Saturday, December 14, 2019

Protons (52): A correction and a few thoughts on satiety

There has never been a completed concept of the Protons thread. Logic and data have allowed it to emerge and I still have no idea where it will end, but there have been a few mis-steps on the way. A reader recently pointed my incorrect post from 2013 where I was looking to see how fasting or ketogenic diets might blunt insulin signalling. Nowadays my feeling is that it is high physiological ROS generation which achieves this. At the time I clearly got it wrong with:

"We appear to have two basic states of the electron transport chain. There is the situation under fasting or ketogenic dieting conditions. Here delta psi is low, complex I throughput is low and there is plenty of FADH2 input through electron transporting flavoprotein dehydrogenase coming from the first step of beta oxidation of real fats, like palmitic acid. With a low delta psi it is near impossible to generate reverse electron flow through complex I so activation of insulin signalling is rapidly aborted by the continuing action of tyrosine phosphatase".

That does not appear to be the case and, having thought about it, my email reply went like this. We had been chatting about ketones, delta psi, RET and insulin resistance from ketones vs from saturated fats. I may as well copy/paste some of it here, slightly edited for clarity, and place a link within the 2013 post:

"My thinking currently is that ketones do not induce insulin resistance unless, like glucose, there is enough input via complex II to do this. So RET is possible but will only occur when the cell has adequate caloric supply. If you combined ketones with stearic or palmitic acid the long chain fatty acid would undoubtedly input at ETFdh and drive RET, rather than it being the ketones. Incidentally, this probably also represents "cellular satiety". Clearly under physiological conditions ketones will normally be associated with elevated FFAs.

The differential effects of FFAs vs ketones would be that FFAs would then drive insulin resistance in cells which can metabolise them, muscle etc, but ketones would drive far less RET in cells which require some small amount of glucose in excess of the energy supplied by the ketones themselves, ie neurones…

On the adipocytes things look more complex. Undoubtedly both ketones and FFAs exert a negative feedback on lipolysis in addition to any effect of their driving/not driving RET during oxidation. But some degree of insulin signalling is essential to physiology in addition to this negative feedback, otherwise we get diabetic ketoacidosis due to failure of insulin availability to oppose glucagon.

Once you start to think about stearic acid plus glucose you have to differentiate between cellular levels and dietary levels. Simply treating isolated adipocytes with elevated glucose and elevated long chain FFAs will result in ROS. If you set your experiment up correctly (no MUFA, no PUFA, high glucose) the resulting RET will result in apoptosis or necrosis. There is an infinite supply of papers doing this to almost any cell type.

In the whole animal things are different. If physiology is functional the stearic acid will provoke a prompt first phase insulin response and will effectively augment insulin delivery via the portal vein to the liver. Insulin acting in the liver will limit glucose release to the systemic circulation and so limit the need for systemic hyperinsulinaemia to deal with the glucose. Then the animal stays slim as there is minimal systemic hyperinsulinaemia.

If physiology is non functional we are talking DM T2 which is largely the aftermath of chronic PUFA ingestion and things then become even more complex. The low carb approach side steps the problems of failure of correct insulin secretion/hepatic signalling by simply reducing the reliance on any sort of insulin signalling beyond the most minimal needed. Then stearic acid becomes problem free. When (or if) physiology normalises then some degree of glucose consumption by mouth might be acceptable along side saturated fats but by then anyone with any sense will be fat adapted and unwilling to go back to a mixed diet".

This set of thoughts is currently relevant as Brad Marshall has taken the concept of stearic acid as the best physiological generator of adipocyte physiological insulin resistance and converted it in to a moderate carb, highly saturated fat diet with interesting results. You can read about his croissant diet on his blog Fire in a Bottle: Introducing The Croissant Diet. This experiment is based on the PhD of Valerie Reeves where a mixed macro diet based around stearic acid markedly limited weight gain in db/db mice. The db/db mouse is an extremely severe obesity model as it lacks functional leptin receptors. So a complete lack of leptin signalling can be side-stepped, still in the presence of starch, by supplying roughly 40% of calories as predominantly stearic acid. Not low carb. Not ketogenic. It works (from my point of view) by directly manipulating ROS generation (ie increasing it) at the electron transport chain level to signal "cellular" satiety, with appropriate ability to resist insulin's fat storage signal. This will be recapitulated in the brainstem neural circuits which control whole body satiety. Signalling from the ETC is core. It works by generating physiological insulin resistance and clearly over-rides any effect from leptin signalling.

Also in the comments of the last post came this gem from ctviggen, worth a post in its own right. Interesting paper. Limited insights within the discussion but great data!

