I will always be grateful to Bikman for introducing me to 4-HNE in his book Why We Get Sick. (I think Tucker Goodrich told me he was the one to introduce that to Bikman.) It was a key part of my learning and jump started my efforts to kick n-6 (nearly 2½ years ago). That said, I completely agree with you that we should be focusing on mechanistic models. In econometrics, we call the descriptive stuff "reduced form" and the mechanistic stuff "structural." All economists know that the structural stuff is what we should actually care about.
I read Hungry Brain a few years back and the main message I got from it was "manage stress, sleep well, and don't eat tempting/calorie-dense food." It wasn't particularly enlightening. However, there were some good nuggets about the history of leptin and I also have the following note written down that is somewhat unbelievable: " 'We ate more calories in 1909 than in 1960' – a paper by Kevin Hall." Going to have to track that one down!
Hungry Brain for sure had many interesting nuggets. For example the flavor-lacking “sludge diet” experiments. I actually managed to track down that study and the diet was largely seed oil :D (If I found the right stuff, it’s been a while now.)
Unfortunately, I didn’t think Guyenet had much to offer besides collecting a handful of interesting anecdotes and recounting the leptin story.
OK I think I tracked down the bit about calories in 1909 vs 1960, but it wasn't actually from Hall. If Claude is to be trusted (big caveat, but I don't have Hungry Brain in print form to verify myself), the 1909 vs 1960 comparison is in Figure 4 of the book and it's gross food availability instead of food intake.
People like Hall and Guyenet then like to argue from this that we must have been moving a lot more back then, which is how they explain why there wasn't an obesity problem in 1909 despite all those available calories. Of course, that's not the only explanation for what happened, and it also doesn't work for the 1980-2025 time window.
And also Pontzer pretty much debunked "move more -> higher CO" :D
But yea it's only ever food availability. Actually knowing what people eat is just impossible unless you lock them up; and it's difficult to lock up millions of people.
So CI is unknowable, CO is assumed. If CICO doesn't work out, it's just assumed that the people must be lying about CI and secretly eating donuts under the blanket.
Lovely analogy. Of course, the inverse of insulin resistance suffers from the same myopia. Doctors spending decades pushing stuff on people because it "improves insulin sensitivity", apparently never once stopping to think that maybe it's not the best idea to throw open the door for the ice cream man at every possible opportunity.
I think Peter D. has the best model of insulin resistance/sensitivity.
I imagine it something like driving a car along a road. You don’t just have turn the wheel in the correct direction on average, you have to follow every turn in a relatively narrow margin!
If you run off the road halfway there it’s no use that you were “right on average.”
Similarly, being “more right sensitive” or “more right resistant” isn’t useful, you need to be turning right at the correct time, but not the wrong time.
I think it's less 'an explanation' than 'the thing you're trying to explain'.
There are various hormones, and for a lot of them, the gland which makes the hormone can fail for some reason, and then you usually get a well known disease with a name which you can fix by giving people exogenous hormones.
So, to take the thyroid gland as an example, we pretty much know how that whole system works, and most often you can get an autoimmune disease which destroys your thyroid gland, and then there's no thyroid hormone in your blood, and there's a vast list of nasty symptoms that are all basically 'your metabolism is running slow and that screws everything'.
This is *primary* hypothyroidism, and it was discovered by the Victorians, and it's easy to detect, and you can fix it by giving people the hormone.
But sometimes you see people where the levels of hormones in the blood are fine, but they have all the symptoms anyway, and one way to describe that would be 'thyroid resistance'. I am one of these people, or was anyway. And sometimes you can fix the symptoms by giving people extra hormones, and sometimes you can't.
You haven't actually explained anything here, any more than saying that opium puts people to sleep because it has a 'dormitive potency', but at least you've got a concise description for what's happening to them.
And most of the hormones have associated primary disorders, and also have much more mysterious 'resistance versions' where we don't actually know what's going on.
The resistance versions are sometimes explained by genetic mutations in hormone receptors, but those are for obvious reasons very rare! And those disorders you can't fix using the hormone, because it just doesn't work.
But I think quite often you see the symptoms of a hormone problem but the hormones are there, and you need a way to describe that, and 'hormone resistance' is not a bad way?
