Adipose tissue retains an epigenetic memory of obesity after weight loss

I kinda went down a rabbit hole a while back with certain treatments that can kill adipocytes, as there's actually some significant research backing both heat-generating and cold-generating treatments. They do kill fat cells, and they are flushed out of the body. But people who undergo such treatments do not lose fat. At best, these devices can reshape your fat, pulling it out of one area and distributing it more evenly in other areas.

The problem is that when you kill an adipocyte, it releases all of its triglycerides, which are then free to move around the blood stream. But when blood triglyceride levels are high and there isn't significant oxidation, other metabolic processes are triggered to start to store them. So you kill an adipocyte, release the triglycerides, which get reabsorbed into still living adipocytes, which now get engorged and then multiply again, replacing the fat cells that have been killed.

After learning quite a bit about these processes, I think these devices might actually be useful, not for losing fat, but by eliminating this sort of fat memory. In other words, they should be used after significant weight loss, because adipocytes are relatively empty and externally triggered apoptosis can kill the cells without releasing significant quantities of triglycerides which can be reabsorbed and trigger adipocyte mitosis. I think this would effectively reset that person to a state as if they had never been fat in the first place. Thoughts?

Similar adaptions occur in muscle. The extent of new muscle fiber development (hyperplasia) is debated, so there are multiples factors influencing how muscle retains some memory of past strength ability.

Once you’ve reached a level of physical strength it’s easier to return to that level in the future. This has been a topic of debate in the sports world because past anabolic steroid use could therefore carry benefits into the future long after the athlete has stopped using the steroid. Non-professional athletes shouldn’t get too excited about using steroids, though, because the damage steroids do to the body’s own hormone systems also has lasting effects unless you plan on doing TRT for the rest of your life, which has its own downsides.

For average people this does show the importance of getting at least some exercise when you’re young. It’s much easier to get a little bit fit when you’re young which then makes it easier to stay fit in the future. Never too late too start.

How do glp-1 drugs such as semaglutide, terzepatid and retatrutide impact apoptose?

"Tirzepatide promotes M1-type macrophage apoptosis and reduces inflammatory factor secretion by inhibiting ERK phosphorylation" [1]

[1] https://www.sciencedirect.com/science/article/abs/pii/S15675...

Yea, this actually explains the transcriptional expression and weight gain very well. Strong than the methylation evidence imo. I didn’t see any causal analysis only correlated and the cells still being there makes sense.

Is this true? When I looked into this issue it seemed the medical consensus is that fat cells are mostly constant throughout life, and weight gain happens through adipocyte hypertrophy.

>> But when you lose weight, they don't apoptose

Googled for "Adipocyte apoptosis" and oh boy... It does happen, but I don't trust the AI summary. This looks like a deep rabbit hole.

"An ounce of prevention is worth a pound of cure" continues to be an undefeated aphorism.

I am pretty sure the only way to reduce the number of cells is liposuction

For me, sugar was the reason I couldn't lose weight. I got a CGM (continuous glucose monitor) and got my blood sugar under control, and with very little effort I lost a lot of weight.

I use 90% cacao Lindt to control my sweet tooth. 1/2 the bar has 4g of sugar, and I consume it over hours. It also has the side effect of reducing my hunger. If you eat much of 90% chocolate, it makes you feel nausea. The trick is to put a small chip in your mouth and let it melt. It's quite delicious and I've not had any sweets in 80+ days.

Insulin sensitivity is a real thing. The less sensitive to insulin you are, the more of it is produced to process a given amount of glucose. And the more insulin (anabolic) is produced, the less glucagon (catabolic) is.

In other words, low insulin sensitivity means your body remains in the feeding (fat building) state more, as opposed to fasting (fat burning).

Insulin sensitivity decreases with age, and with excessive intake of particularly simple carbs. It can be improved through fasting, certain dietary supplements, and low carb diet.

All of this is, to the best of my knowledge, not disputed or 'bro science'.

