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Comment by smooth_remmy | Hacker News Reader

Petro Dobromylskyj is one of the foremost experts of fat metabolism. He has a blog called Hyperlipid where he's been blogging about fat metabolism and interpreting research for close to 10 years.

He thinks the GLP-1 inhibitor drugs will be a disaster in the long term because they 1) cause weight loss but also 2) cause the body to create lots of new adipocyte (fat cells). Increasing the number of adipocytes is very unusual after puberty. As long as you are taking the GLP-1 inhibitor drugs you will lose or maintain weight, but as soon as you stop you will gain a lot of weight back.

Here is the blog post: https://high-fat-nutrition.blogspot.com/2023/01/glp-1-agonis...

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I don't know if I'd call a veterinary anaesthetist a foremost expert on fat metabolism. His thoughts on insulin signaling are not consistent with the consensus among obesity researchers. He thinks glp-1 works through uncoupling or fat browning which is just not true.

The consensus among most obesity researchers is the cause of obesity is primarily neurological, not metabolic. Basically the brain can't properly regulate weight in the current obesogenic environment. When you look at GWAS most of the genes related to obesity are active in the brain, (as opposed to genes for diabetes which are more closely related to fat/metabolism etc...).

I'd describe Petro Dobromylskyj as a smart hobbyist with an outsiders views of obesity, not a foremost expert on fat metabolism.

Is human metabolism really so different from other mammalian metabolism?

1. If the expert consensus is that the cause is neurological rather than metabolic, it seems more important to not that human neurology really is so different than other mammalian neurology.

2. Clinical anesthesiology is pretty far from this topic.

yes. yes it is.

The only published paper I can find by him is on small animal ventilation, so I don’t think he’s a “foremost expert” on fat metabolism in animals either.

He is basically the world's leading expert, but you can only see credentials, lol.

What makes this person the world's leading expert?

depth and breadth of knowledge and deep curiosity and persistence.

Many in the middle ages used those qualities to spend lifetimes investigating alchemy and witchcraft.

World leading experts usually have an impressive publishing record in the field, often a top academic research position and a long record of speaking at important global conferences on the area.

Does he have all those? I'm honestly asking, I've never heard of him.

No he doesn’t.

Hey, you basically worship credentials, so you're not going to be impressed with a person who doesn't have them regardless of their breadth and depth of knowledge. I don't know what to tell you.

That’s not credentials, that recognition by others of expertise in a field.

Given that injections cost ~ $1000/month, you're saying basically that it'll be a great recurring revenue stream for the companies. A CFO's wet dream.

consider that treating obesity-related consequences also costs money and enriches companies as well. I think its worth it

Considering the benefits of good diets and exercise, I think it's worth it not trying to hack or shortcut our way to a healthy life with weird drugs or whatever.

I did a little bit of research and for people in the UK it appears to be substantially less. I found a few health companies offering it for <$250/mo. I’ll probably wait until it’s readily available on the NHS but it is tempting.

My US doctor recommended it to me last week and said there was a way for it to cost about $200/mo if I want to do that. I thought it was strange that he said it that way instead of just saying the price, but I didn't follow up because we were 45 minutes into the appointment and I was ready to get out of there.

I'm supposed to book a follow up appointment after I've read about it, so I guess I'll find out what he means then.

Pretty much every expensive medication has a copay assistance program in the US.

For trirzepatide: https://www.mounjaro.com/hcp/savings-resources

They typically are income blind and make your out-of-pocket price negligible. I'm on a med (Skyrizi) that's $18k per shot, one every three months; their assistance program ensures I don't pay more than $5.

They chip in on the deductible/coinsurance/copay, you don't skip the medication due to cost, and they still get significant money out of your insurer. Everybody wins, until everyone's premiums go up next year.

Goddamn your healthcare system is fucked up.

Is it? Isn't this exactly the outcome you'd hope for?

Individual consumers pay basically nothing and companies are still incentivized to innovate and create new medicines

Individual consumers aren’t paying nothing. The cost is just being hidden from them so they don’t flip over the tables.

