Monday, September 17, 2012

Protons: Linoleic acid in the hypothalamus

Hi all, just getting my head above water now that we have two or three locums at work to cover some of the (rather difficult) gaps in the rota!

Before we look at the fat mouse study which wins the prize for most miserly hoarding of data, I just wanted to put up a brief post, based on that paper, about breaking your hypothalamus with a high fat diet. Just to re emphasis: This is NOT what happens to a human after 7 days on a high fat diet.

Remember Schwartz's rats? Put them on a high fat diet and this happens to food intake:

Note the very sudden and dramatic spike in the intake of food, shown by the red line which I've added to emphasise the abrupt change from baseline chow consumption. We can ignore the red oval for this post. What happens in the VMH neurons of these rats?

This is what happens:

The dark brown staining cells on the right are dying, the rats have been eating "cookie dough", which they "can't get enough of", for seven days. The nice healthy cells in the left hand photomicrograph are from rats on crapinabag. The basic idea appears to be that feeding rats a bit of fat and sugar makes them eat so much, starting in just one day, that by seven days their VMH is killed by over indulgence. You eat too much, you kill your brain. Simple. This is, of course, absolute bollocks.

At the risk of repetition, we can produce exactly the same lesions in the VMH with MSG or gold thioglucose (or an ice pick if you must be crude and don't want nice pictures). This injury results in fat gain which must be compensated for by overeating. Rats will gain weight more slowly if they are on low fat diets than on high fat diets because of the effects of increased de novo lipogenesis which I've discussed in previous posts.

Want pretty pictures from GTG injured rats? Here's some random immuno from a random paper, there's a lot of it around, only black and white though:

Gold thioglucose on the right, arrow marks the injury area. And I just noticed the same pics, also in black and white, from fat injured rats from elsewhere in the Schwartz paper (mirror imaged compared to the GTG pics, random choice of which side of brain got sectioned!) after just a week on their high fat diet:

So we can produce the pretty black stains of dying cells with gold thioglucose (or MSG if we looked at neonatal immuno) but this injury preceeds the loss of calories in to adipocytes and subsequent "hyperphagia". THE INJURY COMES FIRST.

Let's really look at the bizarre idea that non-forced "overeating" causes subsequent damages your VMH. This is how it works for over eating by a gold thioglucose injected rat, no yummie high fat diet needed: It simply decides to over eat crapinabag because this has suddenly and randomly become delicious and so it becomes obese. We all know overeating CAUSES the VMH injury in fat fed rodents. So how do GTG injured rats get the injury first and over eat secondarily? Gold thioglucose obese rodents might SEEM to have a chemical lesion causing obesity but clearly they get fat first, travel back in time (squeezing in to a time machine as obese chrononaughts) and retrospectively force the researchers to give them the injection of GTG to obtain the lesion in their VMH which they are going to produce in the future by eating too much crapinabag. Got that? You've all watched Back to the Future. I watched parts I and II but never managed part III. It's simple time travel. Ditto MSG and ice-pick (ouch!) obese rodents. Self inflicted injuries using time travel.

Or we could abandon such stupidity and say that high fat diets injure the VMH first and this injury increases fat storage by decreasing sympathetic tone to adipocytes, as it does.

And I suspect it's superoxide, generated by a high F:N ratio (classically derived from palmitic acid at an F:N ratio of 0.47) in POMC neurons, which probably does the damage. You all know POMC neurons, the ones in the VMH with both gluokinase to sense (via metablism) glucose and CD36 to monitor FFA status (via metabolism again). No lactate for the energy status sensing neurons of the VMH...

So the question is, as always, what happens to the VMH of a C57BL/6 mouse (bred to get fat on a high fat diet) when put on a high fat diet which does NOT generate superoxide in POMC neurons? You can do this.

No one has done the necessary immuno staining under these conditions to get the pretty pictures of dying (or non dying) cells, as far as I know. But it's easy to look at the weight gains, which are a reasonable surrogate for POMC injury. Schwartz again using rats:

Not the most lucid graph, but it gives the basic idea. The control weight gains on the left are comparable to the weight gains shown for day 14.

