Thursday, February 09, 2017

Musing about linoleic acid

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TLDR: I have long wanted to know how you could have differential insulin resistance between adipocytes and the rest of the body. Linoleic acid appears to be the answer
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This is a set of thoughts, jotted down without references, that have been of interest to me over the last six months while I have neglected poor old Hyperlipid.


Linoleic acid produces excessive whole body insulin sensitivity.

Adipocytes distend under this effect.

Distended adipocytes release unregulated FFAs.

FFAs cause insulin resistance which eventually overcomes the excess systemic insulin sensitivity.

Hyperinsulinaemia results.



Here we go.

I have nothing against the role of both sucrose and refined starch in the pathogenesis of both obesity and insulin resistance. Anyone who has read Weston Price or Vilhjalmur Stefansson will be only too aware that the substances most easily transported over long distances to affect unacculturated peoples were sugar and flour. No one was carting margarine or corn oil to the Arctic in the early part of the last century. Both fructose and alcohol, both of which deliver largely uncontrolled calories in to cells, can clearly generate aspects of metabolic syndrome. However I am interested in linoleic acid and free fatty acid release from adipocytes at the moment, so I'll leave the case against sugar for the time being. So, linoleic acid:



One of the core ideas which came out of the Protons thread was that palmitic acid is a generator of physiological insulin resistance. The complementary fatty acid is palmitoleate and this generates less insulin resistance for when insulin action is desirable.

The function of physiological insulin resistance is to limit ingress of calories in to a cell when there is a surfeit of calories available. Or to limit the ingress of glucose when glucose is in short supply and it's best not to waste it on non-glucose dependent tissues.

In to this well balanced system comes linoleic acid as a bulk nutrient. The oxidation of linoleic acid, by the Protons hypothesis, produces even less insulin resistance than palmitoleate and so undermines the ability of a given cell to refuse caloric ingress in excess of its needs. Failure to develop insulin resistance means that insulin continues to act.

Continued action of insulin in a calorie replete cell results in diversion of excess calories to intracellular triglycerides (+/- glycogen). This is very reasonable in adipocytes, at the cost of obesity, but less acceptable in tissues such as muscle, liver and pancreas.

The underlying pathology is continued inappropriate insulin sensitivity.



But obesity is a condition more normally associated with insulin resistance.

From the Protons point of view the question is: How can linoleic acid acid, which results in pathological insulin sensitivity whole body, eventually result in insulin resistance, also whole body?

Insulin activates lipoprotein lipase and inhibits hormone sensitive lipase. Combined, these effects facilitate fat storage in adipocytes. But there is another lipase which controls both basal and stimulated lipolysis known as Adipocyte Triglyceride Lipase (ATGL). One, amongst the several, factors which control ATGL is perilipin A, a protein which surrounds the lipid droplet in adipocytes. It is probably an interaction between ATGL and perilipin A which determines the increase in basal lipolysis as adipocyte lipid droplet size increases.


So there is a balance. Linoleic acid is allowing increased insulin action and so causing fat accumulation with a suppression of both FFA release and adipocyte lipid turnover. ATGL is looking to limit adipocyte distension by allowing lipolysis, so raising FFAs, outside of the control of insulin. But will only act on basal lipolysis in response to progressive lipid droplet expansion.

For as long as the pathological sensitivity to insulin exceeds the FFA release driven by ATGL we can have worsening obesity but metabolic syndrome is delayed.

Once ATGL mediated lipolysis raises systemic FFA levels enough, despite insulin continuing to act on adipocytes, we can then have systemic insulin resistance with insulin sensitive adipocytes. Insulin resistance when combined with a carbohydrate based diet requires elevated insulin levels which will continue to act on the insulin sensitive adipocytes. Which will increase ATGL driven lipolysis...

This is metabolic syndrome.

Once the elevated glucose from insulin resistance kills off enough beta cells then insulin levels drop, glucose levels rise, HSL is disinhibited so FFAs rise. You might even get ketoacidosis. This is type 2 diabetes. ATGL might even take a break.

The first approach to correcting it is carbohydrate restriction, so dropping hyperinsulinaemia and minimising the vicious cycle. Doing something about the kilos of linoleic acid stored in an obese person's adipocytes is an altogether longer term project.

Peter

38 comments:

bill said...

last line second to last paragraph:
AGTL s/b ATGL?

Gretchen said...

Good post.

Peter said...

Ta bill

Thanks Gretchen. mtG3Pdh is a whole other story but linoleic and a-linolenic papers are coming out left right and centre!

Peter

Gretchen said...

What does "Ta bill" mean?

Peter said...

Ta = Thank you, ;-)

Gretchen said...

Aha. Then what's the bill? I'm not up on internet lingo.

Peter said...

Hee hee. bill is the name of the commenter who pointed out a typo! And ta goes back to my childhood, if not further. Some things are simpler than they seem!!!!!!

All the best

Peter

Gretchen said...

Confusing thing was that if you google "ta bill" you find references to "traveling allowance bill" forms, which they call "ta bill."

I got accustomed to "ta" when I was in England but didn't make connection here.