They pay via premiums - mine went up to $2,792/month this year - or if their employer pays those, via the resulting wage impact.

And, as a result, we spend 2-3x what the rest of the OECD spends on healthcare - public and private spending - with roughly the same health outcomes.

Agreed. Injecting a milliliter of fluid worth as much as a new car makes me twitchy.

Your doc was probably referring to purchasing semaglutide from a compounding pharmacy, which is usually in the $200/month range (depending on dose). Compounded versions don't typically come in the user friendly "injection pen" format that brand name versions do, so not everybody is comfortable with that option.

Interesting. For an $800/mo savings, I can get real comfortable self administering an old-fashioned shot.

14mg Rybelsus can be had for about $200/mo through Canadian pharmacies.

Look at 1800rxonline.

I thought the UK had government healthcare?

It does but it doesn’t mean you get any treatment available. They carefully make decisions on what treatments they can/should provide. This may be offered eventually but at the moment it’s a case of be very fat and get offered gastric sleeve or just be overweight and no treatments are offered other than advice about losing weight

Any sort of new care option, you're looking at 20-30 year window before it may become an option?

Semaglutide is available on the NHS but I wouldn't currently qualify. It'd only be prescribed if I met certain criteria such as having type 2 diabetes.

It's a case of either paying for a private prescription now, or waiting until it's made more accessible on the NHS.

The only thing I see from him on google scholar is about mechanical ventilation for small animals. What's his background?

Here is an introduction I found from his blog:

>I am Petro Dobromylskyj, always known as Peter. I'm a vet, trained at the RVC, London University. I was fortunate enough to intercalate a BSc degree in physiology in to my veterinary degree. I was even more fortunate to study under Patrick Wall at UCH, who set me on course to become a veterinary anaesthetist, mostly working on acute pain control. That led to the Certificate then Diploma in Veterinary Anaesthesia and enough publications to allow me to enter the European College of Veterinary Anaesthesia and Analgesia as a de facto founding member. Anaesthesia teaches you a lot. Basic science is combined with the occasional need to act rapidly. Wrong decisions can reward you with catastrophe in seconds. Thinking is mandatory. I stumbled on to nutrition completely by accident. Once you have been taught to think, it's hard to stop. I think about lots of things. These are some of them.

Oh man, the first result for him on Google is a link to a YouTube video. That makes my BS meter instantly peg.

What kind of crap do you watch on YouTube that manages to taint the entire platform?

youtube consistently steers everyone who touches it to more and more extreme content with the passage of time. It's not unique, and often times that content tends to be anti-science.

I'm not the OP but youtube is tainted for anything other than entertainment and a few select channels like the ones by PBS e.g Space Time.

That's in stark contrast to my opinion about YouTube. I have a huge list of highly trust worthy subscriptions / reference channels and no other social media platform comes close. If you live on your subscriptions channel, you never need to worry about content being thrown at you, or radicalization rabbit holes.

I can easily find upper graduate university lectures for complex topics. YouTube makes it easy to link first sources unlike other image/video platforms. Also, since they appear on official pages of reputed sources (conference channel, university channel) there is a certain level of reliability irrespective of who the speaker is.

Lastly, search for any popular video on YouTube and you will see just as many 'response' videos. While not intentional, it helps avoid echo chambering as the counter argument is readily available .

> If you live on your subscriptions channel, you never need to worry about content being thrown at you, or radicalization rabbit holes.

Ok, but you understand why someone might be weary that the most common first hit for someone might be an arbitrary youtube video given your premise is living on the channels you've subscribed to.

The bulk of youtube's content is garbage. You have to go sifting through the content over time, suffering through the recommendation engine (or a shortcut - ask friends who've already lived through that nightmare) to find the geese who lay the good eggs.

There's a lot of crap on YouTube; that taints things.

Every time some rando on the 'net claims "do your own research" they'll send a link to a YouTube video of some charming BS artist with no qualifications peddling ideological garbage to whomever is credulous enough to watch it uncritically.