Now, here is what happens if you take a C57BL/6 mouse and put it on to 35% of calories from fat if you keep the F:N ratio of that fat well below 0.47, using omega 6 PUFA with an F:N ratio of 0.42, as the primary source of fat:

Ignore the top two lines (for now) and look at the weight gain of the mice in the bottom two lines. One group weaned on to crapinabag, the other weaned on to 35% of calories from fat, but a fat with a low F:N ratio. There is zero, zilch, nil difference in weight gain over three weeks. There is no excess weight because there is no VMH injury. No one generates significant superoxide from a low F:N ratio fat like linoleic acid. That appears to include the POMC neurons of C57BL/6 mice.

C57BL/6 mice (and Long Evans rats) are specifically bred to get fat on palmitic acid (sometimes plus fructose) based diets. They fail to deal with the absolutely normal levels of superoxide produced in POMC neurons in the VMH which are crucial to energy status sensing. They do not have the luxury of developing insulin resistance as their job is to monitor both glucose and fatty acid levels. They are not allowed to run on lactate with an F:N ratio of 0.2 the way much of the brain does. They take whatever plasma gives them and do their best to cope with it. Or, in the case of rodents bred to become fat on high fat diets, not cope with it.

Before we go looking at the linoleic acid paper a bit more carefully I think it's worth trying to look at energy sensing rather more peripherally than the POMC neurons of the VMH. Then we can come back to the fat mice and try to think about what's going on using the meagre data available. Because it's quite interesting.



Bill said...

I’m enthusiastically anticipating an infographic on diet, F:N ratios, the VMH, tissue-specific insulin resistance, fat mass, etc…

Robert Andrew Brown said...

Fascinating concepts and may thanks for all your posts.

Do you have a link for the C57BL/6 high linoleic acid diet study 4th par from the end .

Any thoughts on this one.

Very much with you on the importance of oxidation stress

George Henderson said...

Are the rats burning dietary fats in their POMC neurons? Is this a situation where the oxidation of dietary fats in the brain is producing a (rather sudden) effect?
I just want to check I'm reading this correctly.

ItsTheWooo said...

Simple answer to this.

The diet wasn't rewarding to the altered fatty acid composition failed to produce eating. We know this because no over eating occurred, which is the way we can tell if something is rewarding or not.

Regarding the hypothalamic damage occurring even before fat gain and over eating: Clearly this is evidence the food is SO REWARDING even the thought and mere perception of it was sufficient to instantly damage the brain, even before increased feeding could then cause the obesity. The thought burned holes in their head, sort of like how the catholics will threaten that thinking impure thoughts will make you go blind.

PS I am a prominent obesity researcher.
No I am not on medication, I'm high ON SCIENCE!

Leave me to my laboratory... I am close to developing a drug that will burn the pleasure centers out of our skulls. We will all be very docile and pure true human beings, holding our noses eating soggy boiled potatoes. Humanity must be saved.
~signed, a missionary of the church of Real Science.

blogblog said...

I'm a world famous scientist! I've co-authored FIVE peer-reviewed papers!


ps Respect my authoritas!

Kindke said...


OK thats where I get lost. Do we know the "why" for that?

Peter said...

Hi Robert,

is the study.

George, yes through CD36, except I'd specify plasma FFAs, rather than simply use the term dietary. By the time the chronic changes kick in at several months the problem will be adipocyte derived palmitate plus hyperglycaemia which is the trigger. Humans probably do this late phase of the process. But, acutely, dietary ghee seems to be rather bad for selected strains of rodents. BTW, do you have this one? The liver is such an interesting organ. Got to go back there some time.

Woo (and blogblog), you crack me up. I just love the reward hypothesis. The only way you can tell if a food is rewarding is by watching if it makes you obese. This is the proof. I love it.

Kindke, I don't have the answer on what is wrong with C57BL/6 mice but the choice ranges from defects in UCP2, SOD, Mn uptake in to mitochondria, Fe uptake wherever you like, Mg uptake... Anything which affects the core process of dealing with a simple free radical signal which needs damping after being listened to and responded to.


BTW, anyone might argue the mice weaned to linoleic acid failed to gain weight as they were just pre pubertal kids who can eat what they like without getting fat. This is possible, but the F:N ratio of linoleic acid does fit rather well as a poor generator of superoxide when we come to increasing fat mass, sometime soon.

karl said...

Peter, I'm confused right now. ( Some time ago I was trying to sort out all the different fats and it became a HUGE subject on it's own - so I never finished this page: )

Palmitic acid is 16:0 - and messes with the LOX-1 receptor AND 18:2 ω-6 linoleic acid increases LDL oxidation - oxLDL is what LOX-1 takes up.

