Lipotoxicity: When tissues overeat

Recent findings
Excess lipid accumulation in non-adipose tissues may arise in the setting of high plasma free fatty acids or triglycerides.  Alternatively, lipid overload results from mismatch between free fatty acid import and utilization. Evidence from human studies and animal models suggests that lipid accumulation in the heart, skeletal muscle, pancreas, liver, and kidney play an important role in the pathogenesis of heart failure, obesity and diabetes.  Excess free fatty acids may impair normal cell signaling, causing cellular dysfunction. In some circumstances, excess free fatty acids induce apoptotic cell death.
Having stumbled across some disturbing information on elevated free fatty acids, I went back and dug up this review paper I had found a while back. 

IF the low carb gurus are correct -- and LC essentially makes MORE NEFA/FFA's available in circulation -- then I do worry about the long term benefits of LC. Fats in circulation can be as triglycerides or NEFA/FFA's but for some reason NEFA/FFA's aren't measured often (or at least paid attention to). In this regard, I don't want to be lulled into a false sense of security by low trigs.

Circulating NEFA/FFA's are to dietary fats what blood glucose, BG is to dietary carbs.  We have receptors to sense this nutrient level just as we have receptors to sense BG levels.  Elevated NEFA/FFA is as much a symptom of diabetes as are elevated BG levels -- perhaps moreso for Type 2's?
High plasma FFA and triglyceride levels lead to increased import of FFAs into non-adipose tissues, contributing to intracellular lipid accumulation.
As much as we all hate fat, adipocytes are where we're supposed to store fats.  I wonder sometimes if the reason I weigh so much more than I look like I do is because I'm storing fat in my muscle where perhaps it doesn't show up so much volume-wise.

Intracellular FFAs or their metabolites activate a serine/threonine kinase cascade that ultimately results in reduced insulin receptor substrate-1 tyrosine phosphorylation, reduced insulin receptor substrate-1-associated phosphatidylinositol 3-kinase activity and failure to promote translocation of the GLUT4 glucose transporter to the plasma membrane in response to insulin stimulation.
This gets all complicated, but basically this again demonstrates how elevated NEFA/FFA induces insulin resistance.  There are some in the LC community who hail this development.  The theory is IR is good because this directs glucose to the brain and our skeletal muscle is happy to thrive on ß-oxidation of fatty acids.  So the following questions to ponder arise:

  • What does this do for those who have a few carbs here and there ... as most of the LC community does (whether on plan or off) from time to time?

  • Is zero carb 24/7/365 dangerous or the only truly safe version of LC??

  • If LC manages one nutrient level that is elevated in T2 diabetics (BG), but exacerbates the other (NEFA/FFA), is it really a healthier dietary management strategy?


Unknown said…
Hi CS, have you been able to better answer these questions in the intervening months?

Anonymous said…
I think you are partly on the right track in your vindication of insulin.

I think you are barking up the wrong tree by worrying about NEFA. I think if NEFA is elevated in diabetics it is an effect an not a cause. Kind of the way you think the elevated insulin is an effect of the pathology producing liver IR, and is not the cause, right?

Most papers I read that talk about "liptoxicity" in regard to NEFA or FFA are just veiled extensions of the lipid hypothesis. If something bad is happening, it must be a fat causing it!

Show me an epidemiologic marker of NEFA levels that tracks coronary risk at one tenth the magnitude HBA1C does, and I'll start to worry. 'Til then, I know which poison I prefer.
CarbSane said…
Welcome to my blog Kurt!

Regarding the NEFA and the lipid hypothesis, I'm amazed at the HUGE body of research on NEFA out there, much of it in the diabetes realm. While you'll often see statements like "obesity caused by high fat diet", etc., the research on mechanisms, progression, etc. is quite solid by the much-maligned scientists. For starters, dietary fat is not even mentioned in most studies as these researchers are well aware that the source of NEFA is release from fat cells. I've blogged on a number of articles on the development of IR (the root of all metabolic evil), and the NEFA seems to come first and precipitate the other things. Two such posts:

I think you may find this review article a bit of a paradigm shifter:

Lastly, my personal interest in this is due to the fact that I get the occasional racing heart so when I discovered the connection between elevated NEFA and sudden cardiac death, there's no way I think I can ever dismiss this from my mind!