Are there good YT channels? Yeah. But 9 times out of 10 (or more) when I search for some rando's recommended expert and the first result is a YT video, it's crap. Utter crap.

I nearly choked when my sister-in-law told me a couple years ago about some really convincing anti-vaccine information she had read which made her very nervous. I asked her what she'd heard, and she gave me a link to a YT video by Dr. Shiva. Yes, THAT Dr. Shiva. Ha! I tried to break it to her gently, but I'm pretty sure she still decided he was a credible source of information.

Note that they're also talking about Google search ranking. People who are actual experts in things tend to have meatier hits at the top than J Random Vlogger.

> one of the foremost experts of fat metabolism.

What makes you say that? In my experience, there are no 'experts' in empirical fields who are no themselves deeply and practically engaged with actual research. Being well-read does not make you an expert. Writing blog posts and appearing on YT doesn't make you an expert. Critics are not experts. To be an expert in anything you have to get your hands dirty.

Nothing I can see from this guys publications or bio make it seems like he's an expert in human fat metabolism at all, let alone a 'foremost' one. I base this on a fairly cursory survey, so I'm happy to be corrected. But convincing corrections would absolutely require details regarding what he has contributed to the field.

So drug companies should be seeing alarm bells going off. You can profit off this drug, and it's an endless supply of revenue.

With every weight loss intervention when you stop you gain back the weight. GLP-1 agonists don't seem to be any different than another other intervention.

The point is that you could gain back the original weight plus more. Most adults who become obese have not increased their number of fat cells - their fat cells just become larger.

The GLP-1 drugs literally increase the number of fat cells.

How does liposuction fare in long term fat loss?

> Weight gain was reported in 43 percent of the responders, with 56 percent of them gaining between 5 and 10 pounds 6 months after their surgery. Fat return was reported in 65 percent of the responders. https://pubmed.ncbi.nlm.nih.gov/16651945/

Liposuction isn't a solution for fat loss beyond some localised cosmetic reduction. You can't use it to put a morbidly obese person in normal BMI range.

My point is that you end up with fewer fat cells, but unsure whether this has any impact on weight regain.

(Which is worth assessing if there are concerns about these drugs increasing the number of fat cells (otherwise unusual in adulthood) and creating a risk of fat volume rebound beyond initial levels after discontinuation).

Weight is back to baseline within a few months after lipectomy and sometimes greater than baseline. In animal models there is regeneration of fat cell number following lipectomy along with increase in cell size, and which mechanism predominates depends on how large the fat cells were before (manipulated by reducing food). This is the critical fat cell size hypothesis, and in humans there is similarly evidence that fat cell number increases (hyperplasia) in advanced stages of obesity after the cells reach critical size (hypertrophy) but I'm not aware of that being studied in situ in lipectomy recovery. I'd make a confident guess that it depends on how obese the patient is and perhaps their baseline number of fat cells.

But there are a lot of different mechanisms and feedbacks at play and I'm not sure how much insight can be gained from comparing localised lipectomy to systemic adipocyte proliferation resulting from a drug.

This sounds especially bad cosmetically, because the fat will show up in some place it didn't used to. I would imagine it could make you look even worse.

Liposuction is no answer. Your body puts back the removed fat cells in other places.

The human body has VERY strong setpoints about weight. Fat cells "remember" the weight that you had when they were created. You have to hold your weight at a point for something like 3-5 years before your body relents enough that the setpoint moves.

How do fat cells encode the information about one's weight when the cells are created?

It's probably not the fat cells, it's much more likely the hypothalamus.

Maintenance of lipid concentration when formed.

The aggregation of the tiny setpoints creates your larger setpoint by either drawing out from or pushing into your bloodstream the lipids that they have.

This is one of the most infuriating things about the "you just need to eat less" crowd. That's simply the first step. But you somehow need to maintain that for years while your body readjusts since fat cells turn over fairly slowly in your body (about 20-25% per year).

Maintaining a lower body weight while your body is actively fighting you for years is a superhuman level of willpower that very few of us can muster.