A lot of people blame failure to lose fat on a "slow metabolism" but this is usually incorrect. Have you had an actual resting metabolic rate (RMR) test to quantity your baseline total daily energy expenditure?

Fat adaptation is a real thing. Endurance athletes focused on longer events will target some of their training around that energy system. This is more complex than can really be explained in an online comment but basically you want to do long training sessions below your lactate threshold in a glycogen depleted state.

It is well known that if you gain muscle then lose it, it is easier to regain it than the first time (IIRC, the cells store extra nucleii?). This could be a similar effect but with fat cells.

The physical mechanism is mitochondrial uncoupling proteins (UCP). They regulate how much energy is wasted as heat when converting ADP to ATP, determining how efficient one’s metabolism is. When you lose weight, your UCP proteins start wasting less and less energy when producing ATP, which is one of the things that makes dieting so hard.

Actually affecting that pathway is largely beyond us at the moment (that’s the bro science) but the mechanism is relatively well understood.

> It always did feel like it was easier to gain weight than lose it, especially fat weight and not muscle weight for me.

It is the exact, polar opposite for me. I cannot gain even if I eat junk all day.

Fat adaptation is not bro science, it is what happens when you do not consume enough carbohydrates to meet your TDEE so your mitochondria “learn” to become really efficient at burning fatty acids. It’s the whole premise behind keto/low carb. When used to our modern high-carb diets, the adaptation takes some time for genes to activate, since we eat a lot and never have long enough fasting periods to be able to quickly switch between glucose and fatty acid metabolism.

I have had a slow metabolism since I was a teenager. I don't think I've ever experienced a day in my life where I haven't thought about my weight, body composition, or felt guilty about eating food. And I'm not even that big. I've just never had the physique I wanted, and I always attributed it to having a slow metabolism.

I'm turning 40 in May, so since the start of February, I've finally pulled up my bootstraps and started taking my health seriously. I was likely 225 lbs at 5'10". Easily 32+% body fat.

The first thing I did was a deep extended fast, drinking only water, electrolytes, supplements, bone broth, and black coffee. I was able to shed a good amount of weight, fast. However, the longest I could fast for was 6 days; No matter what I tried, I could not figure out how to get good sleep. I tried once more for 4 days, and saw no improvement, so I stopped trying to fast. Mentally I could handle it, but without quality sleep, there was no way I could continue. This was mid-March, and I was at 204.5 lbs.

Also in mid-March, I did a VO2 max test, while fasted for 72 hours. It was very apparent that my metabolism was fat adapted. My VO2 max was very low at 33.8 ml/kg, which was to be expected. My RMR was found to be 1998 kcal/day, and my fat max HR was 161 bpm. Crossover to 100% carbs was at 179 bpm.

Since then, I've done a 180, and started eating about 1800-2000 kcal per day. My first goal is to ensure I eat 170-200g of protein per day, through as much whole food as possible, using whey or protein when needed. The rest of my diet is very clean, with no real restrictions on fats, and keeping carbs as low as possible. It's a fairly ketogenic diet, but I don't get worked up if my net carbs go to 50+g. Foods are usually Greek yogurt, flax, pumpkin seeds, nuts, eggs, berries, fish, poultry, and green vegetables/salads. If I ever add fat to anything, it's extra virgin olive oil first, then maybe butter/cream (i.e. in coffee). I take a number of supplements like Omega-3 fish oils, multivitamins, magnesium, and make my own electrolyte drink. Creatine as well.

I find that by the time I've done all of this, I have a very difficult time eating, and even trying to fit anything else in. I am never hungry, nor do I feel cravings for other foods. We just came back from Miami, and I had some ice cream with the kids, and some baked goods. I enjoyed them, but I was very excited to be back to my normal foods.

Since then, I've been running 3-4 times a week, focusing on Zone 2 training. I do 4 days a week of weightlifting, focusing on the big compound lifts. I have a 10K race on May 11, and a sprint distance triathlon on July 27 that I'm training for.

