Is it the general theory that your diet alters the lipid content of the membranes of your cells making them more insulin sensitive (a good thing) and your weight changes are a proxy for insulin response?
I don't have specific mechanistic theories in mind, I try to keep myself to "PUFAs bad?" on the basis that PUFAs seem like the sorts of things that might be bad.
Of course it's no surprise that fat cells that are already loaded with huge amounts of fat might be reluctant to take up extra.
But if I was getting all speculatey, then I would guess that most insulin related effects are to do with human metabolism not being tuned to using PUFAs as a major energy source (burning them hammers on various special pathways that probably aren't designed for heavy use).
I'm not really thinking about cell membrane changes, except to note that if you change the composition of the membrane it could well make it more or less permeable to various things. And in particular if the composition of the inner mitochondrial membrane changes that could sod up the entire system on which energy production is based.
But obesity and anorexia look to me like consequences of homeostat dysregulation, so probably more to do with some sort of disruption of leptin signalling, and it seems like PUFAs in the blood-brain barrier can reduce its permeability to leptin.
Or they might somehow be disrupting the leptin receptors themselves, or something. That's the sort of question that a biochemist should be able to answer after a lifetime's work, it's not something I'm going to be working out myself. But I'd be drawn to those sorts of explanations as being obvious ways in which PUFAs might cause obesity, if they do indeed cause it, which I'm not at all sure about.
"But if I was getting all speculatey, then I would guess that most insulin related effects are to do with human metabolism not being tuned to using PUFAs as a major energy source (burning them hammers on various special pathways that probably aren't designed for heavy use).)
Actually this is what researchers observe: "During fasting/refeeding cycles and increased levels of exercise, tissue PUFA concentrations have been shown to deplete rapidly in both humans and rats. These studies show that most PUFAs, including α-linolenic acid (ALA) and linoleic acid (LA), are preferentially oxidized in periods of exercise or fasting. During refeeding, SFAs and monounsaturated fatty acids (MUFAs), such as palmitic acid and oleic acid, are also more rapidly replaced than any of the PUFAs. Similarly, the concentrations of most plasma PUFAs and MUFAs have been shown to be significantly lower in rats fed a high fat ketogenic diet than in controls. The predicted increase in FA oxidation in free-ranging cheetahs is therefore likely to also skew their serum FA profiles toward lower proportional serum concentrations of PUFAs and MUFAs relative to SFA." (web search - Tordiffe Comparative serum fatty acid profiles)
Excerpt: Fatty acid composition in the Western diet has shifted from saturated to polyunsaturated fatty acids (PUFAs), and specifically to linoleic acid (LA, 18:2), which has gradually increased in the diet over the past 50 y to become the most abundant dietary fatty acid in human adipose tissue. (web search - sEH-derived metabolites)
Excerpt: Obesity sometimes seems protective in disease. This obesity paradox is predominantly described in reports from the Western Hemisphere during acute illnesses...adipose triglyceride composition corresponds to long-term dietary patterns...Saturation interfered with triglyceride’s interaction and lipolysis by pancreatic triglyceride lipase, which mediates organ failure. Unsaturation increased fatty acid monomers in vivo and aqueous media, resulting in greater lipotoxic cellular responses and organ failure. Therefore, visceral triglyceride saturation reduces the ensuing lipotoxicity despite higher adiposity, thus explaining the obesity paradox. (web search - Vijay P. Singh saturated fat)
The COVID-19 problem: Separately, on analyzing global COVID-19 mortality data and comparing it with 12 risk factors for mortality, they found unsaturated fat intake to be associated with increased mortality. This was based on the dietary fat patterns of 61 countries in the United Nations' Food and Agricultural Organization database. Surprisingly, they found saturated fats to be protective. (web search - Vijay P. Singh COVID-19)
This type of research is all fine, but you can pretty much prove anything you like in this way. See e.g. Tucker Goodrich for a convincing demonstration of why PUFA is in fact the antichrist and responsible for all ills, or the entire medical establishment for why PUFAs are great.
Obviously I'm more sympathetic to the Tucker position, but in neither case do I feel that I'm taking much inspiration from the literature. Whatever you already think is true, you can justify it with endless pointless papers whose entire purpose is to take up space in the literature.
