Tuesday, September 14, 2021

Modelling energy intake (2): Corn oil

This post has been waiting around for some time so I thought I'd just put it up before settling down to read

but I'm also looking at

and this one is pure Protons and ruminants

ditto this

and there might be at perhaps two more post on canagliflozin. Maybe.

When on earth I'll get to post on these I have no idea. Working on it!

Anyhoo. Back to today:

I thought it might be interesting to very, very crudely apply Kevin Hall's mathematic model to a much more interesting study. This one came my way via Jacob in comments quite a few weeks ago.

Response of body weight to a low carbohydrate, high fat diet in normal and obese subjects

This graph is an example of one single individual out of a total of five people in 1973, so we are talking about near-anecdotal data, but fascinating never the less.

The diet contained a fixed 168g/d of carbohydrate and 64g/d of protein plus a variable amount of fat over time. This is the weight change curve for subject "1", as far as I can make out:

This person lost around 2kg in the first 10 days on the diet then regained just a small amount over the following 25 days. For comparison if we now go on to look at Table 3 from Hall's

How Strongly Does Appetite Counter Weight Loss? Quantification of the Feedback Control of Human Energy Intake

we can see that a standard "lifestyle intervention" (Weight Watchers and exercise perhaps????) established an enforced caloric deficit of around 700kcal per day, which was eroded by hunger ("appetite") at something like an exponential rate, approaching the re establishment of baseline caloric intake with persistent ongoing hunger:

In the first month or so this caloric deficit triggered something around 2kg of weight loss. So if we took the graph for subject 1 at the top of the post we might reasonably assume an initial deficit of in the region of 700kcal with a rapid onset of hunger which would try to erode this weight loss effort. Something like:

Absolute CI decrease + CO increase = hunger, ie real life.

Except the subject in the graph at the top of the post was not in a weight loss study. He/she was in an overfeeding study. Carbohydrate and protein were kept fixed (and non-ketogenic) and progressively more fat was added to the diet, in steps, every five days. Here is the graph with the calorie intakes illustrated for this particular individual.

Yes, that is just under 6000kcal/d at a stable reduced weight.

Two things come to mind.

First is that it is stated that all subjects consuming over 2700kcal/d of fat felt warm all of the time and sweated easily. Second is that DLW measurement of TEE would certainly pick this up perfectly well and estimate a massive "calories out". Those would be as heat. Reversing-engineering weight loss to estimate changes in food intake is clearly completely out of its depth here. What happened?

The fat was corn oil.

Linoleic acid -> 4HNE -> activates uncoupling to blunt insulin signalling and causes insulin resistance per se -> hot, sweaty weight loss.

It takes a significant amount of linoleic acid to do this, well in excess of that needed to augment fat storage.

This effect appears to apply just as well to humans as it did to those mice in The ginger paradox (3), even when overfeeding is exogenously enforced. Clearly the mice which actively lost weight "effortlessly" (ie mice never do the human "appetite" battle unless they are exogenously semi-starved) on safflower oil used uncoupling to blunt insulin signalling and so increase lipolysis and adipocyte derived calorie supply.

Subject 1, on corn oil, had a peak of around 84% of calories from fat which put the linoleic acid percentage in the region of 40% of 6000kcal, well in to uncoupling levels. Corn oil in the 1970s was suggested to be around 45% LA.

Now, what would be expected to happen if we massively over fed with a lower LA, less uncoupling fat? The estimate for LA in olive oil in the 1970s was 7%. In this next graph the maximum LA percentage was 6% of calories, which is more akin to an obesogenic dose than to an uncoupling dose. Overfeeding olive oil does this:

That is 9kg weight gain in 40 days, and still going.

Now, what might we expect if we tried the same thing with beef fat? My expectations:

Weight gain would be even greater.

Metabolic syndrome would develop rapidly.

It should be much harder to sustain a 6000kcal diet of mostly beef fat than it was from either an uncoupling or  an obesogenic fat source.

The group didn't try overfeeding beef fat, sensibly.

There are a number of studies which I have picked up over the years which suggest that the uncoupling effect of double bonds kicks in at essentially all levels of their metabolism. At low levels the effect is over-ridden by the effect of failing to limit insulin signalling in adipocytes as per the Protons concept, leading to weight gain ie insulin still signals perfectly well and it does so more than is physiologically appropriate, especially in the immediate post prandial period. As uncoupling comes to predominate the ability of a low mitochondrial membrane potential to markedly suppress ROS generation becomes progressively more and more dominant, so insulin signalling becomes profoundly blunted. It will never get to high enough levels where insulin-induced insulin resistance should have kicked in, so the Protons concept becomes irrelevant. Under uncoupling, mitochondrial metabolism is functionally hypoinsulinaemic, it should resemble that of reduced insulin gene dose mice in Jim Johnson's lab where reduced insulin signalling was simply the end result of reduced insulin production, 24/7. It should also resemble ketogenic, hypoinsulinaemic eating.