YET - elevated BG appears to fuel the LDL => oxLDL process.

They type-II epidemic we are experiencing is caused by some change in what we eat - but all the explanations are based on epistemological crap that ignores the fact that several things changed at once. ( refined vegi oils, sugar consumption, refrigerated meats, corn fed food supply, soy, whole grains etc etc etc ).

So I'm VERY interested in your hypothesis - but I'm not sure I know what it is? I'm thinking you are suggesting that Palmitic acid plus sugar foods ( is it fructose dependent?) combine to damage the VMH?

My understanding is that Palmitic acid is found in Coconut, palm - but also there is a bit in Butter, cheese, milk and meat.. but I'm not convinced that these foods are causative on their own.

What am I missing?

Elliot said...


If I'm following the plot correctly, Peter isn't saying that palmitic acid causes VMH damage per se. Instead, it's that it generates more superoxide which typically causes normal physiological insulin resistance when it's needed, BUT mice which are specifically bred to become fat on these diets probably can't handle the otherwise unproblematic amounts of superoxide and so sustain damage to their VMH. (Someone tell me if I've got this seriously wrong!)

Eva said...

Elliot, that's what my take on it was. But jumping ahead, if mechanism is established in rats and that other linked study has already mentioned indications suggest similar VMH POMC damage may also be present in obese humans, the next questions will be what causes it in humans and if the cause is removed, can there be any recovery? I'm betting Peter will tie it to superoxide generated by diet, but also there is MSG to consider as that is already used for that purpose in high doses. Smaller doses but longer term may also do it for some people. What other excitotoxins may also do it? Permanent/persisting damage to VMH may explain why even lowcarb healthy diets do not totally cure some. Of course they say now that new neurons can grow even in adults, but it may require for those that are sensitive total elimination of all damaging elements and in order to do that, you would need to correctly identify all damaging elements and go without at all times for a long time. Assuming repair is possible, but call me an optimist, I like to think it is if we can figure out the right way and get people to actually do it.

Peter said...

Elliot, Eva and Karl,

Basically yes. It also looks to me very much as if a ketogenic diet takes control right out of the brain and puts it back to the adipocytes and pancreas. Either that or ketones fueling neurones allows better function of those remaining. Have to see how it all pans out. As always, I'm lucky to not have answers to anything much, just a lead which appears to hold up. Better in some places than others of course!


karl said...

Petro Said

I would bet on the first explanation.

One observation: Once this damage is done - I've seen nothing to suggest that it can be reversed and the need to stick with a ketogenic diet appears to be life-long.

Petro said some more:

Petro, I spend a lot of time telling people what I think we don't know. I am seriously angry with the folks using epidemiological correlations to claim causation - and greatly confusing the public.

I also recognize your voice as one of the few voices of clarity and science that even Feynman would respect in this very complicated subject with lots of muddied water. You opinion matters a lot to me - especially when you point out what we don't yet know.

Let us assume that damage to VMH is what is causing the T2D epidemic - what clues are there of what is causing the great increase in damage? A few possible explanations:

Palmitic acid: - has the selective breeding of feed-stocks (corn etc) changed in someway to increase it in the meat we eat?

Fructose containing sugars: Is there any evidence fructose can do this damage - perhaps indirectly by spiking Trygly? Or via circulating fructose, which is very reactive and glycates proteins? If we eat large dosages of fructose, there is a point where the liver backs up and I wonder if fructose starts to circulate?

High BG itself: Increases in systemic inflammation.

An auto-immune disorder?

Increases in dietary O-6 => ARA? IF this is true, we should see populations that eat more O-6 have less T2D. Is there anything that supports that?

For me this quest started out when I asked my internist what constituted a healthy diet - I was annoyed when he said he didn't know - now I think I was lucky to have him for my doc.

Ran into this that might be of interest:

George Henderson said...

@ Peter, Karl

Reading Karl's "fats" page after reading the abstract Peter supplied led me to this:
Evidence from in vitro studies shows that increased intake of polyunsaturated fatty acids leads to increased oxidative stress, which may be associated with endothelial damage. We measured the urinary levels of 8-iso-PGF2α and nitric oxide metabolites as well as plasma slCAM-1 levels from healthy subjects after strictly controlled diets rich in either linoleic acid (LA, C18:2 n-6) or oleic acid (OA, C18:1 n-9).