Without mechanism or proper experiments of the sort that no-one ever does, we know nothing.
Even on the comparatively easy question of 'what happens to your PUFA percentage when you lose weight' it seems that you can find a variety of different answers in the literature, and no way to decide what the correct way to model it is. And for the question of 'what happens to your PUFA percentage if you don't eat any at all', nothing except George Burr's original attempt to introduce EFA deficiency in a human being back in 1930 (That's the sort of thing that a real scientist would do!).
For my model above I just picked the most pessimistic guesses I could find.
I've decided that I'm going to follow my intuition, give up PUFAs and see what happens. Fuck around and find out, as they say.
"Without mechanism or proper experiments of the sort that no-one ever does, we know nothing."
I would say that we know nothing for certain without proper experiments. And actually, Olaf Adam has done some of the proper experiments that address the mechanistic aspects of excess arachidonic acid intake. (web search - Olaf Adam arthritis)
As for Tucker Goodrich, he has not attempted to explain why increasing serum levels of linoleic acid improves insulin sensitivity. Worse yet those who do or analyze experiments of that sort have no mechanistic explanation for the observed benefit. (web search - Heidi T.M. Lai Omega-6 polyunsaturated fatty acids and adiposity)
That said, this is one item on my experimental wish list:
A human weight loss trial in which linoleic acid intake is restricted to 3% energy or less and arachidonic acid intake is restricted to 80 milligrams or less per day. That can be achieved by emphasizing grass-fed dairy and ungulate meat. The appropropriate metabolic marker would be changes in adipose tissue arachidonic acid content. This comment Olaf Adam sent me is the rational for this experiment.
Our studies on healthy volunteers were carried out with formula diets and allowed a precisely defined supply of arachidonic acid over a period of 6 weeks. These studies have shown that the exclusion of arachidonic acid from the diet (vegan diet) causes a progressive decrease of this fatty acid from 11 + 3% of the total fatty acids in the cholesterol esters of the plasma to 8 + 2% after 6 weeks. The later studies on patients with rheumatoid arthritis have shown that an intake of arachidonic acid amounting to not more than 80 mg/day does not increase the concentration of arachidonic acid in the phospholipids of the plasma and in the erythrocyte lipids. From these findings I have concluded that the body's own production of arachidonic acid is around 80 mg per day. This means that the Western Diet provides approximately 2.5 to 5 times the estimated need for arachidonic acid. (web search - Hulbert The under-appreciated fats of life)
You say, "This type of research is all fine, but you can pretty much prove anything you like in this way." Had you said 'infer' rather than 'prove', I would have no objection. The goal of scientific investigation is not to prove a narrative correct. The aim should be to do everything possible to ensure it is not incorrect.
> I would say that we know nothing for certain without proper experiments.
Oh me too! I'm an empiricist first and foremost. And I'd quibble with the word certain even then. Proof and inference are not distinct things in the real world.
But the word 'proper' is doing a lot of work. Without mathematical models of what's going on that make falsifiable predictions it's really hard to know what inferences to draw.
RCT is the right way to check that something you're already pretty sure works actually works and avoid fooling yourself. Observational studies without randomization, blinding, etc are at best clues about what sorts of things to look for.
Just look at the Minnesota Coronary Experiment. One of the best designed and most ambitious studies ever done, and of a type I just don't think would be allowed these days.
And yet we're still arguing about what it means, and about why it wasn't published. I tend to think that the medical establishment really has considered all the evidence in the literature and drawn reasonable conclusions from it, and I certainly don't have anything like the time and expertise to come to such a view myself.
But I also think that they're just wrong and that polyunsaturated fats in large quantities are probably really bad news.
Anyone with an opinion seems to be able to justify it with studies. The other side then points out how the studies actually mean the opposite. And back and forth.
The whole thing is just a spectacular mess. One day biochemistry will be able to tell us what's really going on, and then all the results will make sense.
"One day biochemistry will be able to tell us what's really going on, and then all the results will make sense."
By that do you refer to experiments that will furnish consistently unambiguous results?