Damn, I wish I'd known this decades ago

I specifically asked doctors and they were like "I dunno. Well, that was a fun 5 minute conversation, give me $300"

I guess it's never too late, though. I've been slacking off on getting in shape, since it does take raw willpower 20 times a day every day in order to get there and stay there, and it's not that compelling to think that I'm going to be stuck rolling willpower checks all the time forever.

If I just have to get in shape and force myself to stay that way through raw willpower for ~4 years in order to stay that way for free afterward, though, that sounds like a more worthwhile goal

It is never too late. And please don't beat yourself up when you fail. Simply sigh, dust yourself off, and try to do better. Given that you have to maintain this for years, you will sometimes fail--it's inevitable.

There is increasing amounts of science behind this stuff, but it's also buried behind a gargantuan pile of crap.

Good luck.

> You have to hold your weight at a point for something like 3-5 years before your body relents enough that the setpoint moves.

Is there any evidence of this? I've never seen any evidence the setpoint ever moves down.

It's what I thought of here also. Most notably, liposuction has faired very poorly in studies of long-term health outcomes. Without the requisite changes in lifestyle or metabolism the fat that gets sucked out is replaced very quickly and has almost no decrease in risk of obesity-related illnesses.

> The point is that you could gain back the original weight plus more.

This is also common in all weight loss interventions, though the reason is generally from metabolic slowdown, not the creation of new adipose tissues.

I suppose the concern goes something like this. Under certain metabolic conditions, each fat cell (in a region) decides it needs to be size X, and grows / shrinks accordingly. And under other conditions, each fat cell (in the same region) decides it needs to be size X*3.

If there are more fat cells, then and they all decide to increase in size, then that could be a substantial weight gain, beyond what would be expected otherwise.

They've studied this, they put people om semaglutide then took them off of it for a year. Looks like every other weight loss intervention.

https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.147...

gastric bypass does not have this problem as bad

Kinda, drugs/diet/exercise you can stop. But most people don't undo the gastric bypass surgery. (I don't even know if it's possible)

A family member has had gastric bypass. You can have everything “replumbed” if complications require failing back to something similar to previous state.

https://pubmed.ncbi.nlm.nih.gov/27387697/

With that said, I would be interested if new weight loss drugs negate the need for gastric bypass in the first place. Comes across as medieval and barbaric if the hormones/drugs are superior.

> With every weight loss intervention when you stop you gain back the weight. GLP-1 agonists don't seem to be any different than another other intervention.

Except for one thing: it's fairly easy to not stop a drug. You just... keep taking it. Long-term use of these drugs for maintenance purposes looks entirely feasible. Not quite as easy to maintain as a gastric bypass, but close enough to be a big deal.

The same isn't true for exercise and diet; it's very easy to fall off those wagons.

Does this mean if an obese person took this drug for 2-5 years, changed their diet to eat less, they’d keep it off?

That's something we don't know for certain yet.

> one of the foremost experts of fat metabolism

Is it correct that the source is a veterinary anaesthesiolgist?

https://news.ycombinator.com/item?id=34252195

Yes, he is the world's leading expert on this subject because credentials aren't everything

Count me as a world leading expert as well then.

You actually have to know what your'e talking about to be an expert, though.

I don't see evidence that this person knows what they are talking about. I see they talk a lot about it, but we know very well that talking, including in the specific manner they do (at length, citing lots of stuff), are also traits of people who are completely deceived or deceiving, conspiracy theorists and fabulists, etc.

Credentials aren’t everything but at the least I want someone to be in the field doing things in practice (research or patients) everyone else including me should shut up otherwise.

You go with it then, but personally I wouldn't even let this person anaesthesize me.

>As long as you are taking the GLP-1 inhibitor drugs you will lose or maintain weight, but as soon as you stop you will gain a lot of weight back.

Sounds like the opposite of a disaster for pharmaceutical companies.

Well, on the upside, the demand for this is so great that cheap generics shouldn't be too far away, right? And it seems like an insurance no-brainer to cover it for life, right?

The cheap generics never appear till the last of the patents have expired regardless of demand.