Contrary to the whole "LDL clogs arteries" arguments, where there is little to no evidence that the cholesterol itself does anything, a large fraction of the NEFA research relates to how the NEFA directly impact cell function even leading to cell death. Scary stuff!

In all honesty, I really hope I'm barking up the wrong tree. That so long as carbs are uber low elevated NEFA should not be worried about. But I haven't found that "get out of jail free card" yet. I'll keep looking ;)
CarbSane said…
@Jalal: Welcome to the Asylum! I missed this comment, just saw it.

I've come across a lot more on NEFA since this post, largely associated with insulin resistance. I'm thinking that so long as someone is not exhibiting IR, then their NEFA levels are likely innocuous whatever they may be. Problem is, I don't think most of us have ever had insulin sensitivity assessed. I'm eating a few more carbs these days and do HIIT type activity (not exercise, my woodpile keeps me busy!) - both beneficial to insulin sensitivity.
Larry Eshelman said…

Although I have read almost everything that you have posted and have found your writing extremely informative, this is my first comment,

Your response to Kurt raised several questions -- mainly by what you didn't say.

(1) I was under the impression that you did not associate elevated NEFA with dietary fat, but with fat cells being full and thus leaking more NEFA than they take in. So dietary fat is a culprit only to the extent that one overeats and fills up one's fat cells. In other words, I understood that you see elevated NEFA as an EFFECT of insulin resistance in fat cells, which in turn could CAUSE problems in other tissue.

(2) In the past you have emphasized that elevated NEFA occurred before elevated glucose. Thus elevated NEFA is an earlier sign of insulin resistance than elevated glucose.

(3) You have suggested in other posts, that people worried about insulin resistance should have their plasma NEFA concentration tested. It would seem to me that a person with elevated NEFA would also have elevated plasma triglycerides (i.e., wouldn't the liver respond to the elevated NEFA by creating triglycerides?) So if one's plasma triglycerides are reasonably low, can one assume that elevated NEFA is not a problem?

Anonymous said…
Thanks for the response. My own reading so far does not make me fear NEFA in the least. Even if it is pathologically elevated as part of METSYN, I believe it is only an effect, not a cause. The applicability to HFLC diets or fasting is not appropriate. NEFA has to cause muscle (not liver) IR or one will not be able to feed the brain - Yes I am with Peter on that. The reversibility of this phenomenon has been documented for over 50 years. NEFA levels rise when you fast- do you think fasting is dangerous?

You will be in quite a quandary if you decide that NEFA and elevated blood glucose are both threats, kind of like Dr. Davis who is afraid of both glucose and saturated fat!

I will read those references.
CarbSane said…
Kurt, I look forward to your replies once you've read those references. If they don't give you reason to pause, I look forward as to why.
Nigel Kinbrum said…
RE Occasional racing heart on VLC: Could it have been a Somogyi reaction caused by too much exercise with insufficient muscle glycogen to fuel it resulting in muscles sucking glucose from the blood too quickly?
Melchior Meijer said…

A friend of mine (endurance athelete) started experiencing scary bouts of tachycardia soon after going paleo, often upon light exertion. It scared the hell out of him, but nothng was found during a visit to the ER (so no Afib). During one such an attack (never lasting longer than a few minutes) his type 1 diabetic girlfriend measured his BG three times in 30 minutes and it was perfectly normal (between 4,7 en 4,9 mmol/L).

Just an n=1 of course, but I've read some testimonials from people having the same trouble (a Russian fellow on Dr Eades blog comes to mind) and as far I remember they don't report feeling 'hypo'. My uneducated hypothesis is that chronic, spontaneous under eating (too little energy because of paleo induced appetite suppression) may set off an (adrenergic) alarm response and can thus cause episodes of vagal withdrawal.

This friend of mine is a high achiever, with massive stress reactions to stressors like speaking in public. I am pretty sure CarbSane is a high achiever too, possibly with a natural tendency to have a strong sympathetic reaction to perceived stressors (correct me if I'm wrong, CarbSane!).

Any thoughts?