Thirty-eight volunteers (20 women and 18 men, mean age 27 years) consumed a baseline diet rich in saturated fatty acids (SFA) for 4 weeks and were then switched to either a high LA diet (11.5 en%) or a high OA diet (18.0 en%) also for 4 weeks. During the LA and OA diets, nearly all food was provided for the whole day. A control group of 13 subjects consumed their habitual diet throughout the study.

Urinary excretion of 8-iso-PGF2α was significantly increased after the LA diet (170 vs 241 ng/mmol creatinine, P=0.04), whereas the urinary concentration of nitric oxide metabolites decreased (4.2 vs 2.6 mg/mmol creatinine, P=0.03). No significant changes were seen in the OA group. Significant differences between the LA and control group were found for both 8-oxo-PGF2α (P=0.03) and NO (P=0.02), whereas the OA and LA groups did not differ with respect to any parameter. Also plasma slCAM-1 remained unchanged in both groups throughout the study. In conclusion, the high-LA diet increased oxidative stress and affected endothelial function in a way which may in the long-term predispose to endothelial dysfunction.

I'm going to try to dig this up - because the baseline diet sounds very interesting.
And because nitric oxide is a major player in liver disease; NO. inhibits fibrosis; a critical event in cirrhosis is impairment of endothelial (sinusoidal) cells in the hepatic microcirculation.

George Henderson said...


see table 2 for figures that seem to show that dairy fat is better for your circulation than olive oil.

The experiment lasted 8 weeks. During the first 4
weeks, the subjects were advised to use butter and other
foods rich in dairy fat. The purpose of this period was
to stabilize the baseline plasma values. For the second
4 weeks, 19 subjects were given a high-LA diet and 19
subjects a high-OA diet in a controlled manner. 14 The
two diets were designed to contain similar proportions
of energy from fats, carbohydrates and proteins, similar
proportions of saturated fatty acids (SFA) and similar
amounts of cholesterol. They differed only in their
proportions of LA and OA.
The edible oils mainly used as margarines and on
bread, in bakery products, desserts and in cooking were
high-LA sunflower oil and high-OA Trisu® sunflower oil.

George Henderson said...

Sorry, that was high-oleic sunflower oil - so olive oil is off the hook for now.

karl said...

@George Henderson

At some point I came to realize that the cardiologists are strangly looking at LDL (which is a poor stand-in for oxLDL IMO) instead of the more predictive oxLDL . I think the whole 'LDL being causative of CAD theory' is pretty much broken. As always, correlation does not show causation - and in this case, it has recently occurred to me that the arrow of causation may actually be backward. IF we assume that CAD is an autoimmune disease and recognize that lipoprotiens are part of the immune system - then it is quite possible that CAD causes elevated LDL - not the other way round.

(I'm thinking that cardiologists would be better off basing their interventions on interleukin levels.)

Tying this back to lipids - there are some papers that make the interleukin connections with O-6 and blocking with O-3. (My interest in this is personal in that my Lp(a) WAS 3x out of the normal range and I have CAD to the point of quad CABG.) Particularly suspicious is Il-6 and Il-8 .

Lp(a) becomes oxLp(a) the same way as LDL => oxLDL - apparently fueled by elevated BG. Things that lower oxLDL often also lower BG.

My suspicion is that both the attack on artery walls and the VMH may have a common cause - perhaps an autoimmune disease trigged by elevated trygly(from fructose consumption) or O-6?

George Henderson said...

Fructose hurts vascular epithelial cells by high uric acid lowering nitric oxide - and linoleic acid lowers nitric oxide (probably by some other mechanism).
The impairment of nitric oxide tone could be the trigger that leads to the inflammatory response.

Chip Spitter said...

Sorry for the interruption, but I thought this was worth a nomination for most pointless experiment of the year-

I'll admit I didn't actually read the whole thing but they had me at "whole grain popcorn".


George Henderson said...

@ Chip

(you dropped a digit)

I like this:

Testing the null hypothesis seems to have worked.

Eva said...


I don't think it can be completely the first one or ketogenic paleo should work for everyone. There are some people who lose some weight, maybe go from 600 pounds to 300, but still need to lose 150 or 200 more pounds and can't do it, even on ketogenic paleo. These are often those who were really heavy, suggesting they were more out of balance to start with. But even with keto paloe, something is still broken that ketogenic does not fully fix or bypass. Sure, it helps a lot but it is not the full answer all by itself. The clues to understanding better often are with those situations that are different than expected so those people, IMO, need to be looked at. An added issue is there could well be more than one thing happening at a time to screw up the works. If that is the case, you might get only partial recovery if you only identify part of the problem. Lowcarb paleo is very useful and helps many, but it doesn't fix everything and to fix more, we need to understand better the mechanisms behind it.

karl said...