Of course the real work is working out what's really going on and how to fix it, but giving it a name is not a bad start?
I would like to be able to say 'three years off the PUFAs seems to have mostly fixed my thyroid resistance'. This does seem to be true! And I am quite annoyed that I am still 'tired all the time', but I don't have any of the other symptoms any more.
Yes, the asymmetry of your symptoms is confusing. Then again, the body is under no legal obligation to fail or heal linearly in every dimension across the board.
Nicely written. As for the crown-like structures and dead fat cells, they are removed after a few weeks. What remains are cells that are "afraid", they know that the surrounding cells have died and therefore they start to defend themselves with cellular senescence and permanent insulin resistance.
What’s the mechanism for other cells being “afraid?”
And how does cellular senescence protect against these “ghosts” of past, dead cells?
That one study you quoted a few months bad had this confusing (to me) issue of lots of dead cells → CLS but then those got cleaned up. So… all good, right?! Except, of course no.
Why does IR protect against the ghosts of past dead cells? To prevent debris from coming in?
At week 20, new differentiated adipocytes appear, so they differentiate in an environment with poor antioxidant protection, with a lack of NADPH and low GSH recycling. These conditions make them senescent, which I have described as a “afraid” of good functioning.
"SIRT1 safeguards adipogenic differentiation by orchestrating anti-oxidative responses and suppressing cellular senescence"
From the experiments in Lamming's lab, I would suggest some protective effect of senescent fat tissue in males, which increases fuel levels in the blood and the mice eat less. Female mice have more fat cells, fewer senescent cells, and eat much more, with some dying very young.
I will always be grateful to Bikman for introducing me to 4-HNE in his book Why We Get Sick. (I think Tucker Goodrich told me he was the one to introduce that to Bikman.) It was a key part of my learning and jump started my efforts to kick n-6 (nearly 2½ years ago). That said, I completely agree with you that we should be focusing on mechanistic models. In econometrics, we call the descriptive stuff "reduced form" and the mechanistic stuff "structural." All economists know that the structural stuff is what we should actually care about.
I read Hungry Brain a few years back and the main message I got from it was "manage stress, sleep well, and don't eat tempting/calorie-dense food." It wasn't particularly enlightening. However, there were some good nuggets about the history of leptin and I also have the following note written down that is somewhat unbelievable: " 'We ate more calories in 1909 than in 1960' – a paper by Kevin Hall." Going to have to track that one down!
Hungry Brain for sure had many interesting nuggets. For example the flavor-lacking “sludge diet” experiments. I actually managed to track down that study and the diet was largely seed oil :D (If I found the right stuff, it’s been a while now.)
Unfortunately, I didn’t think Guyenet had much to offer besides collecting a handful of interesting anecdotes and recounting the leptin story.
OK I think I tracked down the bit about calories in 1909 vs 1960, but it wasn't actually from Hall. If Claude is to be trusted (big caveat, but I don't have Hungry Brain in print form to verify myself), the 1909 vs 1960 comparison is in Figure 4 of the book and it's gross food availability instead of food intake.
People like Hall and Guyenet then like to argue from this that we must have been moving a lot more back then, which is how they explain why there wasn't an obesity problem in 1909 despite all those available calories. Of course, that's not the only explanation for what happened, and it also doesn't work for the 1980-2025 time window.
And also Pontzer pretty much debunked "move more -> higher CO" :D
But yea it's only ever food availability. Actually knowing what people eat is just impossible unless you lock them up; and it's difficult to lock up millions of people.
So CI is unknowable, CO is assumed. If CICO doesn't work out, it's just assumed that the people must be lying about CI and secretly eating donuts under the blanket.
Or as the kids call it, Science.
Lovely analogy. Of course, the inverse of insulin resistance suffers from the same myopia. Doctors spending decades pushing stuff on people because it "improves insulin sensitivity", apparently never once stopping to think that maybe it's not the best idea to throw open the door for the ice cream man at every possible opportunity.
I think Peter D. has the best model of insulin resistance/sensitivity.
I imagine it something like driving a car along a road. You don’t just have turn the wheel in the correct direction on average, you have to follow every turn in a relatively narrow margin!
