The phrasing of the title and paper steer the interpretation towards reducing cysteine as a method for increasing weight loss, however I think that the much more interesting takeaway is this:
> Notably, restoration of up to 75% cystine levels in the diet of Cth−/− CysF mice that were undergoing weight loss was sufficient to completely rescue the body weight
This might indicate that cysteine depletion could be one mechanism present in some wasting diseases, and that strategic supplementation of cysteine may be beneficial in reducing excessive weight loss in such diseases. I would be quite interested to see future research in this area.
Cysteine is also an irreplaceable building block of vital proteins required to sustain life. It’s unclear if there is any potential benefit of applying these findings to the problem of human weight loss or fitness.
I agree, for example Pepsin[1] that is the protein inside the stomach that split proteins has Cysteine [2]
> Pepsin forms three between the sulfur atoms of cysteine residues in the peptide chain which hold important roles in the folding of the protein and stabilizing the two domains
Wikipedia's disclaimers on that: "Cysteine can usually be synthesized by the human body under normal physiological conditions if a sufficient quantity of methionine is available."
I would make a stronger statement and say that this belongs squarely on the effect and not the cause side.
I could be wrong, but I doubt it. Amino acid depletion sounds way more likely to be due to some kind of disruption in homeostasis rather than dietary intake.
Cysteine plays a key role in redox metabolism and removing reactive oxygen species (ROS). During brown fat burning, high flux of electrons increases the NADH/NAD⁺ and FADH₂/FAD ratios — shifting redox state toward a more reduced environment, which is exactly what you would need if deprived of cysteine.
This should only act as a clue into driving weight loss. Depleting of cysteine is severe. It would be depriving a team from writing html and discovery the code runs faster… very drastic imposition
> Since this was also a noninterventional study, two possibilities for interpretation of the findings were either that a high cysteine somehow promotes obesity or that obesity influences cysteine turnover, thereby raising plasma tCys.
Cysteine protease inhibitors could be used to reduce free cysteine available to cells. Some natural sources of those are papaya, kiwi, pineapple, fig, apples, and rice.
Cysteine proteases are named after their reaction mechanism, which involves a key cysteine residue within the enzyme. It doesn't have anything to do with the amino acids in the cleaved proteins.
According to the article, you’ll lose so much weight that you need euthanasia if you stop taking NAC - but only if you’re also a mice that also happens to be genetically modified to not produce any Cysteine biologically. Oh, and you shouldn’t eat anything containing cysteine naturally.
Another linked article suggests that NAC administration if anything causes weight loss, and has a lot of opposite effects as cysteine. I don't think they're interchangeable.
If I can use hormones to suppress the urge to consume unnecessary calories while maintaining or increasing muscle mass, I’m willing to pay for it. I’m just using biochemistry to improve executive function. Make it work, make it right, make it fast.
There is no extra credit for making existence harder than it has to be, and it is already hard as is.
Semaglutide is an absolute game changer drug, but it doesn't save you from poor nutrition.
I found that I can work on building a healthy diet independent of semaglutide doing its thing, regardless of how much weight I lost.
I bet people making the same mistake as I did, saying to myself that I will get better at building a healthy diet and then taking semaglutide because I want to see myself as "strong". Or maybe it means that I don't need help.
Better to just do it for your health and figure out the rest. There's no shame in asking for help.
The drugs are the help. Nutrition is of course important (quality macros, broadly speaking, proteins, fats, fiber), but you’re not going to outrun a misfiring reward center demanding you eat when you don’t need to with “willpower” or whatever folks want to call it. There is no shame in needing pharma interventions or other medical assistance. We are imperfect, and that’s okay.
I agree with your understanding of physics, but when you put human decision making in the loop you have to account for that in any solution. For some "eating less and moving more" can have other consequences. O was always taught good engineering requires an understanding of human behavior. I would prefer to eat less and move more.
I used to think this was intelligence related, like less intelligent people were not able to understand how to maintain positive savings (spend only what is possible after contributing to savings).