Dietary Stearic Acid Leads to a Reduction of Visceral Adipose Tissue in Athymic Nude Mice

While all of these ideas were kicking around the concept of fasting as a state of caloric excess emerged. Obviously, not eating makes you hungry. Initially. There comes a point where, when insulin is low enough and FFAs rise to levels approaching over 2000micromol/l (plus ketones), when hunger decreases. Prolonged fasting does not invariably generate ravenous hunger. This is because FFAs (and ketones) represent an energy glut beyond any single cell's imagination and it does not require insulin signalling to access it (there do appear to be other controls on ATP generation). So cells which can metabolise FFAs should behave as it they have more than enough calories so that they should resist insulin. Access to excess metabolic substrate must result in ROS and the appropriate disabling of insulin signalling. Starvation as generator of a caloric excess signal... An interesting concept.

And PUFA, failing to generate adequate ROS, might well lead to glucose "wastage" in to cells such as myocytes which might well result in profound and symptomatic hypoglycaemia, essentially a failure of satiety signalling. Another interesting idea. Which clearly would not happen if metabolism was based around stearic acid...



Amber O'Hearn said...

Hi, Peter,
I have occasionally experienced seeming "fasting intolerance" where despite fasting ketones don't get very high, and I become tired and cold rather than energetic. I had supposed it might be due to elevated insulin making it difficult to access fat stores, but if access is insulin independent, what else might cause this?

Kyle Tengler said...

Do we have any reason not to believe palmitic acid would have similar effects?

Peter said...

Hi Amber,

I didn’t phrase that very well. I would agree that even modestly elevated insulin within the normal fasting range could easily act on adipocytes to limit FFA supply to plasma. How you get to this state is interesting but not directly related to your comment. But you have stated the most likely explanation.

By having a caloric supply which is independent of insulin I was actually thinking of the situation where FFAs are at or over 2000micromol/l. I doubt whether you would need insulin to translocate CD36 to the cell surface to uptake adequate FFAs under these conditions.

You still need the low insulin or to have effective physiological insulin resistance to get FFAs that high and so allow an adequate energy supply, plus to allow adequate ketones to be generated.


Peter said...

Hi Kyle,

I would have thought the two should have been very similar but in this study

Stearic acids at sn-1, 3 positions of TAG are more efficient at limiting fat deposition than palmitic and oleic acids in C57BL/6 mice

both the stearic acid groups appeared to gain a little less fat than the palmitate group... And the higher stearate group had a little less fat than the slightly lower stearate group. So.......... maybe there is a difference.


davemoriarty2 said...

Hi Peter,

How would fructose play into this? I recall fructose being a bad mix with sat fat because of the physiological insulin resistance due to the fat. But brad was eating maple syrup.

Thanks so much,

cavenewt said...

So much of the discussion revolves around weight loss, but there could be other implications. I'm interested in how stearic acid might affect a cancer tumor cell, particularly in the context of the Warburg effect.

Malcolm said...

I guess it depends on the kind of cancer. If eating carbs with the stearic maybe the raised blood glucose is not good?

Having a look on pubmed I've found:
"Overall, these data indicate that stearate inhibits breast cancer cell proliferation by inhibiting key check points in the cell cycle as well as Rho expression in vitro and in vivo and inhibits tumor burden and carcinogen-induced mammary cancer in vivo."
"These preliminary data indicate that stearic acid inhibits tumour development in rats."

So they sound hopeful?

BigWhiskey said...

bone loss in stearic diet?

BigWhiskey said...

Passthecream said...

davemoriarty2 It seems to me that not just quality but the absolute quantities and ratios of substrates must make a difference to the levels of r.e.t.

I have wondered if fructose would increase the amount of ret from a less saturated fat intake eg if a mix of oleate plus fructose ( plus some glucose? ) might approximate the fadh/nad ratio of stearate but I haven't worked through all the details.

This would be the halvah diet. Just in time for Xmas.

le frota said...

Peter, are you aware of any difference between the structure of stearic acid from vegetables or animals? Or is it the same?

BigWhiskey said...

What about the bone loss?

LeenaS said...

Peter and Brad, thanks!

My way of eating Optimal has relied heavily on butter for more than 10 years. The lab work taken last year showed once again that nothing needs to be changed, but it is good to see it being discussed reasonably at least here.

Cheers and merry wishes for the festivities o/

Peter said...

Hi davemoriarty2, fructose is very complex. I had a think about in around the time of the Potato Diet and the Rice Diet. Fructose clearly does several interesting things. It acutely depletes ATP and gives rise to uric acid generation, both of which should decrease ROS. It generates lactate in excess of the ability of mitochondria to metabolise it and it generates palmitate without having to enter the mitochondria. It’s a busy molecule!

cave, the weight-control data look like a surrogate for 24h insulin exposure to me. Hardy’s group are the main people looking at both weight and mammary tumour outcomes in mice and Hardy is a little conflicted. The Bristol paper from Malcolm (thanks) is supportive and the work from Kuala Lumpur is supportive of the weight aspect. At the most basic level we can look at ROS. Next level up is insulin action as a tumour growth promoter. If insulin becomes limited (by stearate) to cross talk between the pancreas and liver with minimal involvement of the systemic circulation you are removing a key hormonal growth promoter from both adipocytes and cancer cells. Combines Protons with Ron Rosedale’s idea that growth promotion precedes the metabolic changes in cancer cells. He’s partly correct, I think.