If you run off the road halfway there it’s no use that you were “right on average.”
Similarly, being “more right sensitive” or “more right resistant” isn’t useful, you need to be turning right at the correct time, but not the wrong time.
I think it's less 'an explanation' than 'the thing you're trying to explain'.
There are various hormones, and for a lot of them, the gland which makes the hormone can fail for some reason, and then you usually get a well known disease with a name which you can fix by giving people exogenous hormones.
So, to take the thyroid gland as an example, we pretty much know how that whole system works, and most often you can get an autoimmune disease which destroys your thyroid gland, and then there's no thyroid hormone in your blood, and there's a vast list of nasty symptoms that are all basically 'your metabolism is running slow and that screws everything'.
This is *primary* hypothyroidism, and it was discovered by the Victorians, and it's easy to detect, and you can fix it by giving people the hormone.
But sometimes you see people where the levels of hormones in the blood are fine, but they have all the symptoms anyway, and one way to describe that would be 'thyroid resistance'. I am one of these people, or was anyway. And sometimes you can fix the symptoms by giving people extra hormones, and sometimes you can't.
You haven't actually explained anything here, any more than saying that opium puts people to sleep because it has a 'dormitive potency', but at least you've got a concise description for what's happening to them.
And most of the hormones have associated primary disorders, and also have much more mysterious 'resistance versions' where we don't actually know what's going on.
The resistance versions are sometimes explained by genetic mutations in hormone receptors, but those are for obvious reasons very rare! And those disorders you can't fix using the hormone, because it just doesn't work.
But I think quite often you see the symptoms of a hormone problem but the hormones are there, and you need a way to describe that, and 'hormone resistance' is not a bad way?
Of course the real work is working out what's really going on and how to fix it, but giving it a name is not a bad start?
I would like to be able to say 'three years off the PUFAs seems to have mostly fixed my thyroid resistance'. This does seem to be true! And I am quite annoyed that I am still 'tired all the time', but I don't have any of the other symptoms any more.
Yes, the asymmetry of your symptoms is confusing. Then again, the body is under no legal obligation to fail or heal linearly in every dimension across the board.
Nicely written. As for the crown-like structures and dead fat cells, they are removed after a few weeks. What remains are cells that are "afraid", they know that the surrounding cells have died and therefore they start to defend themselves with cellular senescence and permanent insulin resistance.
What’s the mechanism for other cells being “afraid?”
And how does cellular senescence protect against these “ghosts” of past, dead cells?
That one study you quoted a few months bad had this confusing (to me) issue of lots of dead cells → CLS but then those got cleaned up. So… all good, right?! Except, of course no.
Why does IR protect against the ghosts of past dead cells? To prevent debris from coming in?
There is a post from Peter about the dead cells being maximal at week 16 and almost clear at week 20.
"Adipocyte Death, Adipose Tissue Remodeling, and Obesity Complications"
https://doi.org/10.2337/db07-0767
At week 20, new differentiated adipocytes appear, so they differentiate in an environment with poor antioxidant protection, with a lack of NADPH and low GSH recycling. These conditions make them senescent, which I have described as a “afraid” of good functioning.
"SIRT1 safeguards adipogenic differentiation by orchestrating anti-oxidative responses and suppressing cellular senescence"
https://pmc.ncbi.nlm.nih.gov/articles/PMC10828476/
From the experiments in Lamming's lab, I would suggest some protective effect of senescent fat tissue in males, which increases fuel levels in the blood and the mice eat less. Female mice have more fat cells, fewer senescent cells, and eat much more, with some dying very young.
https://mct4health.blogspot.com/2025/08/restricting-protein-or-certain-amino.html
"Lifelong restriction of dietary branched-chain amino acids has sex-specific benefits for frailty and life span in mice"
https://doi.org/10.1038/s43587-020-00006-2
I think there’s a similarity between CICO and this economics blog post
“Accounting does not explain anything. That’s why we have price theory.”
https://pricetheory.substack.com/p/never-reason-from-an-accounting-identity-c4f?r=3s5ta&utm_medium=ios
Thanks, I’ll check it out