Bob said...

Seems contradictory to say that the rise in FFA's will cause systemic insulin resistance when there are "kilos of linoleic acid stored in an obese person's adipocytes". In addition, the presence of LA as a bulk nutrient has likely already impacted liver and other tissue, presumably by signalling the liver to store more glycogen than it might otherwise. And perhaps signalling the pancreas to produce less insulin that it might otherwise (from Protons 12).

Seems like a whole smorgasbord of confounders in this tale. How do we square this circle? Is my layman mind making any sense here?

Bob said...

Okay, I think I have my answer. Protons 29 showed that LA as a LCFA does plenty of uncoupling. So it makes sense that leaking FFA's, saturated or not, provide the insulin resistance described.

The other questions I raised are clearly asides, but it certainly would be interesting to know the interplay between the insulin sensitivity of say, hepatocytes and pancreatic cells.

Apologies if the tone of my previous comment sounded combative. Not in the least my intent.

Peter said...

Bob, yes, it's a messy system. And there are some papers which make the endocannabinoid story slightly more significant too...

And in all probability there will be a non FADH2:NADH inhibition of the ETC at the CoQH2-complex III point, to deal with FFAs of 1200micromol in a young, fit, health, fasted bloke.

Peter

Jonathan said...

What is HSL? I'm trying to interpret your comment, "HSL is disinhibited so FFAs rise."

I love this post; it so nicely explains some mysteries I've long wondered about. To clarify the sequence of cause and effect for myself, I made the following summary for my notes:

linoleic acid -> insulin sensitivity (all tissues)
insulin sensitive adipocytes -> large adipocytes (obesity)
large adipocytes -> Adipocyte Triglyceride Lipase (ATGL) causes FFA lipolysis
high serum FFAs -> systemic insulin resistance *except* perhaps adipocytes
insulin resistance + carbs -> high serum insulin/glucose = metabolic syndrome
elevated serum glucose -> pancreatic beta cells die = type 2 diabetes
lots of dead beta cells -> insulin drops, glucose rises, "HSL is disinhibited so FFAs rise. You might even get ketoacidosis."

NY said...
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NY said...
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NY said...

How the longer term project of dealing with kilos of linoleic in adipocytes would look like?

annlee said...

@Jonathan - HSL == Hormone Sensistive Lipase.

annlee said...
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DLS said...
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Peter said...

DSL,

13-HODE

NY, depends on adipocyte lipid droplet turnover. On weight watchers it will never happen, on a ketogenic diet it might happen faster but it will generate more 13-HODE. "Ordinary" turnover time is thought to be about 5 years but I can't find the paper off hand...

Peter

DLS said...
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Peter said...

DLS, more on 13-HODE in the next post. I'd be careful.

Peter

DLS said...

but.. peter, stephan guyenet eats a lot of peanuts! o wait... crap. btw he an other guys are unconcerned with " whole foods high in omega-6" because =/= oxidized rancid veg oil crap. but im doing like 200gr a day... looking forward to yr post. plz plz try to include 1 dumb down resume in the post... n the meantime ill try- really hard- to lower my peanut intake, ( still have a 20kg bag...) just 2 days of "restriction" ( 100gr) and my abs start to pop, skin and health are perfect so far... so we'll see. edit. >>>> how about 100gr macadamias a day???? thy have more cals and are expensive as fk but no o6....

DLS said...
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Peter said...

DLS, ultimately you will have to make your own decisions. If you follow Dr Guyenet, you're f***ed. Don't follow me, I've no idea where I'm going!

Peter

gallier2 said...

Don't follow me, I've no idea where I'm going!

Brilliant! That's the right attitude.

DLS said...

not following anybody, just doing my thing. so far so good, im the youngest 39 old guy in the world. to bad my adipocytes are loaded with linoniun... well nobody's perfect. i know is not your thing, but looking forward to yr detailed " what i eat 2017 edition post" with results...

Shaza said...

TA very common parlance in Australia too! So Ta Peter!

Robert Andrew Brown said...

Peter - GREAT to see you back producing thought provoking often fascinating debate.

I referenced your post in the Springer related chapters linked below including in respect on CPT1A Innuit.


DLS

These pathways are complex interlinked interdependent etc. Oxidative stress and the downstream consequences of excesses is arguably the core issue.

LA is not inherently bad; it depends how it is metabolised; simplistically I suggest it depends if it directed to energy production or tissue creation and repair. Peroxisomes and peroxisomal related pathways arguably play a big part.

The Kung_people eat a high Omega 6 nut the mogongo as a staple (which also contain significant amounts of an obscure Omega 3) during the dry season and were free of western disease but may have exhibited a slightly higher inflammatory profile compared to other groups. (google Kung and Omega six and you will find lots of debate)

They ate nose to tail, worked hard for their food etc.

If you are lean active and exercising hard you are likely largely partitioning off your LA intake to energy and likely through in part activation of peroxisomal related energy pathways which are activated by exercise and fast.

Net antioxidant nutrient related intake will also factor, so eating whole nuts is not the same as eating oxidized refined vegetable oils, industrial processed fried high Omega 6 poultry fat etc.