@ George


Have to see what they are using for "high fat". (crisco - corn oil - lard ?)

I have become convinced that studies that look at all fats, without differentiating which fats, are not going to be illuminating - and there is way too much that we don't know.

@ Eva
There are other things that cause weight gain besides T2D ( thyroid, medications, stress, O-6?, low testosterone - etc etc ) . There is an old medical saying: "The patient might have fleas AND mites." .. don't assume only one disease.

The most common reason people are over weight appears to be T2D .

I also suspect that there is an addiction to foods that raise serotonin - both in the gut and in the brain. Carbohydrates have that effect. There is a learned response to eating foods (comfort foods) high in carbs that does not just go away when people quit carbs. The habit of eating when stressed out remains.

There is evidence of reduced RNA expression for serotonin receptors in the brain with SSRI drugs - producing a real addiction that they suppose can take over 6 weeks to renormalize. Going low carb probably requires a similar renormalization - and if people ate lots of carbs as children, the addiction to serotonin could be more permanent. (There are other bits that have to do with dopamine enhancing foods.)

Most of the learned eating response is quite speculative and I don't know of anyone doing systematic research that would actually clarify what we really know (not that there aren't papers produced).

( Sadly, most papers have the primary goal of continuing the flow of grant money and achieving tenure as their primary goal - doing a paper that might upturn accepted hypothesis are therefore risky - which explains why sometimes the conclusions are at odds with the data. Hopefully the data isn't fudged so that we can still learn a bit. I am constantly amazed at the major flaws in logic in constructing the so-called experiments in some of these papers. We are actually lucky to have a few scientists that are principled enough that science isn't going backwards. )

Eva said...

Karl, no, I am not talking about people who still eat too much on paleo lowcarb, that's a diff issue. These people still lose appetite as is common on low carb, and they are not eating much. It's just that they fail to lose fat even when eating small amounts of calories, even to the point of physical tiredness. They just can't lose the weight no matter what. It's actually starting to become a better known phenomenon and lipoedema is what is called when it's just lower body fat that won't go. Also, it's a common prob in metabolic wards for obese. Seems like some people can't lose fat even when eating tiny amounts. Probably a lot of undiagnosed lipoedema and broken metabolisms out there. If a doc sees a fat person, he/she common assumes it MUST be from overeating so those only get lectures, and are not taken seriously. Also a lot of Cushings disease goes undiagnosed that way for long periods. Most docs don't know what to look for and they just assume instead that you are a fat glutton.

Anyway, on subject of excitotoxin brain damage, found this interesting article on aspartame given to rats in water. SUpposedly, the amount of aspartame was similar to what could be in the realm of normal human consumption:
Rats developed clear damage to frontal cortex. 4 weeks of no aspartame after the damage yielded partial recovery in the recover group so some recovery at least may be possible. Makes me wonder if the rats had a year to recover, how far they would have gotten. Also I am seeing a lot of mention out there about research showing excitotoxins compromise (apparently temporarily thankfully) blood brain border and cause demylination which is not good! Time to step away from the diet coke you lowcarbers! ;-P

George Henderson said...

@ Karl,
the high-fat meal was only 43% fat, 45% carbs, not a low-carb meal.
The control meal was lower calorie as well as low fat..
So it doesn't tell us anything about macronutrients, but it does say something very interesting;
the more these obese people ate at one meal, the more they ate at the next.
And the difference between obese and normal weight was, that only obese had a high insulin level from the first meal.
Obviously insulin wasn't a satiety hormone.
If it was about food reward, wouldn't the second meal be as or more desirable without the first?

blogblog said...

@George Hendersen,

"I'm thinking that cardiologists would be better off basing their interventions on interleukin levels."

This seems to be an American obsession. Australian (and presumably NZ) cardiolgists don't seem to put much emphasis on biological markers. In most cases you won't even be referred to a cardiologist unless your GP suspects a very serious problem.

George Henderson said...

@ blogblog,

wrong blogger. If I was a cardiologist I wouldn't bother with cytokines; I'd check my patient's fridge, pantry, ashtray, and empties, CD collection (or whatever passes for records these days), and take some odometer readings (city driving is sedentary AND stressful).
That and the scales and sphigmomanometer should give me a nice set of risk factors before the lab even gets to work.