But with age I think rationalization is the more powerful force that outweighs intelligence. I notice that people who struggle with money usually have powerful convictions that are silly and capricious, but they are unable to see that. They build arguments upon rationalizations instead of facts or data. Spending money on rationalized things makes perfect sense in their mind.
I think it's a three-circle venn diagram of knowledge - intelligence - rationalization. You can accrue a lot of knowledge via rote memorization, but it doesn't mean that you are intelligent. And you can have limited knowledge of a subject, but somehow "just get it" which comes with intelligence. And finally, you can have intelligence but utterly fail to see beyond rationalizations.
You're talking about emotions. Rationalization is the end process of abusing your intelligence to serve your faulty emotions, rather than understanding and interacting with your emotions so that it serves you rather than the other way around.
You would do well to watch some of those weight loss shows like 1000 pound sisters, and see the *human* in them.
It is way, way, *WAY* more than a “motivational hump”. Many of the very heavy are suffering from the effects of horrible, life long and weight-amplifyed-and-amplifying trauma.
That is a brilliant idea! I honestly wish I'd thought of that before. All I've gotta to is overlook a few billion years of evolution telling my mouth to demolish a buffet to stock up for the scarce times. Piece of cake!
Genetics obviously doesn't break the laws of physics. You cannot get fat without calories in exceeding calories out. With that said, if dieting means you are ravenously hungry all the time, leaves you feeling overwhelmed with stress or leaves you lacking energy to do the bare minimum you need to do (i.e. work, chores, caring for kids, etc), then you're going to find it very difficult to lose weight. These are the actual problems people struggle with when trying to lose weight, which I think lean people often struggle to relate to.
I can relate. I was overweight most of my life. I had to peel away layers of bad narrative and misunderstanding, and also train my discipline circuits to get "lean". And it's still a struggle every day. I'm one of those people who gain weight on a lot less calories than other people. My wife is 2 inches shorter and weighs 50 lbs less than I, and eats twice the calories per day. Mind you, we track every gram of food and weigh it on a scale, and enter it into a diet tracking app (Cronometer in our case). So I am SUPER familiar with everything you are saying.
What I am getting at is that most people are not able to initially grasp this nuance, and the fundamental fact is that there IS a threshold of calories where you WILL lose weight no matter what. It's up to every individual to work on their motivation, but frankly that's orthogonal to the facts of the matter, and it's better to be direct rather than tell half-truths because it's "complicated". I almost never see discussions of motivation and differences in metabolism in these types of threads elsewhere, and to just assume the average person understand these factors is a mistake. The first thing people need to learn is that cutting down food will lose weight, point blank. Then you can add on layers about metabolism and motivation as the journey continues.
> What I am getting at is that most people are not able to initially grasp this nuance, and the fundamental fact is that there IS a threshold of calories where you WILL lose weight no matter what.
Once you cross this threshold, the organism activates every failsafe evolution devised since the first metazoan arised, to ensure you stop and come back.
People who are on a healthy weight just don't have motivational issue. I have a good friend that eats garbage and she knows and wants to change that. She's still not gaining weight.
A properly calibrated body will just do what it's supposed to do. For the rest of us, it's an uphill battle.
Yea, I get what you're saying. It is unhelpful when people act as if cutting enough calories and/or increasing exercise enough won't lead to weight loss, because obviously it will. Insufficient motivation is definitely a problem for a lot of people, but I think it is also possible to be so metabolically deranged that motivation actually becomes a secondary issue when you have very strong hormonal signals telling you that you need to eat more.
I don’t think standard humans measure enough data to check the mass balance of their body’s system. I seem to remember an episode of CSI where that kind of behavior was used as evidence of an eating disorder.
Joking aside, being overweight is mostly about body density, not mass. Few people get upset about having too much lean muscle or the food inputs needed get there; that is a different set of health risks.
Whether your body converts incoming calories to muscle or fat or whatever else does actually depend (to some variable extent) on genetics, along with many other factors. Glossing this as “breaking the laws of physics” is a straw man.
