Metabolic and Epigenetic Memory
How Weight Gain, Loss, and Regain Leaves Their Mark on Us
I’mma need a minute to set up some context with this one, so bear with me.
In 2022, the WHO reported that 2.5 billion people worldwide were overweight or obese.1 That’s about one-third of the total global population of 8 billion people. This rate lags behind the rates of adult overweight and obesity in the US and the UK, which both hover around two-thirds.
Given these numbers, it might seem ironic that losing weight is actually pretty easy for most people—in the short term anyway. If we define “diet” as an eating intervention, a temporary change to one’s dietary habits, it’s been demonstrated that anyone can lose weight on any diet. The trick is to choose something that works for you, something that you can stick to.2
As I’m always harping on about: instead of choosing a “diet” that works for you, you can just as well choose a dietary pattern that works for you. Any “diet” is simply attempting to help you get into an energy deficit while not making it feel like you’re in one. The problem is that after a few months, energy balance is reached, so weight loss slows before stopping altogether.
Then, folks get demotivated and stop the “diet”. The fact is that short-term “diets” and changes are just that: short-term. And when a dieter returns to their baseline eating, for some reason, the weight returns. Actually, the reason is not mysterious. Whereas the “diet” helped them achieve an energy deficit without feeling too restricted, the baseline eating pattern puts them in a slight energy surplus, even though they don’t feel like they are and may not even feel satisfied with their foods and meals.
Thus, the diet and short-term weight loss are easy enough. The problem is what’s referred to as weight loss maintenance, the long-term ability to stay at the lower body weight. Research shows that only about 20% of people are able to maintain weight loss long-term.3
Ouch.
And long-term is defined as greater than one year, and meaningful weight loss is defined as about 10% or greater.
I came across this stat in my own journey of losing over 100 lbs., something that, no joke, scared me. I had just been successful at something I had struggled to do for many years as I battled a hyper-inflated appetite, and I knew I hadn’t quite figured it all out, and that I could easily fall back into my old ways and basically put that fat suit back on.
This was 4-5 years ago already—all of 2019 and the first half of 2020—but I don’t feel like I’m in any danger of gaining any of that weight back.
I know I have my systems in place; I know what foods and meals give me the most satiety and satisfaction; I know how to track food; I know how to realistically estimate energy, calories, and macros in foods when I can’t track (like when I’m at a restaurant). I know how much energy (calories) I can eat to put me in a deficit, to keep me in maintenance, and to put me in a surplus. I have a reasonably accurate understanding of how much energy I burn and how much I can burn with activity, like lifting weights and cardio.
Still, despite these tools and systems, if they were all wiped from my memory, I still think I wouldn’t be in much danger of gaining that lost weight back. And I’ve often wondered why.
I may have found some things that can explain why, and hopefully, if you’ve struggled with weight loss, it can also help you understand why long-term weight loss is not easy. Most importantly, we can arm ourselves with some knowledge to help us achieve our health, fitness, and body composition goals.
Metabolic and Epigenetic Memory
Concepts I’ve just recently stumbled upon, Metabolic Memory is a theory that specifically came about from researchers studying diabetics and were trying to understand and control hyperglycemia (elevated blood sugar). The theory states that “a prior period of hyperglycemia increases the long-term risk of complications. Conversely, a period of near-normal glycemia produces long-term beneficial effects on complications, with such effects persisting even though subsequent levels of glycemia may have risen.”4
That is, wherever your health is currently sitting, whatever your baseline happens to be for a period, the body remembers that state. In the case of blood sugar, having a period where your blood sugar is elevated beyond what the body is accustomed to, even if you return to your normal levels, the body remembers the deviation, and it increases risks of future metabolic disorders. By contrast, if you’re typically accustomed to having more elevated blood sugar and you have a period where you can temper those levels, the body remembers that “normal” period, which it endeavors towards, which seems to lower risks of future complications.
Though this theory of metabolic memory focuses on hyperglycemia and glycemic control, what this is really getting into is Epigenetic Memory.