O Numnos said...

George Henderson said..

"Evidence from in vitro studies shows that increased intake of polyunsaturated fatty acids leads to increased oxidative stress.."

You might be interested to know that a well-known brand of margarine that traded (still does actually) on it's "low in saturates high in polyunsaturates" credentials actually reduced the levels of PUFA in it's product for that very reason - on the QT with no fanfare of course - and this was prob late 80's/early 90's.

George Henderson said...

Ah yes, the trend towards "high oleic" seed oils. I guess they are trying for a cheaper version of olive oil.
The code of conduct that governs fish-and-chip shops in New Zealand recommends a limit on PUFA in deep fryers, not sure what but less than 30% from memory. I can't find the ref online.
In the Finnish study their high-oleic sunflower oil was less inflammatory than normal sunflower oil, but it still stank compared to the butter that was eaten at baseline and by controls.

George Henderson said...

unfortunately this study may not be designed to differentiate between PUFA and oxidation product content.

But this is interesting:
The plasma phospholipid fatty acids varied according to the type of cooking oil used (Figure 1⇓). The concentration of saturated fatty acids was greatest in those who used only sunflower oil (P = 0.05; Figure 1⇓); the concentration of MUFAs was greatest in those who used only olive oil (P < 0.001; Figure 1⇓); and the concentration of n–6 fatty acids was greatest in those who used sunflower oil or mixed oil (P < 0.001; Figure 1⇓).

Why did sunfllower oil elevate phospholipid SFAs? Is it higher in SFA than olive oil? Or was some from endogenous palmitate produced from glucose under extra insulin due to more omega 6?

blogblog said...

@George Hendersen,


The reason for low PUFA cooking oils has NOTHING to do with health. PUFAs readily oxidise causing a rancid taste.

High oleic oils are very resistant to oxidation so they last longer.

Cooking oils should have as little taste as possible - that is why extremely bland oils (eg sunflower oil) are used for frying.

Eva said...

You guys are lucky. In America, 'healthy' vegetable oil rules the day for fry oils. Some people even complain about the 'high' satfats in corn oil which is only 13% sat fat!! There have been quests to get corn oil not used for fry oils cuz of this 'high' satfat. The best that can be found is peanut oil which is higher in MUFA instead and at least has a higher burn point, plus the fries do taste a lot better. Sadly though, since french fry taste can't come from the beef tallow or lard fry oil like in the olden days, they also usually add a bunch of 'natural flavor' to the fries as well, like glutamate which is MSG but without the sodium. Ironically, I'm seeing MSG and glutamate marketed now as a 'healthy' replacement for salt!! Sometimes I get this strange desire to beat my head on a wall..

twitchyfirefly said...


As someone with a rare, supposedly autoimmune neurodegenerative disease (multifocal motor neuropathy) I have been conducting this experiment on myself--ketogenic diet--for 1.5 years and counting. I confess I can only dimly follow many of Peter's posts and the equally challenging comments, but it's remarks like this that give me renewed determination.

karl said...

Eva wrote:
"Karl, no, I am not talking about people who still eat too much on paleo lowcarb, that's a diff issue.."

And that is also not what I was talking about - my point, once again, was that there can be more than one disease causing weight gain.

@Eva Re:aspertain

I would not recommend aspertain as an artificial sugar - BUT if you dig into the details - the dosage of a can of soda-pop 131mg/80kg 1.6mg/kg - compared with 250mg/kg.

They are also pumping 5ml of water into their stomach which would be somewhat equivalent to pumping 1.6l of water into a human stomach everyday. There really isn't a control - they would have to force feed straight water.

Finally, they are also using albino rats which are full of recessive genes.

This is not what I would call a quality paper. There are lots of similar papers around that can be used to support most any position you want to take.

Also, Peanut oil is 45% linoleic acid and not something we evolved to eat anymore than aspertain.

We probably should eat more insects...

Jack Kruse said...

George Henderson said..


You need to read more about DHA, the key PUFA in human evolution.

Eva said...

I was NOT advocating peanut oil, only saying it's the least bad fry oil of what is available at restaurants in the United States.