For this entire month, I have stayed at a constant 207.5 lbs +/- 0.5 lbs. I have been tracking other measurements like circumferences and body fat (using calibers and BIA scale), and it's apparent that I have gained strength, regained muscle mass, and improved my overall fitness. Running is still at a slow pace, but actually enjoyable now. My wearables estimate that my VO2 max is 37 ml/kg; they did show 33 ml/kg last month when I had the test, so they seem to be correlated.

I think the hardest part of the last month has been the sheer amount of work I've put in, only to watch the scale stay steady. I track my intake rigorously, weighing everything I can and using MyFitnessPal to track it all. How are people able to eat anything else? I couldn't add rice or grains to my diet even if I wanted to, I would easily hit 2500+ kcal per day.

People eat that much? Or rather, burn that much? I burn 2000 kcal per rest day, and maybe 2800-3200 kcal on workout days.

I will stick with this, since it is working to improve my health and fitness. It would just be nice to see the scale move without having to fast for multiple days. Cursed slow metabolism.

The problem with diets based only on calories is that they don't take satiety into account, nor health.

Calories is what makes you gain/lose weight, it's basic physics. Satiety is what makes you want to eat more/less. Nutrients are what is making you healthy.

Fiber and protein tends to make you feel full. Lack of them allow you to eat large amount of calories without feeling full. You need to keep track of micro and macro nutrient to stay healthy.

https://www.fourmilab.ch/hackdiet/

Thank you for sharing, I'd never seen this before. It's an incredibly good read (and relevant for me) so far.

More like "just take these GLP-1 agonists for the rest of your life". Those seem to have an effect on addictions etc. But at least when it comes to weight, people seem to put it back on once they quit. Perhaps the GLP-1 agonist is lacking an epigenetic reset button ...

You should definitely watch the Doctor Who episode Partners in Crime.

For me weightloss worked over a long period of time with a couple of strategies.

1. One was not eating breakfast, this works well when I'm in the office. Then you have fasting built into your daily routine. This has many metabolic benefits.

2. Switching to a low carb diet (keto). I never thought I'd quit eating bread, but reducing carbonhydrates (esp. sugar) and eating more eggs & meat had the biggest effect on my weight. More so than doing sports. This is just a rough guideline, I don't follow this very strictly.

3. Sports + Fasting: Sometimes on the weekends I go on a hike or do some sports and only eat when I get home in the afternoon (e.g. steak). This forces my body to take the energy from the fat reserves.

Don't try to lose weight fast. Don't do a diet for a limited amount of time. Change your eating habits to something you can live with permanently. Avoid sugar in drinks, it's so easy to get a lot of calories without feeling full. Sugar in general will give you hunger attacks. For me personally I feel best if I have a big part of calories coming from protein, followed by less carbs and some fat. But removing sugar from drinks alone lost me 30kg, without changing any other habits. Better for the general health as well.

Going to the gym helped me immensely. Not so much in losing weight directly but in feeling better and fresher.

Weigh yourself every day. Journal it. This sets up an objective metric to calibrate against.

Set medium term goals. Don't try to lose 20 kilos in six months. Lose the next kilo by this time in two weeks. Similarly, don't try to lose 0.1 kilos by tomorrow. Weight naturally fluctuates day to day based on water intake, sodium intake, muscle fatigue, and other things. But in the range of 2-3 weeks, you should be able to lose enough weight to see signal in the noise of day to day fluctuations.

If you aren't hitting your medium term goals, find a way to cut calories more. Starting the first month doing a comprehensive calorie log is valuable to help calibrate what foods and portion sizes are relatively problematic.

The rest is just finding eating patterns that work for you that help keep calorie levels low enough. There's a lot of advice about ways to do that, and most need to be taken with a grain of salt, but it's probably true that you can min/max at the margins by increasing fiber intake, increasing protein intake, drinking more water, eating more raw plants, intermittent fasting, and that sort of thing. But you'll mostly see fractional improvements on top of the bottom line math: calories burned need to exceed calories consumed.