One example off the top of my head: eating lots of protein to build muscle can be hard on the liver.
Exercising a lot is generally healthy, but high impact exercises (running comes to mind) can cause your joints to wear out a lot faster.
This is all also assuming an average, healthy person with no existing medical conditions. Things get trickier if you have exertional asthma, any kind of condition that can cause fatigue, etc.
The normal claim is a bit weaker, that under caloric restriction the body situationally reacts by doing a lot less work. You also see reports of reduced cognitive abilities and whatnot, consistent with lower energy expenditures.
I think those reports are overblown, especially with little mismeasurements on the order of 1Tbsp of butter or the fact that many foods have labeled calories 20% less than the actual caloric content, all of that combined with thinking that exercise is more impactful than it actually is (especially weight training), but the core claims aren't totally ludicrous at face value.
I don't have the reference study on hand, but I believe the brain requires approximately 600 calories a day, or 150g of carbs. Switching over to use ketones requires going into ketosis, which most people never do.
When you look at how our hormones are affected by different types of macronutrients, there are dietary ways to restrict calories, prevent hunger from becoming an issue, and still maintain a decent level of mental acuity.
I've found that aiming for 150g of carbs a day and .7-1g protein/pound of body weight to be fairly self-regulating. I have to eat more carbs on days I do BJJ (pretty glycogenic sport, but, admittedly, has become less demanding the closer I got to my black belt), but using that target as a rule of thumb has worked out well for me over the years.
When we talk about CICO, there is the reality of our hormones that we have to consider--at least in terms of human behavior. There are ways to diet with ease and no discomfort, but yo-yoing between binging on snacks and trying to not eat anything isn't very feasible.
No, no, I've seen such comments here on HN as well. It is definitely more nuanced, as genetics does play a role, but still, not one that violates the Law of Conservation of Energy.
Starving yourself is not a healthy way to lose weight. It is not an effective way either, since you will either gain it all back when you decide to eat again or get an eating disorder.
Straw man. No one is claiming they aren't more complicated, but food intake is cornerstone, the foundation to understanding weight and weight loss. The complexity and nuance should be layered on top of this. Many ignore the foundation. See my other comments in this thread.
The phrasing of the title and paper steer the interpretation towards reducing cysteine as a method for increasing weight loss, however I think that the much more interesting takeaway is this:
> Notably, restoration of up to 75% cystine levels in the diet of Cth−/− CysF mice that were undergoing weight loss was sufficient to completely rescue the body weight
This might indicate that cysteine depletion could be one mechanism present in some wasting diseases, and that strategic supplementation of cysteine may be beneficial in reducing excessive weight loss in such diseases. I would be quite interested to see future research in this area.
An overview of other studies investigating cysteine and glycine sources and effects (from 2023; video or transcript):
https://nutritionfacts.org/hnta-video/how-to-get-less-cystei...
so... basically limit proteins especially from meat?
Cysteine is also an irreplaceable building block of vital proteins required to sustain life. It’s unclear if there is any potential benefit of applying these findings to the problem of human weight loss or fitness.
I agree, for example Pepsin[1] that is the protein inside the stomach that split proteins has Cysteine [2]
> Pepsin forms three between the sulfur atoms of cysteine residues in the peptide chain which hold important roles in the folding of the protein and stabilizing the two domains
[1] https://en.wikipedia.org/wiki/Pepsin
[2] https://biology.kenyon.edu/BMB/jsmol2021/Cat_Marko/index.htm...
Cysteine is not an essential amino acid. Humans can synthesize it from methionine.
These mice were GMO’d to be incapable of synthesising cysteine.
Wikipedia's disclaimers on that: "Cysteine can usually be synthesized by the human body under normal physiological conditions if a sufficient quantity of methionine is available."
I would make a stronger statement and say that this belongs squarely on the effect and not the cause side.
I could be wrong, but I doubt it. Amino acid depletion sounds way more likely to be due to some kind of disruption in homeostasis rather than dietary intake.