I do hope Dr Harris reflects a bit more on NEFA's.
Larry Eshelman said…

I'd like to elaborate on my previous comment (above). I've read the "Diabetes: mellitus or lipidus" article that you recommended to Kurt. My take on the article is that temporarily elevated NEFA is no more a problem than temporarily elevated glucose, provided one's metabolism isn't broken. The problem is when one's adiopose tissue become insulin resistance and leak more NEFA than they can take in. I don't see anything in the article that counters Kurt's statement: "The applicability to HFLC diets or fasting is not appropriate."

Given your past obesity, however, I can see why you might be concerned: Apart from the discussion of fatal ventricular arrhythmia and fibrillation and sudden cardiac death, there is the statement that "Obese women who reverted to normal weight after caloric restriction, did not respond to a fatty mean with appropriate fat oxidation compared with matched non-obese women."

If I understand you correctly, you agree with Kurt that neither dietary carbs (at least not starches) nor dietary fat per se causes insulin resistance. However, once one's metabolism is broken both excess carbs and fats could be a problem.

Finally, I'd like to hear your answer to my third point in my previous comment (above). In particular, wouldn't the liver respond to the elevated NEFA by creating triglycerides? So if one's plasma triglycerides are reasonably low, can't one assume that elevated NEFA is not a problem? The "Diabetes: mellitus or lipidus?" article seems to indicate that this might be the case.

--Larry E
CarbSane said…
Nige, I did have the racing heart also when I was heavier, but not those other skiddly feelings. They very well could have been caused by that as one time in summer before last I had an episode I had a BG meter and measured in the mid-low 60's. Ate a bowl of wild rice, symptoms went away and BG up in the 80's. The time I thought I was having a heart attack and ended up in the ER, the only thing they found with bloodwork was that potassium was a bit low. They did give me two rather large horse pills of K, so maybe it was very low. Perhaps the K-containing diuretic I used to take daily, and fairly regular K supplementation now has done the trick. Dunno. I do still get the occasional racing for no reason, but not the skiddlies.
CarbSane said…
@Larry: Welcome! Thanks for reading and contributing. Your points 1&2 are pretty accurate summaries of my thoughts. For a "normal" person, I also think point 3 should hold. But I know that elevated NEFA can be associated with high fat (low carb) meals (, blogged on while we know low carbers tend to have lower triglycerides. I wonder if those lower fasting trigs are not misleading and it's just because with lower insulin more FFA's are "stripped" from VLDL in cirulation?

As to IR, high fat meals do elicit a transient insulin resistance that I don't think is harmful per se for the low carber. But if that IR is essentially chronic, I do wonder if it prevents insulin from doing its many other protective/anti-inflammatory functions in our bodies.

I would agree that temporarily elevated NEFA may well not be dangerous any more than BG spikes. Unfortunately the linked study above only went to 4 hours, but note the trajectory of the 75 min timecourse ( ... how long do the FFA's stay elevated? I think anything over 600 is considered elevated above normal. If a low carber is consuming 3 high fat vlc meals a day, what's the 24 hr AUC (total exposure)? Things I worry about.

@Kurt, stay tuned. I had some lipotoxicity NEFA stuff in the hopper that I'll exhume and publish in the next week or so. NEFA are definitely something to be as concerned with as BG levels.
CarbSane said…
Re: NEFA levels rise when you fast- do you think fasting is dangerous?

They rise, but are not excessive, and rise because they are subsequently taken up by our cells and burnt for energy. NEFA levels rising excessively in the fed state is my concern.

You will be in quite a quandary if you decide that NEFA and elevated blood glucose are both threats, kind of like Dr. Davis who is afraid of both glucose and saturated fat!

If it were just *me* deciding it I would agree, but there's a ton of research indicating that NEFA alone have direct deleterious effects.
CarbSane said…
@Melchior, you may be on to something. I'm not really prone to anxiety attacks and such but one could definitely describe many of these episodes as just that. The racing heart is not just with LC, but it's when it's coupled with the other feelings that only occurred when low carbing that it gets really scary. I'm not sure I ate quite as little stint 2 as I did this last time though, and in the distant past I used to fast for one day a week and have fasted for several days at a time as well w/o experiencing this.