Whether it is via 4-HNE/UCPs or 2, 4-dinitrophenol, high enough levels of uncoupling will absolutely blunt insulin signalling, with subsequent increase in access to adipocyte calories and consequentially suppressed hunger, leading to adipose tissue loss without increased food intake, with a few small caveats thrown in.



raphi said...


I read that in diseases affecting the respiratory chain a higher membrane potential actually decreases ROS, a seeming exception to the norm whereby ATP synthase shutdown lowers mitochondrial membrane potential and thus increases ROS. If I got that right, are diabetics helped by Metformin because it inhibits mtG3PDH => increases mitochondrial membrane potential => lowers ROS?

Passthecream said...

Metformin has had me scratching my head lately. Mtg3pdh isn't uniformly expressed across all cell types which is one complication, and perhaps the Metformin effect on it is more involved with pancreatic cells thereby insulin production, but this mito membrane version of g3pdh is fad(h) bound/dependant so I have been trying to understand just how the effect of metformin differs from eg fatty acids with a different f/n ratio. Why is the effect of Metformin on the ETC not the same as that of pufa for instance? I briefly had an Aha! moment when I read the above about the uncoupling effects of pufa, but it is unclear to me atm.

raphi said...


"Why is the effect of Metformin on the ETC not the same as that of pufa for instance?"

I started narrating an answer in my mind but soon realized I was bloviating. I don't know. I couldn't even call upon complex 1 effects given they're not meaningful at physiological levels...

Jonathan said...

Well, I wish they had done the beef fat experiment. I would be fascinated to know for sure how it would turn out.

You hypothesize greater weight gain. But if I understand the Protons concept right, the beef fat would have made the adipocytes more insulin resistant. So is your belief that the body would have generated as much insulin as necessary to force the beef fat into the adipocytes, as it has nowhere else to go?

Monica said...
This comment has been removed by the author.
Monica said...

I guess weight gain would be the result of overfeeding, but in real life, with peripheral insulin resistance, you are not hungry so you lose weight. Yes, I would love some research on beef fat.

Peter said...

Hi raphi,

That's probably worth a post in its own right. I have thought about it on many occasions and the basic difference appears to be in the effect on the liver. Metformin suppresses hepatic glucose output from gluconoegensis based on glycerol or lactate. This is based on the rise in NADH:NAD+ ratio in the cytoplasm. Converting lactate to pyruvate requires NAD+ but lactate can still enter mitochondria for oxidation via the TCA. Working on the basis that metformin is specifically excluded from mitochondria then complex I will still supply plenty of NAD+ to convert lactate to pyruvate to enter the TCA. Also in the cytoplasm of the liver glycerol will be phosphorylated to glycerol 3 phosphate but requires NAD+ to convert the glycerol 3 phosphate to dihydroxyacetone phosphate. Metformin, by blocking the glycerophosphate shuttle, makes both reactions unfavourable.

BTW there is some evidence the metformin does actually inhibit complex I at therapeutic levels by acting on the cytoplasmic side of the membrane component of complex I, but this does not seem to be terribly relevant compared to the redox changes at therapeutic dose rates in the cytoplasm...


Peter said...

Obviously in addition to suppressing insulin secretion directly and blunting insulin induced insulin resistance...


Peter said...

Jonathan and Monica,

Absolutely. Overfeeding is not real life!


raphi said...


Thanks, I had whiteboarded your explanation and think I got it. I didn't know there were (small?) therapeutic effects on complex 1 from metformin on the cytoplasmic side of the mitochondrial membrane - good to know!

Peter said...

Found it.


To me, any complex I inhibition is an off target toxicity at any concentration. After all, the Galega officinalis plant hates all herbivores/omnivores, even those who should stick to eating fatty meat!


Passthecream said...

Galega O. is a legume relative btw. Another black mark against the bean family.

karl said...

I had missed the Galega officinalis connection up to now - interesting..

I can think of several dietary factors that drive T2D/obesity. So every time I go to the grocery store and look in other people's carts, I think of this obvious experiment to run. (This has become a very strange habit - but my unscientific observations tend to link T2D with CIAB and sugar drinks - but I bet there is more to learn)...

A checkout lane that weighs the customer - but not the cart - a LASER scanner gets a height - we now have a rough BMI - and what is purchased. Not perfect, but by combining the UPC codes scanned with food content labels - one should be able to find correlations - and my hunch is there might be surprises to be found.

These correlations wouldn't mean much on their own, but could direct further research. Some correlations could be large enough to mean something .. we really could use this data.