Funny because cysteinuria doesn’t do this (pee out cysteine)
Cysteine plays a key role in redox metabolism and removing reactive oxygen species (ROS). During brown fat burning, high flux of electrons increases the NADH/NAD⁺ and FADH₂/FAD ratios — shifting redox state toward a more reduced environment, which is exactly what you would need if deprived of cysteine.
"Systemic cysteine depletion in mice causes lethal weight loss"
I didn't read much after that
Maybe you should have.
This should only act as a clue into driving weight loss. Depleting of cysteine is severe. It would be depriving a team from writing html and discovery the code runs faster… very drastic imposition
(In mice)
This 2012 study in humans says
> Since this was also a noninterventional study, two possibilities for interpretation of the findings were either that a high cysteine somehow promotes obesity or that obesity influences cysteine turnover, thereby raising plasma tCys.
https://onlinelibrary.wiley.com/doi/full/10.1038/oby.2011.93
In genetically modified mice.
(So far)
(also observed to be lethal in cases)
Cysteine protease inhibitors could be used to reduce free cysteine available to cells. Some natural sources of those are papaya, kiwi, pineapple, fig, apples, and rice.
Cysteine proteases are named after their reaction mechanism, which involves a key cysteine residue within the enzyme. It doesn't have anything to do with the amino acids in the cleaved proteins.
So, does taking NAC make me fat? If I stop taking NAC, will it help me lose weight?
According to the article, you’ll lose so much weight that you need euthanasia if you stop taking NAC - but only if you’re also a mice that also happens to be genetically modified to not produce any Cysteine biologically. Oh, and you shouldn’t eat anything containing cysteine naturally.
Gotcha. So basically I’m going to be fat no matter what, you’re saying.
Another linked article suggests that NAC administration if anything causes weight loss, and has a lot of opposite effects as cysteine. I don't think they're interchangeable.
Interesting. I missed that.
If only there were NAC that doesn't stink opening the bottle.
Is this the same as homocysteine?
[dead]
[flagged]
We detached this subthread from https://news.ycombinator.com/item?id=44194015 and marked it off-topic.
If I can use hormones to suppress the urge to consume unnecessary calories while maintaining or increasing muscle mass, I’m willing to pay for it. I’m just using biochemistry to improve executive function. Make it work, make it right, make it fast.
There is no extra credit for making existence harder than it has to be, and it is already hard as is.
Regeneron’s Semaglutide Plus Trevogrumab Combo Demonstrates Superior Fat Loss with Reduced Muscle Wasting in Obesity Trial - https://www.pharmexec.com/view/regeneron-semaglutide-trevogr...
Western society still has the puritan ethic baked into it. If life isn't pain and suffering and struggle, it's worthless.
You’re right unfortunately. Onward.
Semaglutide is an absolute game changer drug, but it doesn't save you from poor nutrition.
I found that I can work on building a healthy diet independent of semaglutide doing its thing, regardless of how much weight I lost.
I bet people making the same mistake as I did, saying to myself that I will get better at building a healthy diet and then taking semaglutide because I want to see myself as "strong". Or maybe it means that I don't need help.
Better to just do it for your health and figure out the rest. There's no shame in asking for help.
The drugs are the help. Nutrition is of course important (quality macros, broadly speaking, proteins, fats, fiber), but you’re not going to outrun a misfiring reward center demanding you eat when you don’t need to with “willpower” or whatever folks want to call it. There is no shame in needing pharma interventions or other medical assistance. We are imperfect, and that’s okay.
I agree with your understanding of physics, but when you put human decision making in the loop you have to account for that in any solution. For some "eating less and moving more" can have other consequences. O was always taught good engineering requires an understanding of human behavior. I would prefer to eat less and move more.
You talked as if eating less and moving more is easy.
Like, that's like the primary challenge of public health intervention.
If it was so easy, people would do it and we wouldn't be talking about it.
People will do literally anything to get rich except earning more and spending less.