As for the the aspartame study, yeah, they were saying they had to control for rat metabolism being faster. I don't know enough about that to say either way. Likely they were exagerating. What I found was 180 mg aspartame in a can of soda, probably it varies by type of soda. If you are 100 pounds (45 kg) then you could get 4 mg/kg in one can. Personally I am not sure if adding fat to your butt (making lower mg/kg) will make your brain any safer. With free refills at most restaurants, you could get it to 40 or 50 mg per kg daily which is considered the upper safety limit by govt agencies. I do know people who drink that much. I used to drink it too although not that much. It's addictive. You crave it if you don't have it and caffeine or sweet sources from other sources will not kill the craving.

The rat study was not a long term study. If it can do damage visible in photos at 5 times dosage over a short period, IMO, it's of concern. You have to assume the ill effects start even before something shows in photos. You also have to consider that many diet soda drinkers drink it daily for decades, not just a few weeks.

Plus add MSG and other excitotoxin intake to the mix. MSG is in almost all processed foods now because the FDA has classified it as a 'natural flavoring' and so it can be hidden under that title.

But mostly I posted that study here because of similarities to the original post. And plus it showed partial recovery after 4 weeks and we were discussing if neurons can heal or regrow after an MSG frying. Anyway, if MSG can fry rat brains cells and cause obesity, and there is a continuing surge in human obesity, it's logical to wonder if we also have fried brain cells and if so, what might be doing it.

Jeffrey of Troy said...


"Let us assume that damage to VMH is what is causing the T2D epidemic.."

Another explanation:
excess carbs --> insulin spike --> fat gain --> inflammation --> insulin resistance --> type 2 diabetes

re: obesity-starts-in-the-brain-2/

I think the hypothalamus reads the total dietary fat intake, and if it remains too low for too long, the brain shuts down the activity of the fat-burning enzymes as a survival mechanism - even if total calories are high enough.

"We probably should eat more insects..."

You first..

George Henderson said...

@ Jack Kruse, comment was a quote; I see plenty of evidence that AA (Ok, ARA)and DHA are safe (and vetted by evolution) in a matrix of SFA and some MUFA, such as one finds in either ruminant fats, or in fish plus coconut diets.
I don't think we need vegetable PUFAs nor are these beneficial beyond the generous amounts already supplied by said animal fats and any dietary veges.
Fish oil is as bad as corn oil at 30% of calories, but who, apart from a lab rat, does that ?

blogblog said...


Aspartame and MSG have been very extensively studied for decades. The evidence of them being dangerous in the quantities occuring in food is non-existent. In fact there is no plausible mechanism for either substance being harmful in realistic dosages.

Glutamate (MSG) occurs in virtually all foods.

Aspartame is a simple dimer of two common amino acids found in virtually all foodstuffs.

blogblog said...


unfortunately many people in the paleo movement have the bizarre idea that most pre-agrarian humans lived on some sort of steak-based Atkins Diet.

Inuits, Great Plains Native Americans and the Masai are amongst the most extreme examples of very limited traditional diets and should never be considered the be the norm.

The reality is that most HGs ate highly varied diets with large quantities of plant matter, insects, reptiles, fish etc.

Even the Masai and traditional Inuits ate reasonable quanties of plant matter when it was available.

Eva said...

Blogblog, have you done a search and really read the research? It's out there if you take the time to get past wikipedia. Also to consider, artificial production of MSG yields 5% impurities that do not exist in natural forms. ONly L-glutamic acid exists in nature and it is the only one that enhances taste. The artificial stuff also has D-glutamic acid and other impurities like pyroglutamic acid, mono and dichloro propanols, heterocyclic amines, etc. D-glutamic acid does not exist in nature.

George Henderson said...

Further more, the monosodium salt of glutamate could increase uptake and alter transport.
There is a monosodium salt of alpha-lipoic acid which is effective at 1/10th the normal dose.
Besides, I get sick on MSG, so blog blog is calling me a liar. I demand satisfaction. You sir are not a gentleman. My seconds will be calling on you this evening.

Also, aspartame is not a simple dimer but a methoxylated dimer, a noval compound, and it has immune-modulating properties, with some reduction of osteoarthritis inflammation. Would you put aspirin in your food?

Aspartate and glutamate are likely to be additive excitotoxins, if not in fact synergists.

Modern hunter-gatherer lifestyles may not be representative of paleolithic diet but an adaptation to less large game, more human population, and post-ice age global warming; mesolithic.

George Henderson said...

Oh yeah, I came here to post this
not debate excuses for CIAB with

Seems that excess linoleic acid gives you the anandamide munchies.