You wrote, "RCT is the right way to check that something you're already pretty sure works actually works and avoid fooling yourself. Observational studies without randomization, blinding, etc are at best clues about what sorts of things to look for."
I would say RCT is a good way to evaluate observational studies.
If a nutrient intervention is highly reproducible, with large, specific, and reversible effects, then an RCT is not inherently necessary to establish efficacy. Specifically, human trials involving linoleic acid and arachidonic acid have been typically of short duration.
Olaf Adam addressed this problem. "We know from many studies that the "silent inflammation" characteristic for the prevalent diseases of western societies has a latency period of more than 10 years before the consequences such as arteriosclerosis and myocardial infarction become apparent. The body is evidently able to avert the consequences of an unfavorable diet for a long time. To do this, there are numerous regulatory options, such as substrate or product inhibition in the case of enzymes or the inhibition of transport to or incorporation into cells. Arachidonic acid has a very special metabolic pathway that offers possibilities for regulating absorption from the intestine, transport in the chylomicrons, metabolism via the enzymes involved and also for incorporation into the cells. For example, we have found a completely different efficiency for the uptake of arachidonic acid into the cell membrane for platelets compared to erythrocytes or granulocytes. It is therefore very likely that regulation options on the metabolic pathway of arachidonic acid can, to a certain extent, compensate for changes in intake. Only when too much arachidonic acid is present in the food for a prolonged time do these protective mechanisms apparently fail and inflammation and the manifestation of lifestyle diseases is seen. This explains the long latency period with which the diseases of civilization occur."
You might want to think in terms of cell membrane arachidonic acid concentrations. Here is a clue as to what to aim for. "The degree of fatty acid unsaturation of mitochondrial membrane lipids has been found to be one of those biochemical parameters that are most strongly correlated with longevity, when different species of mammals and birds are compared, with a low degree of fatty unsaturation being correlated with less lipid peroxidation and a longer normal life-span. (web search - Anna Haug Individual Variation)
It does seem bad to have easily oxidized things hanging around in a warm oxygenated environment like the body. I certainly think something like that must be going on with heart disease. There are probably lots of similar problems too.
Is it the general theory that your diet alters the lipid content of the membranes of your cells making them more insulin sensitive (a good thing) and your weight changes are a proxy for insulin response?
I don't have specific mechanistic theories in mind, I try to keep myself to "PUFAs bad?" on the basis that PUFAs seem like the sorts of things that might be bad.
Of course it's no surprise that fat cells that are already loaded with huge amounts of fat might be reluctant to take up extra.
But if I was getting all speculatey, then I would guess that most insulin related effects are to do with human metabolism not being tuned to using PUFAs as a major energy source (burning them hammers on various special pathways that probably aren't designed for heavy use).
I'm not really thinking about cell membrane changes, except to note that if you change the composition of the membrane it could well make it more or less permeable to various things. And in particular if the composition of the inner mitochondrial membrane changes that could sod up the entire system on which energy production is based.
But obesity and anorexia look to me like consequences of homeostat dysregulation, so probably more to do with some sort of disruption of leptin signalling, and it seems like PUFAs in the blood-brain barrier can reduce its permeability to leptin.
Or they might somehow be disrupting the leptin receptors themselves, or something. That's the sort of question that a biochemist should be able to answer after a lifetime's work, it's not something I'm going to be working out myself. But I'd be drawn to those sorts of explanations as being obvious ways in which PUFAs might cause obesity, if they do indeed cause it, which I'm not at all sure about.
"But if I was getting all speculatey, then I would guess that most insulin related effects are to do with human metabolism not being tuned to using PUFAs as a major energy source (burning them hammers on various special pathways that probably aren't designed for heavy use).)