I used to think this was intelligence related, like less intelligent people were not able to understand how to maintain positive savings (spend only what is possible after contributing to savings).
But with age I think rationalization is the more powerful force that outweighs intelligence. I notice that people who struggle with money usually have powerful convictions that are silly and capricious, but they are unable to see that. They build arguments upon rationalizations instead of facts or data. Spending money on rationalized things makes perfect sense in their mind.
I think it's a three-circle venn diagram of knowledge - intelligence - rationalization. You can accrue a lot of knowledge via rote memorization, but it doesn't mean that you are intelligent. And you can have limited knowledge of a subject, but somehow "just get it" which comes with intelligence. And finally, you can have intelligence but utterly fail to see beyond rationalizations.
You're talking about emotions. Rationalization is the end process of abusing your intelligence to serve your faulty emotions, rather than understanding and interacting with your emotions so that it serves you rather than the other way around.
[flagged]
Your take sounds a little black/white to me.
Not everyone can “just not eat”. Some people are more driven by their hunger (perceived or “real”) than others.
Some have an easy time sustaining a caloric deficit, for others it’s super hard.
Genes and gut biota play a big part in this. It’s not always just a lack of discipline :)
https://www.health.harvard.edu/staying-healthy/why-people-be...
https://www.nature.com/articles/s41367-019-0011-7
You would do well to watch some of those weight loss shows like 1000 pound sisters, and see the *human* in them.
It is way, way, *WAY* more than a “motivational hump”. Many of the very heavy are suffering from the effects of horrible, life long and weight-amplifyed-and-amplifying trauma.
> You can't just make money by just getting off your butt
You kind of can, or at least i think you can to the same extent that you can lose weight by eating less and exercising more.
There are complications that make it very non-trivial in both cases.
That is a brilliant idea! I honestly wish I'd thought of that before. All I've gotta to is overlook a few billion years of evolution telling my mouth to demolish a buffet to stock up for the scarce times. Piece of cake!
It's almost like we have a billion years of evolution working against us in the "willingly reduce your caloric intake and fat reserves" department
People will do literally anything else other than just completely abstain from sex if they don't want (more) kids.
This seems vastly less useful and safe than just taking Ozempic.
[flagged]
Genetics obviously doesn't break the laws of physics. You cannot get fat without calories in exceeding calories out. With that said, if dieting means you are ravenously hungry all the time, leaves you feeling overwhelmed with stress or leaves you lacking energy to do the bare minimum you need to do (i.e. work, chores, caring for kids, etc), then you're going to find it very difficult to lose weight. These are the actual problems people struggle with when trying to lose weight, which I think lean people often struggle to relate to.
I can relate. I was overweight most of my life. I had to peel away layers of bad narrative and misunderstanding, and also train my discipline circuits to get "lean". And it's still a struggle every day. I'm one of those people who gain weight on a lot less calories than other people. My wife is 2 inches shorter and weighs 50 lbs less than I, and eats twice the calories per day. Mind you, we track every gram of food and weigh it on a scale, and enter it into a diet tracking app (Cronometer in our case). So I am SUPER familiar with everything you are saying.
What I am getting at is that most people are not able to initially grasp this nuance, and the fundamental fact is that there IS a threshold of calories where you WILL lose weight no matter what. It's up to every individual to work on their motivation, but frankly that's orthogonal to the facts of the matter, and it's better to be direct rather than tell half-truths because it's "complicated". I almost never see discussions of motivation and differences in metabolism in these types of threads elsewhere, and to just assume the average person understand these factors is a mistake. The first thing people need to learn is that cutting down food will lose weight, point blank. Then you can add on layers about metabolism and motivation as the journey continues.
> What I am getting at is that most people are not able to initially grasp this nuance, and the fundamental fact is that there IS a threshold of calories where you WILL lose weight no matter what.
Once you cross this threshold, the organism activates every failsafe evolution devised since the first metazoan arised, to ensure you stop and come back.