One could draw out total amount of PUFA vs SAT - sugar, carbs, protein. There could be particular bar codes that have high correlations - things we are not yet looking at.

Eric said...

Mostly off topic again but it involves mice, fat and a change of chow. The message sound like garden variety lipophobia but plenty of facts are provided. This needs someone like you, Peter, to pick apart and put into perspecitve :)


David said...

Google probably has the information already. Just a matter of matching the size of clothes purchased with grocery typical grocery baskets.

Robin said...

Hi Peter,

I'd be interested to hear what you make of this study in mice. The mice were fed isocaloric diets either high in LA or SFA (safflower vs. coconut oil). The mice were given either T3, T4 or no hormones (control). There's data on change in bodyweight and basal metabolic rate.



karl said...

Another paper I ran into -- polysorbate 80 is in a lot of processed foods..
Mitochondria mediated?


Peter said...

Hi Robin,

A slightly difficult study. Putting mice on thyroid hormone increases their metabolic rate, quite a lot. Just a little more so if the fat is coconut oil rather than safflower oil. But the mice on coconut oil lost no weight whereas the mice on safflower oil lost quite a lot. Yet both groups had pretty much the same high metabolic rate?????? Does this mean the mice on coconut oil spontaneously ate more food than the mice on safflower oil?

Both diets were ad-lib, they were only isocaloric in terms of composition. It’s interesting because vets deal with thyrotoxicosis all the time and if, in those cats for which treatment is impossible, simply feeding as much saturated fat as they like to eat to maintain weight would be crucial as a proportion of these cats are euthanised for emaciation rather than for cardiovascular catastrophe…

Am I missing something? The paper doesn’t discuss it and I can’t see food intakes reported.


Peter said...

karl, sounds delightful!

Eric, paywalled...

cave, yes, it would be shocking if the USA did not suffer COVID problems in proportion to the incidence of metabolic syndrome, aka the lipid hypothesis. There may be a way to go yet.


cavenewt said...

Peter, I'm assuming your comment to me was in response to my comment on a different page? About the below article? For those readers who don't obsessively follow every single Hyperlipid comment ;)

"Most COVID-19 hospitalizations due to four conditions" March 9, 2021 https://www.nih.gov/news-events/nih-research-matters/most-covid-19-hospitalizations-due-four-conditions

Peter said...

cave, absolutely! Mea culpa.

Re Eric's link, the paper which underpin's it is pretty awful with no details of the high fat diet used other than it was random lard based, 42% fat and made the animals fat (and we can assume hyperinsulinaemic) probably secondary to PUFA loading. Who knows what any individual aspect means?


karl said...

Ran into yet another surprising paper:
"...suppressed cell proliferation by promoting ROS-mediated mitochondrial apoptosis pathway and inducing S phase arrest in CRC cells, suggesting..."


Haven't dug into the details - but suppressing colorectal cancer cell growth seems like a good thing.

I have a 'hunch' that ROS is also a signal used in the immune system - back when I did a rather deep dive into so-called anti-oxidants, I was thinking if the were really absorbed they might cause cancer. I am rather convinced that the popular polyphenols mostly stay in the intestines - might act as chelating agents that prevent the absorption of heavy metals? I am sure I don't know - other than the popular narratives about anti-oxidants are mostly BS.. good for selling stuff. Nice to have color in one's foods - but clear understanding is hard ..

One last observation - I've been on a low-PUFA diet for some years now - it is possible that it has changed my thermal regulation - if I eat a bit too much of anything, I get warm now - More cold tolerant. Could I be changing some set-point? I'm wondering if a side effect of PUFAs is causing thermal regulation problems similar to hypothyroidism? Is this something like a change in metabolic setpoint? Like to see some papers on animals.. What happens to livestock's metabolic rates when they put them on corn? This could be a slow effect - so no one is likely to associate it with the dietary changes??

Peter said...

karl, a bit like https://pubmed.ncbi.nlm.nih.gov/19267249/ where "This anti-metastasis effect may be due, at least in part, to the ability of stearate to induce apoptosis in these human breast cancer cells"... Just add ROS.


Eric said...

Sorry, didn't realize you now have to register with NYT even to read your free 3 articles / month.

Here's the study:

But that is also paywalled with no free articles.

Peter, is that the one you referred to above? I couldn't even get to the point where they talk about lard. But if that was lard from hogs fattened with depleted corn, we know what it really is, corn oil in disguise.

Chad said...

Karl, try https://fireinabottle.net/torpor-sloth-and-gluttony-part-1-americans-ate-a-lot-in-1939/

Brad Marshall has some interesting articles on PUFA negatively impacting metabolism. I have been on a low PUFA diet for 2 years and my body temp is now at 98.6 whereas it was always in the 97s before, sometimes as low as 97.2.

cavenewt said...