Malcolm, yep.

Pass, LMAO

le frota, Chemical stearic acid monomer is just one invariable molecule. Food derived stearic acid will undoubtedly come in differing forms as in where on the glycerol backbone the stearate(s) are mounted and what the total dose will be. Lamb/beef suet will be different again. The overall effect is not clear at the moment but in real life I tend to favour beef suet!


That's an interesting paper at

Simple test: What concentration of glucose did they use in their alpha-MEM for cell culture with stearate? Outside of a SCD1 KO mouse, how many mammals run pure palmitate/stearate in their blood stream w/o any MUFA? How did they make the obese mice obese? Hint: it’s not saturated fat! The authors have blood on their hands! Classic example.


Peter said...

Happy Solstice, Christmas and New Year LeenaS!

Best wishes


BigWhiskey said...

Thanks for the response. Yes, Great Health, Wealth and Charity to Us All!

Philippa said...

"If physiology is functional the stearic acid will provoke a prompt first phase insulin response and will effectively augment insulin delivery via the portal vein to the liver."

Hi Peter, could you clarify....does stearic acid promote a greater first phase insulin response than other fatty acids/nutrients? Or do you just mean in healthy physiology there will be a robust first phase insulin response to any meal?

Peter said...

Hi Philippa,

You just need Fig 3 or Fig 4. This is an isolated pancreas prep. A whole animal behaves a little differently as there is a huge effect on first pass hepatic extraction and the effect of a phase 2 response, both of which alter the systemic levels of glucose, insulin and stearate.


Philippa said...

Thanks Peter, that's fascinating. Although how much of the fatty acids from the meal in question would be 'seen' by the pancreas? I thought fats from a meal were packaged up in chylomicrons rather than ending up in the portal circulation. Wouldn't the fatty acid supply to the pancreas (at the beginning of the meal when the glucose first arrives there) be the endogenous fatty acids that were circulating in the fasting state....thus representing the fatty acid composition of body stores rather than the composition of the meal? Or am I just getting confused?

Mark said...

how many stearic acid drops do I put in my Big Gulp so I don't get fat?

shtove said...

Interested in views on Atoro beef suet, the standard brand in UK supermarkets. It provides about 45% sat fat, whereas Britannia dripping has a sat/mono/poly ratio of 57/36/03. It also is 15% fortified wheat flour - presumably white flour, which would fit the fireinabottle experiment.

My understanding of suet is that it is exclusively organ (mostly kidney) fat, with a high stearic acid content, whereas dripping is mostly muscle fat. Plus I've read that it is clear of added hormones - I wonder if that is true.

Peter said...

Hi shtove,

Interestingly I looked this up a couple of days ago. If you don't mind some carbs from wheat the Atoro suet is a pretty good bet. No good for me though. Getting raw suet is a nightmare for me. Mail order from London needs coolbox packaging etc and the delivery is way more than the cost of the suet. I had a local butcher source a couple of kilos early on in my carnivory but he's been unable to get any for months. Currently I'm on Britannia dripping and, in combination with zero carb, this seems to be quite functional. I have been asked to put a little weight back on so have incremented from 60.6kg to over 62kg and will aim for 63-ish kg... Just eating slightly more meat and lots more fat. BTW lamb hearts from Morrisons are quite fatty and this fat handles like suet.


Puddleg said...

What I'm thinking now is that endocannabinoids are the way n-6 disrupts insulin signalling.
E.g. Joe has high n-6 in adipose is a little overweight.
Joe tries to eat less or exercise more, releasing n-6 as anadamide, or is circadian disrupted, releasing AG-2.
These increase glucose uptake and lipogenesis, just like insulin, so now Joe has the Munchies.
If Joe had less n-6, then the n-3, n-9 and palmitate in his adipose would be used to made endocannabinoids and analogues that would increase fat oxidation and reduce inflammation when Joe eats less or exercises more, making automatic weight correction a lot easier.
But because Joe's experts recommend he eat soy oil and limit saturated fat, the little n-3 he consumed has vanished without trace, and the conversion of n-6 to endocannabinoid is out-competing the other entrants into that pathway, oleate and palmitate.

Passthecream said...

Peter, could you just warm the suet mix to melt out the fat? Maybe in water so it floats then throw away the wheat sludge?

Zoomie said...

In research, I came across this after listening to Sylvia Tera interview. Seems as though this virus disrupts the balance. What are your thoughts on now this ties in with ROS Theory and if it is a compounding factor. Peter & Brad? Your thoughts? (AD36 Virus - Obesity link)