I wonder how breaking old habits and establishing new habits over a year or so would stop a serious rebound?

It is, in my personal experience, all to easy to fall back into the old habits.

No doubt. The old habits are easier. It’s way easier to order in food and lay in bed than to cook and workout. Of course, it’s overly reductionist to assume weight loss is as easy as “stop laying around, eat healthy, and exercise.”

It kind of is that simple, but there are so many factors that help prevent us from good habits. I think my biggest issue is that food is one of the few things in my life that’s ever evoked a positive response for me. I’ve gone years without being fat, but it comes back because of some issue I encounter, and I lack the tools to deal with it in a better way. So I get depressed and eat, and eventually hate myself for falling apart again, and so we go, forever and always.

The low success rates of diets suggest very hard to establish new habits

Many things are hard, but that does not mean they should not be done.

If there are easy alternatives with the same outcomes, hard things absolutely should not be done (unless you're practicing for an emergency situation where the easy thing is not available.)

Even in a utilitarian framework, there is more to consider besides outcomes, such as costs.

Examples of costs could be be the reoccurring monetary cost for the rest of your life, and being dependent on the supply of medicine to maintain your health.

Additionally, there are personal advantages to being an individual that is capable of doing and regularly practices "hard things".

Problem with diets is that your body responds to this new habit by panicking, thinking you’re going through a famine and reduces metabolism to compensate for reduced caloric intake while increasing hunger. It’s like if you’re he body responded to brushing your teeth every day by making you obsess over caramel corn. Most habit changes don’t have this “body actively fighting you with increasing ferocity” effect that caloric restriction does.

Good diets are simply a healthy human diet, which should not send your body into panic after an adjustment period.

This is similar to exercise. You body goes through a period of panic and resistance.

This is why consistency is important for both diet and exercise, so you dont have to struggle and battle to rebuild the habit.

But what if your “good diet” DOES send your body into a panic? That is, physiologically, what occurs with many obese people when they lose weight, REGARDLESS OF WHICH DIET THEY PICK.

Keywords were "after adjustment period". Your body will Panic if you quit smoking, alcohol, or many hard drugs. That doesn't mean it's a bad idea to do so.

Your body will also panic if you start working out vigorously, confront hard but necessary situations, or many other aspects of human life.

If a prescription help someone make a productive transition, that's great. My point is simply that I'm cautious of potentially lifelong crutches to avoid making difficult changes, and there's value in cultivating the ability to maintain your personal homeostasis if you can

Again, with the idea it’s just a willpower thing to overcome some hurdle. The “panic period” is permanent for many obese people. There’s literally no end to fighting your body once you’ve lost substantial weight, it’s ALWAYS trying to lower metabolism and increase hunger to compensate. It’s not a few months and then you’re good, it’s forever. This is why a treatment like this is so necessary.

I think the big lesson from Semaglutide is that bad eating habits are not the primary cause of obesity. More likely they are correlated due to common causation.

N of 1, but I've gone off it for months and maintained my weight.

How much did you lose, how long did you take it, and how long have you been off of it?

380->340 over 6 months. I was off for 6 months and maintained 340 with diet changes and exercise. You cannot go back to the old diet and expect to maintain. I'm back on now to lose some more.

Some other things I've learned:

Take the first shot on an empty stomach. Expect the first 3 days to be rough. Hunger is more than one sensation, and when you have severe calorie deficit, your body will feel very bad (at least at first).

It is critical to control your food environment - don't bring junk food home, don't go to restaurants too often.

I learned to slow down and enjoy the food reward, instead of trying to chase it. No words will tell you how to do this for yourself.

There is a feeling that I call "future hunger", where I don't feel bad, but I feel like I will in a while. In the past, my body and mind would get frantic when I felt this way. Now I have a very small snack and ask myself "do you feel bad right now, or do you feel like you're going to feel bad". Again, these words may not translate.

More than one serving of salty and sugary snacks should NEVER be within arms reach, and preferably not in the same room. Your mind will remember these snacks and oftentimes eat them without conscious effort.

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