Re Eric's post of 27 Sept and Peter's reply on 2 Oct.

The paywalled New York Times article referred to by Eric is "High-Fat Diet May Fuel Spread of Prostate Cancer." It's based on the study "An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer." https://sci-hub.se/https://doi.org/10.1038/s41588-017-0027-2

From the article (editorial comments mine):
'Dr. Pandolfi has long tried to study prostate cancer spread in mice, but the rodents were not much help. Few genetic manipulations made prostate cancers spread in the animals as they do in humans.

'Then one day, at a meeting with colleagues, Dr. Pandolfi had an idea: “What are the mice eating?” he asked [maybe this should've been his first question?]. It was mouse chow, his co-workers said — a low-fat, vegetarian concoction.

'“Why don’t we try a simple experiment?” Dr. Pandolfi recalled asking. “Why don’t we put our mice on a high-fat Western diet?”

'It was the missing link. Mice with prostate cancers that had lost PTEN and that were fed a high-fat diet quickly developed tumors that grew rapidly and spread. It was as though fat in the diet had an effect similar to the loss of PML, the protective gene. Then the group asked a bigger question: Could they could protect mice from metastatic cancer by blocking fat production? That led to the experiment with a new obesity drug, fatostatin. It not only halted the cancer’s spread in the animals, but made it regress.

'...High-sugar diets also cause obesity. Are the prostate tumors in men who became fat by eating high-sugar diets equally susceptible to metastasis? If they are, what is the mechanism?

'...Dr. Pandolfi and his colleagues are planning a clinical trial with fatostatin to treat prostate cancer in humans.

'They also wonder if low-fat diets might help these patients, and what kinds of dietary fat might fuel prostate cancers. “You cannot just say, ‘Don’t eat fat,’” Dr. Pandolfi said.' [Eureka! An enlightened question.]

Make of it what you will, this is from the methods section of the paper:

'For HFD feeding, male mice were given a dietary chow consisting of 60% kcal fat (Teklad Diet TD.06414) starting at the age of 12 months and continuing for 3 months. All other mice were fed standard chow consisting of 17% kcal fat (Lab Diet 5008). Male mice were housed one per cage during preclinical studies of both HFD and fatostatin.

'...In vivo treatment. Ptenpc–/–; Pmlpc–/– mice at 12–13 months of age were treated with fatostatin (15 mg/kg) or corn oil (vehicle control) by intraperitoneal (i.p.) injections, every other day for 2 months. Mice were then euthanized, and mouse tissues, including prostate tumors, were dissected, weighed and processed for histopathology and molecular analyses.'

Malcolm said...

Teklad Diet TD.06414

Fat is mostly lard, a little soybean oil (approx 10:1). I guess we'll never know the PUFA content of the lard.

Passthecream said...




Passthecream said...


This is real. Calcium soaps of FA are the slimiest of soaps, not soluble in water or much of anything in fact they are best described as greases but someone has worked out, since cows cannot digest unprocessed fats and oils in their grass-oriented low pH first stomach that turning the fats into soaps gets around that problem. It's big business getting cheap oil-derived feedstocks into ruminant digestive systems.

Guess which heart-healthy fatty acid is the top choice of source material for this?

karl said...

I suspect that high PUFA diets are carcinogenic .. A study that looked at MRI - Linoleic acid content of people vs cancer rate would be interesting - I suspect this is a long term effect. Mess with the immune system and caner-cells have a chance to out-grow the normal immune system check on misbehaving cells?


Interesting data point:


Of course the death rate varies greatly with age - and in the USA where most people are on the popular humming-bird-diet-fortified-with-PUFA.. the death rate is higher..

JR said...

Hi, Mercola seems to grasp bigger issues (LA maybe worst), but mechanism is "under development" me thinks:
"Cycling back to the issue of LA again, it's important to recognize that excessive LA in your diet can cause extreme reverse electron transport flow through complex I in your mitochondria with the production of high quantities of superoxide and H2O2, which actually causes you to become insulin resistant. So, insulin resistance is not restricted to excessive carb intake.

Limiting LA will also help reduce oxidative LA metabolites, which are the most pernicious sources of oxidative stress in your body. These oxidized LA metabolites (OXLAMs) prematurely destroy mitochondria and limit your ability to efficiently create ATP.

When you eat an excessive amount of LA, the disruption it causes in your mitochondrial electron transport chain causes your fat cells to become insulin sensitive. This is the last thing you want. While you want your somatic cells to be insulin sensitive, your fat cells need to be insulin resistant"

He is co-writing a book with Chris Knobbe, so there is hope.
Rgds JR

Peter said...

Agree, but at least people are starting to think in the correct direction. A few detours are inevitable...