT gene activity). Simply put, a high carbohydrate, low fat diet resulted in lower CPT gene activity. This means the CPT gene produced less CPT. And, combined with the previous data, it also means that methylation of the CPT gene decreases its activity.

- Fat intake was positively associated with CPT mRNA levels. Simply put, a high fat, low carbohydrate diet resulted in greater CPT gene activity. This means the CPT gene produces more CPT. And, combined with the previous data, it also means that reducing methylation of the CPT gene increases its activity.

4) CPT gene activity influenced the prevalence of type 2 diabetes. Specifically:

- High CPT gene activity was positively associated with the risk of type 2 diabetes.

- Low CPT gene activity was negatively associated with the risk of type 2 diabetes.

Putting this all together, as the authors had predicted,

High fat, low carbohydrate diets reduce methylation of the CPT gene. This activates the CPT gene which results in more CPT being produced. This improves fat metabolism, but also increases the risk of developing type 2 diabetes.

2) High carbohydrate, low fat diets increase methylation of the CPT gene. This results in less CPT being produced. This is OK because there is little fat to be metabolized. However, it also has the advantage of reducing the risk of developing type 2 diabetes.

In short, the results of the study confirmed all the predictions of the author’s unifying hypothesis.

Putting it all together, the authors concluded, “Our results suggest that the proportion of total energy supplied by carbohydrate and fat can have a causal effect on metabolic diseases [like type 2 diabetes] via the epigenetic status (DNA methylation) of the CPT gene.” Simply put, their data suggested that high carbohydrate, low fat diets reduced the risk developing type 2 diabetes.

What Does This Study Mean For You?

Let me start by saying that occasionally I like to give you a peak behind the curtain and talk about emerging areas of research. We should think of this article as the beginning of an exciting new area of research rather than as a definitive study.

I should start with the disclaimer that this study looks at associations between diet, methylation of the CPT gene, and risk of developing type 2 diabetes.

Associations do not prove cause and effect. This study does not prove that epigenetic changes to the CPT gene caused the reduction in type 2 diabetes risk.

High carbohydrate and high fat diets likely influence the risk of developing type 2 diabetes in other ways as well. For example, the fiber in healthy high carbohydrate diets may support friendly gut bacteria that reduce the risk of developing type 2 diabetes.

I also don’t view this study as one that settles the debate as to whether low carb or low fat diets are better for reducing the risk of type 2 diabetes. It does not clinch the argument for low fat diets. Rather, this study suggests a mechanism by which low fat diets may reduce the risk of metabolic diseases.

In summary, this study does not end the debate as to whether low carb or low fat diets are best. However, it does remind us just how complex the human body is. It reminds us that simple assumptions about how foods affect our bodies may not be the correct assumptions. It also helps us understand why nutrition can be so confusing.

The Bottom Line

In recent years, DNA sequencing has become all the rage. It seems like everyone is offering to sequence your genome and tell you what kind of diet is best for you.

That is where epigenetics comes in. Epigenetics is the science of modifications that alter gene expression. In simple terms, both DNA and the proteins that bind to DNA can be modified. This does not change the DNA sequence. But these modifications can determine whether a gene is active (turned on) or inactive (turned off).

Epigenetics makes nutrition more complicated, and more confusing. For example, diabetes is characterized an inability to control blood sugar levels properly. Accordingly, it seems only logical that carbohydrates, especially sugars and simple carbohydrates, are the problem.

This study showed that high carbohydrate, low fat diets cause epigenetic modifications to a gene that reduces the risk of developing type 2 diabetes and other metabolic diseases. Conversely, high fat, low carb diets have the opposite effect.

This mechanism is consistent with multiple long-term studies showing that whole food, low fat diets reduce the risk of developing type 2 diabetes.

This study does not end the debate as to whether low carb or low fat diets are best. However, it does remind us just how complex the human body is. It reminds us that simple assumptions about how foods affect our bodies may not be the correct assumptions. It also helps us understand why nutrition can be so confusing.

For more details read the article above.

These statements have not been evaluated by the Food and Drug Administration. This information is not intended to diagnose, treat, cure, or prevent any disease.