As noted elsewhere here, it's a lot of exercise to burn off a few pieces of bacon. Exercise is good for weight loss, but again, it's mostly at the margins for the average person, especially if that person is not an athlete.

I think you need to make it sustainable. I never had to do it consistently but even I know... Nobody is going to live hungry all the time. Nobody is going to grow old counting calories every damn day.

So rather than just eating less make sure to work out some. Consistently. Id suggest strength training. I did a full body strength training workout 2-3 times a week. Some may suggest doing leg days, arm days, etc but going there takes time on itself and i have other places to be than the gym.

To match that strength training eat more protein. Things like chicken are your friend. This tends to be higher on the satiety index so you'll feel full faster and you'll eat less without it being so painfull. Eat a bit of protein with every meal Really there's a whole lot of other stuff that you can fill yourself up with that won't be too bad for ya. And when you go for a carb? Get the complex one if it's a choice. It'll dampen that peak in insulin.

Avoid the sugary stuff. It's addictive for sure but taper off. Eat before going to the store. Make the hard decisions there not with the easy snack within reach in the evening.

Do a bit of everything that works until it becomes second nature. Overfocusing on one silver bullet doesn't tend to work.

I might consider working with a cognitive behavioral therapist. Since you’ve already lost weight, you do know (in big picture terms) how to lose/not gain weight: eat a healthy diet consistently and get regular exercise. For most people who struggle with their weight, there are emotional eating patterns or even just bad habits that are just hard to break on their own.

Of course knowledge about diet and exercise is immensely valuable, but if there are psychological factors getting in the way, it’s going to be harder to adopt a consistently healthy lifestyle.

Probably my only good advice is to not take internet advice too seriously, which I'm sure you are aware of. The most epistemologically sound advice i can give is try everything and find what works for you. Lots of internet people advocate for low carb approaches for many apparently valid reasons. Recently, i tried eating whole food plant based and it's been an amazing 2 weeks (yes incredibly short time to report). I'm not trying that hard, i'm eating well, and feel amazing. If i keep going I'll probably supplement protein, vitamin b, omegas, fish, etc, but my weight is just falling off so far, unlike any other eating plan i've tried. Not super strict either. Eating whatever i want when i eat out, but i like how it makes me feel so i tend to stick with it when possible. Your mileage will vary. It's literally 2 weeks so far lol

There aren't any, statistically speaking. All strategies are about equally ineffective, long-term. Only really expensive, high-touch, long-term personal engagements by professionals achieve really significant results, and even there, less so than you might think.

The answers that actually work are "move to an environment where you will likely get and stay skinnier" (maybe a different, skinnier country) or (this one's new! There's finally a semi-reasonable answer to this question!) "take GLP-1 agonists". There's no strategy that'll do it (for outliers, yes, but over a population, no)

Its a lifestyle change not a diet. Don't stop the diet / exercise when you get to the "target" weight.

This idea sucks when you are looking at a plate of lettuce leaves - but you should also avoid extreme diets and extreme exercise as it is unsustainable.

There is not good evidence in favor of that theory.

I had this same experience, but I have not continued to take the medication after a short experiment. I found I could get a similar outcome (subjective experience) through my food selection Today I’ve eaten around 2kg of vegetables today (zucchini, capsicum, eggplant, cauliflower, spinach) all of which was under 500 calories, and I’ve eaten fish. If I eat a massive amount of vegetables and get ~200g protein, I don’t feel I’m depriving myself and am satiated on under 2000 calories, previously I would typically eat over 3000 on a normal day.

As for people lacking willpower, the genetics of hunger mean all of us experience vastly different levels of hunger. You might be interested to read about the family in Pakistan who could not produce a relevant hormone leptin, and the toddlers driven to fighting by insatiable hunger to steal food from each other, and the dramatic change in their lives after medical intervention with leptin injections

I think you mean semaglutide.

The idea is that fasting does encourage aptopsis of cells.

> People that have had larger muscles tend to have an easier time building them back up, as well.

Yes, although I don't know whether that's epigenetic.