Actually this is what researchers observe: "During fasting/refeeding cycles and increased levels of exercise, tissue PUFA concentrations have been shown to deplete rapidly in both humans and rats. These studies show that most PUFAs, including α-linolenic acid (ALA) and linoleic acid (LA), are preferentially oxidized in periods of exercise or fasting. During refeeding, SFAs and monounsaturated fatty acids (MUFAs), such as palmitic acid and oleic acid, are also more rapidly replaced than any of the PUFAs. Similarly, the concentrations of most plasma PUFAs and MUFAs have been shown to be significantly lower in rats fed a high fat ketogenic diet than in controls. The predicted increase in FA oxidation in free-ranging cheetahs is therefore likely to also skew their serum FA profiles toward lower proportional serum concentrations of PUFAs and MUFAs relative to SFA." (web search - Tordiffe Comparative serum fatty acid profiles)
Excerpt: Fatty acid composition in the Western diet has shifted from saturated to polyunsaturated fatty acids (PUFAs), and specifically to linoleic acid (LA, 18:2), which has gradually increased in the diet over the past 50 y to become the most abundant dietary fatty acid in human adipose tissue. (web search - sEH-derived metabolites)
Excerpt: Obesity sometimes seems protective in disease. This obesity paradox is predominantly described in reports from the Western Hemisphere during acute illnesses...adipose triglyceride composition corresponds to long-term dietary patterns...Saturation interfered with triglyceride’s interaction and lipolysis by pancreatic triglyceride lipase, which mediates organ failure. Unsaturation increased fatty acid monomers in vivo and aqueous media, resulting in greater lipotoxic cellular responses and organ failure. Therefore, visceral triglyceride saturation reduces the ensuing lipotoxicity despite higher adiposity, thus explaining the obesity paradox. (web search - Vijay P. Singh saturated fat)
The COVID-19 problem: Separately, on analyzing global COVID-19 mortality data and comparing it with 12 risk factors for mortality, they found unsaturated fat intake to be associated with increased mortality. This was based on the dietary fat patterns of 61 countries in the United Nations' Food and Agricultural Organization database. Surprisingly, they found saturated fats to be protective. (web search - Vijay P. Singh COVID-19)
This type of research is all fine, but you can pretty much prove anything you like in this way. See e.g. Tucker Goodrich for a convincing demonstration of why PUFA is in fact the antichrist and responsible for all ills, or the entire medical establishment for why PUFAs are great.
Obviously I'm more sympathetic to the Tucker position, but in neither case do I feel that I'm taking much inspiration from the literature. Whatever you already think is true, you can justify it with endless pointless papers whose entire purpose is to take up space in the literature.
Without mechanism or proper experiments of the sort that no-one ever does, we know nothing.
Even on the comparatively easy question of 'what happens to your PUFA percentage when you lose weight' it seems that you can find a variety of different answers in the literature, and no way to decide what the correct way to model it is. And for the question of 'what happens to your PUFA percentage if you don't eat any at all', nothing except George Burr's original attempt to introduce EFA deficiency in a human being back in 1930 (That's the sort of thing that a real scientist would do!).
For my model above I just picked the most pessimistic guesses I could find.
I've decided that I'm going to follow my intuition, give up PUFAs and see what happens. Fuck around and find out, as they say.
"Without mechanism or proper experiments of the sort that no-one ever does, we know nothing."
I would say that we know nothing for certain without proper experiments. And actually, Olaf Adam has done some of the proper experiments that address the mechanistic aspects of excess arachidonic acid intake. (web search - Olaf Adam arthritis)
As for Tucker Goodrich, he has not attempted to explain why increasing serum levels of linoleic acid improves insulin sensitivity. Worse yet those who do or analyze experiments of that sort have no mechanistic explanation for the observed benefit. (web search - Heidi T.M. Lai Omega-6 polyunsaturated fatty acids and adiposity)
That said, this is one item on my experimental wish list:
A human weight loss trial in which linoleic acid intake is restricted to 3% energy or less and arachidonic acid intake is restricted to 80 milligrams or less per day. That can be achieved by emphasizing grass-fed dairy and ungulate meat. The appropropriate metabolic marker would be changes in adipose tissue arachidonic acid content. This comment Olaf Adam sent me is the rational for this experiment.