People who are on a healthy weight just don't have motivational issue. I have a good friend that eats garbage and she knows and wants to change that. She's still not gaining weight.
A properly calibrated body will just do what it's supposed to do. For the rest of us, it's an uphill battle.
Yea, I get what you're saying. It is unhelpful when people act as if cutting enough calories and/or increasing exercise enough won't lead to weight loss, because obviously it will. Insufficient motivation is definitely a problem for a lot of people, but I think it is also possible to be so metabolically deranged that motivation actually becomes a secondary issue when you have very strong hormonal signals telling you that you need to eat more.
I don’t think standard humans measure enough data to check the mass balance of their body’s system. I seem to remember an episode of CSI where that kind of behavior was used as evidence of an eating disorder.
Joking aside, being overweight is mostly about body density, not mass. Few people get upset about having too much lean muscle or the food inputs needed get there; that is a different set of health risks.
Whether your body converts incoming calories to muscle or fat or whatever else does actually depend (to some variable extent) on genetics, along with many other factors. Glossing this as “breaking the laws of physics” is a straw man.
What are the health risks with "lean muscle" and "getting there"?
One example off the top of my head: eating lots of protein to build muscle can be hard on the liver.
Exercising a lot is generally healthy, but high impact exercises (running comes to mind) can cause your joints to wear out a lot faster.
This is all also assuming an average, healthy person with no existing medical conditions. Things get trickier if you have exertional asthma, any kind of condition that can cause fatigue, etc.
Overconsuming protein can lead to kidney stones and liver problems. Particularly when mixed with poor hydration.
Exercise-related rhabdomyolosis (muscles break down => myoglobin overwhelms kidneys) is very bad.
Some powerlifting regimens are possibly related to heart damage, the causality isn’t 100% clear to me.
The normal claim is a bit weaker, that under caloric restriction the body situationally reacts by doing a lot less work. You also see reports of reduced cognitive abilities and whatnot, consistent with lower energy expenditures.
I think those reports are overblown, especially with little mismeasurements on the order of 1Tbsp of butter or the fact that many foods have labeled calories 20% less than the actual caloric content, all of that combined with thinking that exercise is more impactful than it actually is (especially weight training), but the core claims aren't totally ludicrous at face value.
I don't have the reference study on hand, but I believe the brain requires approximately 600 calories a day, or 150g of carbs. Switching over to use ketones requires going into ketosis, which most people never do.
When you look at how our hormones are affected by different types of macronutrients, there are dietary ways to restrict calories, prevent hunger from becoming an issue, and still maintain a decent level of mental acuity.
I've found that aiming for 150g of carbs a day and .7-1g protein/pound of body weight to be fairly self-regulating. I have to eat more carbs on days I do BJJ (pretty glycogenic sport, but, admittedly, has become less demanding the closer I got to my black belt), but using that target as a rule of thumb has worked out well for me over the years.
When we talk about CICO, there is the reality of our hormones that we have to consider--at least in terms of human behavior. There are ways to diet with ease and no discomfort, but yo-yoing between binging on snacks and trying to not eat anything isn't very feasible.
Reminds me of Dr Jason Fung presenting on therapeutic fasting and the “two compartment problem”
https://m.youtube.com/watch?v=tIuj-oMN-Fk
No, no, I've seen such comments here on HN as well. It is definitely more nuanced, as genetics does play a role, but still, not one that violates the Law of Conservation of Energy.
> even when under heavy food restriction
Starving yourself is not a healthy way to lose weight. It is not an effective way either, since you will either gain it all back when you decide to eat again or get an eating disorder.
Did you even read the linked study?
>mice fed a HFD-CysF diet were able to lose approximately 30% body weight within 1 week despite maintaining a high calorie intake
Maybe things are more complicated than just conservation of mass.
Straw man. No one is claiming they aren't more complicated, but food intake is cornerstone, the foundation to understanding weight and weight loss. The complexity and nuance should be layered on top of this. Many ignore the foundation. See my other comments in this thread.