Effects of diet are also very long term; so it is difficult to guess at what effect a high peanut diet in a very active person will have long term.

The LA argument is not about peanuts :), but about those eating excess processed linoleic acid in the context of a western nutrient depleted diet and often absent significant exercise or 'intermeal fasts' space between food intake from a long term perspective.

I wrote 6 chapters CH27-32 on 'all of this' for a Springer Book https://books.google.je/books?id=lEgWDQAAQBAJ&pg - sometimes some of them are / were visible on google books searches - )I get nothing beyond the honor of being invited to contribute and a free copy - maybe your institution or library has a copy.)

Peter said...

Hi Robert,

You're welcome. I'd not heard of Springer Books, they look quite interesting!

All the best

Peter

Allan Folz said...

Greetings Robert,

As one who's written the book on O3 :), I was wondering if you might have an opinion you wouldn't mind sharing.

Our son is markedly more cheery and pleasant to be around when he's taking an O3 supplement. He does one pill, which works out to 400mg EPA & 200mg DHA per day.

Being an all things in moderation type of fellow, I sometimes wonder about long-term effects of such a high amount since from what I can tell that is beyond what anyone could reasonably get by way of diet. Too much LA is clearly established as bad, but I could imagine too much O3 also being bad except no one's bothered to look since it's virtually unheard of today given the Western diet. Your thoughts, sir? Ta. ;)

Peter said...

Hi Allan, don't want to jump in on Robert's reply, he knows much more on this than I do. But these are doses which are not going to have a bulk oxidation effect, you are probably looking at high level signalling effects rather than mitochondrial effects. Whether the g-protein coupled effects are Good or Bad is another question. Good might be correct but I haven't looked at it beyond Sauer's work. Overall 0.6g/d is not a lot of fat compared to over 100g of saturated/MUFA fat per day.

Peter

Kaitlyn said...

Ironic that linoleic acid is put on a pedestal because we cannot make it ourselves. Maybe there are good reasons we haven't evolved to create such vulnerable and potentially hazardous molecules!

Nutritionists and cardiologists must have misinterpreted "essential" as a nutritional panacea.

Thanks for the blog, such an amazing intellectual wormhole!

tomer aviad said...

Hi Peter what is your source for the statement "Linoleic acid produces excessive whole body insulin sensitivity". From what I saw there is no real difference between the fatty acids.

http://www.sciencedirect.com/science/article/pii/S002604951400328X

https://www.ncbi.nlm.nih.gov/pubmed/17339025

Peter said...

Hi tomer,

I have the idea from my own Protons concept and it fits well with feeding studies as mentioned in your first reference. In this speculative post I’m interested in the failure to develop insulin resistance which occurs at peak post prandial nutrient supply, when calories available are in excess of what is needed rather than the insulin resistance of fasting.

For short term studies using the acute induction of elevated FFAs I suspect that the induction of insulin resistance has nothing to do with lipid oxidation directly. I have a post in mind based on https://www.ncbi.nlm.nih.gov/pubmed/20573749 where by simply fasting normal healthy blokes they got FFAs to 2000micromol/l. This is utterly physiological and comparable to most lipid/heparin infusion studies. I have another study (can’t find it off hand) where the idea is floated that extra-mitochondrial FFAs or a derivative block the docking site of CoQH2 with complex III. This would markedly reduce the CoQ couple and signal insulin resistance via superoxide generation at complex I, reverse electron transport mediated. It probably doesn’t matter which FFA/derivative drops in to the docking site, the CoQH2 is not going to get in there…. What happens to amplify the signal at the cellular level (ceramides and the like) is interesting bit probably not fundamental.

Peter

Peter said...

"but" not "bit" at the end there

Peter

tomer aviad said...

Hi, thanks for your answer. The mechanism behind insulin resistance from FFA is really interesting and I the protons theory seems to be useful.
I have in mind a theory on more macro level that the body want to spare glucose when fat is available to use as energy (in a form of FFA) thus the cell inhibit GLUT4 receptor and creates "insulin resistance".

The studies I posted in the my last comment was about comparing PUFA, MUFA and saturated fat on the level of the insulin resistance and found no difference, what do you think about that?

Peter said...

I think you are looking at the difference between oxidising a fat which reduces the CoQ couple via FADH2 (saturated) vs one which fails to do so (linoleate) This applies during beta oxidation feeding through to the ETC, ie during lipid metabolism. Under conditions of normal physiological fasting the the FFA levels are so high that this does not apply and a simple block on the ETC at the docking site, using any FFA-CoA, will normalise the potential over production of ATP and coincidentally generate superoxide to signal insulin resistance at the same time (blocking the CoQ-complex III site will reduce the CoQ couple and so raise the NADH:NAD+ ratio). These are distinct processes for differing circumstances. Unfortunately the group suggesting the CoQ docking blockade have published nothing since and I don't trust them anyway! But they're probably correct here. All the ceramide stuff is just downstream knock on effects.

Peter

tomer aviad said...

If I understand correctly at high levels of FFA (from fasting or feeding) the fat type does not matter?