Our studies on healthy volunteers were carried out with formula diets and allowed a precisely defined supply of arachidonic acid over a period of 6 weeks. These studies have shown that the exclusion of arachidonic acid from the diet (vegan diet) causes a progressive decrease of this fatty acid from 11 + 3% of the total fatty acids in the cholesterol esters of the plasma to 8 + 2% after 6 weeks. The later studies on patients with rheumatoid arthritis have shown that an intake of arachidonic acid amounting to not more than 80 mg/day does not increase the concentration of arachidonic acid in the phospholipids of the plasma and in the erythrocyte lipids. From these findings I have concluded that the body's own production of arachidonic acid is around 80 mg per day. This means that the Western Diet provides approximately 2.5 to 5 times the estimated need for arachidonic acid. (web search - Hulbert The under-appreciated fats of life)
You say, "This type of research is all fine, but you can pretty much prove anything you like in this way." Had you said 'infer' rather than 'prove', I would have no objection. The goal of scientific investigation is not to prove a narrative correct. The aim should be to do everything possible to ensure it is not incorrect.
> I would say that we know nothing for certain without proper experiments.
Oh me too! I'm an empiricist first and foremost. And I'd quibble with the word certain even then. Proof and inference are not distinct things in the real world.
But the word 'proper' is doing a lot of work. Without mathematical models of what's going on that make falsifiable predictions it's really hard to know what inferences to draw.
RCT is the right way to check that something you're already pretty sure works actually works and avoid fooling yourself. Observational studies without randomization, blinding, etc are at best clues about what sorts of things to look for.
Just look at the Minnesota Coronary Experiment. One of the best designed and most ambitious studies ever done, and of a type I just don't think would be allowed these days.
And yet we're still arguing about what it means, and about why it wasn't published. I tend to think that the medical establishment really has considered all the evidence in the literature and drawn reasonable conclusions from it, and I certainly don't have anything like the time and expertise to come to such a view myself.
But I also think that they're just wrong and that polyunsaturated fats in large quantities are probably really bad news.
Anyone with an opinion seems to be able to justify it with studies. The other side then points out how the studies actually mean the opposite. And back and forth.
The whole thing is just a spectacular mess. One day biochemistry will be able to tell us what's really going on, and then all the results will make sense.
"One day biochemistry will be able to tell us what's really going on, and then all the results will make sense."
By that do you refer to experiments that will furnish consistently unambiguous results?
You wrote, "RCT is the right way to check that something you're already pretty sure works actually works and avoid fooling yourself. Observational studies without randomization, blinding, etc are at best clues about what sorts of things to look for."
I would say RCT is a good way to evaluate observational studies.
If a nutrient intervention is highly reproducible, with large, specific, and reversible effects, then an RCT is not inherently necessary to establish efficacy. Specifically, human trials involving linoleic acid and arachidonic acid have been typically of short duration.
Olaf Adam addressed this problem. "We know from many studies that the "silent inflammation" characteristic for the prevalent diseases of western societies has a latency period of more than 10 years before the consequences such as arteriosclerosis and myocardial infarction become apparent. The body is evidently able to avert the consequences of an unfavorable diet for a long time. To do this, there are numerous regulatory options, such as substrate or product inhibition in the case of enzymes or the inhibition of transport to or incorporation into cells. Arachidonic acid has a very special metabolic pathway that offers possibilities for regulating absorption from the intestine, transport in the chylomicrons, metabolism via the enzymes involved and also for incorporation into the cells. For example, we have found a completely different efficiency for the uptake of arachidonic acid into the cell membrane for platelets compared to erythrocytes or granulocytes. It is therefore very likely that regulation options on the metabolic pathway of arachidonic acid can, to a certain extent, compensate for changes in intake. Only when too much arachidonic acid is present in the food for a prolonged time do these protective mechanisms apparently fail and inflammation and the manifestation of lifestyle diseases is seen. This explains the long latency period with which the diseases of civilization occur."
You might want to think in terms of cell membrane arachidonic acid concentrations. Here is a clue as to what to aim for. "The degree of fatty acid unsaturation of mitochondrial membrane lipids has been found to be one of those biochemical parameters that are most strongly correlated with longevity, when different species of mammals and birds are compared, with a low degree of fatty unsaturation being correlated with less lipid peroxidation and a longer normal life-span. (web search - Anna Haug Individual Variation)
It does seem bad to have easily oxidized things hanging around in a warm oxygenated environment like the body. I certainly think something like that must be going on with heart disease. There are probably lots of similar problems too.