Epigenetics5 is gene expression. Which genes we turn on and/or off lead to our phenotypes, our physical function and appearance, at a macro level like our muscles and at a micro level down to the building blocks of our cells. As the authors of one paper describe it, these are:
…“Changes in gene function that cannot be explained by changes in the DNA sequence”, leading to the propagation of heritable changes in phenotype…Where epigenetic regulation is dynamic, it is often described as epigenetic memory: a heritable change in gene expression or behavior that is induced by a previous stimulus. The stimulus can be either developmental or environmental.6
If epigenetic memory is heritable, these are DNA “memories” passed down from one generation to another. Environmental stimuli becomes a “memory” not inherited and can affect epigenetic expression, and our bodies will adjust depending on the situation of the memory.
This is where it gets crazy and crazy interesting.
Our bodies remember how long we’ve held a certain body weight and will fight to maintain that weight and/or return to it. The title of one paper sums it up: “Adipose Tissue Retains an Epigenetic Memory of Obesity After Weight Loss.”7 As the authors explain it,
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 responses in an obesogenic environment, contributing to the problematic 'yo-yo' effect often seen with dieting.
They also found similar obesogenic memory in human adipocytes (fat cells).
Another paper, “Physiological and Epigenetic Features of Yoyo Dieting and Weight Control”8 offers some insightful explanations for this epigenetic memory. “The study of epigenetic mechanisms in weight control is further complicated by the recent finding that DNA methylation profiles are instable in adulthood and affected by diet, exercise and weight loss interventions.”
As Wikipedia has it, DNA methylation is the mechanism that changes “the activity of a DNA segment without changing the sequence.” That is, certain genes are expressed, and others are not. So, our diets, exercise activity, and certainly weight changes all start affecting our gene expression.
Furthermore, the authors go on to explain that “Weight loss and a negative energy balance altered the secretion of circulating hormones such as the orexigenic [appetite inducing] ghrelin or the anorexigenic [appetite reducing] leptin, insulin, GLP-1, CCK and PYY.”
Ghrelin is often simply referred to as a hunger hormone and the others as satiety hormones, and weight loss increases the appetite inducing hormones and reduces the satiety hormones. The body remembers the abundance of energy and would prefer to return to that state. It doesn’t know or care about the other detrimental ramifications the extra weight and energy has on our health, and it fights to pull us back up.
Becoming obese does not occur overnight. It takes a considerable amount of time under constant obesogenic pressure to develop adiposity. This length in time also allows an individual's biology to adapt to the new state of obesity. This adaptive process defines a state in which energy expenditure and high energy intake are balanced to defend the newly gained weight and adiposity.
Moreover,
Given the involvement of epigenetic mechanisms in cognition and reward behaviors, it seems plausible that epigenetic mechanisms may also be linked to the CNS hedonic control of food intake and food reward behaviors, and in general to the development of obesity in both the CNS and peripheral tissues.
In addition to the increase and inversion of appetite hormones, losing weight also results in an increase of the dopamine hits we get from eating.
So, what can we do about it?
Are we all doomed to be overweight and obese? Is the answer “Can’t win. Don’t Try”?
The authors of this paper also give some insight into what we can do to maintain weight loss. Remember that gene expression is dynamic. It is not fixed. It responds to our environments or, that is, our lifestyles.
First, “How weight loss is achieved appears to be of crucial importance. If the negative energy balance stems from severe caloric restriction, strong counter-regulatory stimuli come to play. [Therefore] a slow weight loss, e.g. based on switching from an obesogenic to a healthier diet, seems to evade some of the adaptive responses to fully reverse obesity.”
Second, “Limiting or preferentially avoiding weight cycling in the first year after weight loss appears to be crucially important for a sustainable long-term weight maintenance.”
The reason for losing weight slowly and avoiding weight cycling is that “such altered levels of circulating hormones that facilitate weight regain appear to persist for at least 1 year.”
Remember, earlier I said that if I were to lose all my experiences and tools for maintaining my healthy body weight that I’m no longer afraid that I would any of that weight back, let alone all of it.