Eva said...

Speaking of stuff not found in nature, looks like they found a 'breakthrough' for type II diabetes, at least in rats: Sounds like this new drug blocks uptake of fatty acides by muscle tissue. But they are basically admitting they don't know how exactly the whole thing works! Just that type II goes away apparently.

And it has something to do with fat right? And this stuff blocks fat. So it must be good right? (kidding here!)

I dug around in some of the research on it and sounds like the fatty acids are 'shunted' to the adipose tissue, so this won't likely be good for weight loss, but apparently it gets the excess sugar out of the blood. I'm guessing if you block fatty acid uptake, the muscles MUST then use glucose. You are forcing them to take the glucose.

George Henderson said...

DHA influences mitochondria:

Curr Opin Clin Nutr Metab Care. 2012 Mar;15(2):122-6.
Update on lipids and mitochondrial function: impact of dietary n-3 polyunsaturated fatty acids.
Stanley WC, Khairallah RJ, Dabkowski ER.
Division of Cardiology, Department of Medicine, University of Maryland, Baltimore, Maryland 21201, USA.

Recent evidence has linked n-3 polyunsaturated fatty acid (PUFA) supplementation with dramatic alterations of mitochondrial phospholipid membranes and favorable changes in mitochondrial function. In the present review, we examine the novel effects of n-3 PUFA on mitochondria, with an emphasis on cardiac mitochondrial phospholipids.
There is growing evidence that dietary n-3 PUFA, particularly docosahexaenoic acid (DHA), has profound effects on mitochondrial membrane phospholipid composition and mitochondrial function. Supplementation with n-3 PUFA increases membrane phospholipid DHA and depletes arachidonic acid, and can increase cardiolipin, a tetra-acyl phospholipid that is unique to mitochondrial and essential for optimal mitochondrial function. Recent studies show that supplementation with DHA decreases propensity for cardiac mitochondria to undergo permeability transition, a catastrophic event often leading to cell death. This finding provides a potential mechanism for the cardioprotective effect of DHA. Interestingly, other n-3 PUFAs that modify membrane composition to a lesser extent have substantially less of an effect on mitochondria and do not appear to directly protect the heart.

George Henderson said...

Dietary supplementation with docosahexaenoic acid, but not eicosapentaenoic acid, dramatically alters cardiac mitochondrial phospholipid fatty acid composition and prevents permeability transition.

Treatment with the omega-3 polyunsaturated fatty acids (PUFAs) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) exerts cardioprotective effects, and suppresses Ca2+-induced opening of the mitochondrial permeability transition pore (MPTP). These effects are associated with increased DHA and EPA, and lower arachidonic acid (ARA) in cardiac phospholipids.

Peter said...


There are various papers looking at the saturation of fatty acids in mitochondrial membranes. Saturation is associated with longevity and saturation is adjustable by diet but the crucial experiments on lifespan are yet to be done... Worrying, as it would only take a couple of years in mice. Some of the papers on saturation of mitochondrial membrane are are old enough that a positive effect on longevity of intact mice should have made pubmed by now.....


George Henderson said...

The theory states that LA (high 6:3 ratio) slows metabolism, DHA (lower 6:3 ratio) speeds it up. The more unsaturation (DHA more unsaturated than AA) the more "uncoupling" as it were.
It's hypothesised that high LA intakes help to account for increased lifespan of obese, unhealthy populations by reducing saturation (DHA deficient) and slowing metabolic rate.
As you say, should be easy to prove.
This is the only independent review I can find:

Stephan Guyenet said...

As an author on this paper, I can say that you are confused once again.

First of all, the damage we reported wasn't in the VMH, it was in the ARC. POMC neurons are in the ARC, not the VMH. I think it's really funny that a guy who can't even get his neuroanatomy straight is trying to critique a paper by a person who wrote the book on the neuroendocrine control of body fat.

Second, you spend the whole post trying to argue against the idea that the damage resulted from eating too much, but who made that claim? Not us. Is this another straw man that you're using to attack the mean old obesity researchers who don't listen to Peter?

This blog is really a shame because I think you would have the capacity to make useful contributions if you took the time to understand your topics thoroughly and weren't so blinded by your bizarre opinions.

Peter said...

For someone who can't read an obesity study and mis cites appallingly from Pubmed you have a long way to go before I take you even remotely seriously.

It amazes me that anyone does, but that's their problem.