This last point certainly jives with my own experience. That first year after losing all that weight was really hard. I didn’t have my systems in place, or not as well, and unbeknownst to me, my obesogenic hormones were screaming to bring my body weight back up. I white-knuckled and brute-forced my way through it, but now that I’m on this side of it, that wasn’t necessary. I could have been a little more relaxed in my attitude about food and my eating.
Also, as I’ve written about, I have done intentional bulking and cutting cycles each year after maintaining my low weight for a year. First, as the bulks brought on some weight gain, I think it reset some of my appetite hormones. Additionally, I do believe that my body also remembers these phases because the weight loss gets a little easier each time, and the weight gain gets a little harder. My body now defends this lower body weight, so when I bulk, I quickly get full and start losing interest in food. In fact, I think that food even becomes less flavorful when I’m in a surplus. Those are all ways that my body is trying to get me to stop eating, which can explain why people who have never been overweight seem to have an easier time maintaining their weight—they have these same mechanisms working to defend their lower body weight.
Also, going back to that one-year threshold to predict success, in my experience, it’s not a light switch. We don’t hit that point and cross some invisible finish line where we can then relax because our epigenetics and appetite hormones reset. For me, it was a gradient, a gradual transition. Things got easier over time, little by little.
A quick recap:
If you’ve been on the weight cycling carousel for some time:
Understand that your body remembers the body weight that you’ve held for a long time and wants to return to it, whether that’s high or low. You’re not crazy, and you’ll likely face times when you feel like you are.
Lose weight slowly. The faster we drop weight, the more aggressively our bodies respond to bring us back to where we were.
Add consistent exercise to your schedule, which will start expressing the genes and hunger hormones in the direction we want.
If you lose more than 10% of your bodyweight, it’s important to hold that weight without weight cycling or yo-yo’ing to allow your body to accept, remember, and defend that new weight. As the authors of this last paper describe it, even “2–6% body weight regain can already reverse the benefits of losing ≥10% body weight.”
Remember that our bodies and epigenetics are fluid and dynamic and respond to our lifestyles, and you have the power to choose what kind of stimuli you want to present to your body.
Give yourself time. Be patient. Stay consistent. Soon, not only will you reach your goals, but they will be easier to maintain than you can imagine.
World Health Organization. Fact Sheet. “Obesity and overweight”. 1 March 2024. Obesity and overweight.
Johnston BC, et al. “Comparison of weight loss among named diet programs in overweight and obese adults: a meta-analysis”. JAMA. 2014 Sep 3;312(9):923-33. doi: 10.1001/jama.2014.10397. PMID: 25182101.
Wing RR, Phelan S. “Long-term weight loss maintenance”. Am J Clin Nutr. 2005 Jul;82(1 Suppl):222S-225S. doi: 10.1093/ajcn/82.1.222S. PMID: 16002825.
Lachin JM, Nathan DM; DCCT/EDIC Research Group. “Understanding Metabolic Memory: The Prolonged Influence of Glycemia During the Diabetes Control and Complications Trial (DCCT) on Future Risks of Complications During the Study of the Epidemiology of Diabetes Interventions and Complications (EDIC)”. Diabetes Care. 2021 Sep 21;44(10):2216–24. doi: 10.2337/dc20-3097. Epub ahead of print. PMID: 34548284; PMCID: PMC8929187.
D'Urso A, Brickner JH. “Mechanisms of epigenetic memory”. Trends Genet. 2014 Jun;30(6):230-6. doi: 10.1016/j.tig.2014.04.004. Epub 2014 Apr 26. PMID: 24780085; PMCID: PMC4072033.
Hinte LC, et al. “Adipose tissue retains an epigenetic memory of obesity after weight loss”. Nature. 2024 Dec;636(8042):457-465. doi: 10.1038/s41586-024-08165-7. Epub 2024 Nov 18. PMID: 39558077; PMCID: PMC11634781.
Contreras RE, Schriever SC, Pfluger PT. “Physiological and Epigenetic Features of Yoyo Dieting and Weight Control”. Front Genet. 2019 Dec 11;10:1015. doi: 10.3389/fgene.2019.01015. PMID: 31921275; PMCID: PMC6917653.