Fatty Acid Trafficking

Fats are continually being cycled in and out of our fat cells.  In the obese, circulating free fatty acids (or non-esterified fatty acids), NEFA, are often elevated.  These are often accompanied by deposition of fat in non-adipose tissues, aka ectopic fat deposition.  This ectopic fat is implicated in various impairments of cell function and even cell death (apoptosis) that result in insulin resistance, beta-cell dysfunction, etc.  This is often referred to as lipotoxicity.  

This study sought to determine if this lipotoxicity is due to excessive release of NEFA from adipose tissue or from impaired trapping by adipose tissue of the NEFA released from dietary fat.  This work is from Keith Frayn's group.  It might be worthwhile to read my blog post on Frayn's paper on adipose tissue as lipid buffer.

On NEFA and obesity from the Intro to this study:
The release of nonesterified fatty acids (NEFAs) from upper-body subcutaneous adipose tissue is a major determinant of systemic NEFA plasma concentrations (9), whereas visceral fat may contribute fatty acids specifically to the liver. Increased fasting concentrations of NEFA have been related to adipose tissue mass (10) and the presence of type 2 diabetes (11). However complete absence of such relationships has also been described in nondiabetic people (12–14). After a single meal, the postprandial concentrations of NEFA tend to remain somewhat higher in obese compared with lean people (15,16).  Although adipose tissue masses may vary over a 10-fold range between people, reported fasting NEFA concentrations typically only vary within a 2-fold range. This clearly implies a restriction in the release of NEFA from the adipose tissue of obese individuals.
This study used various radiolabels to track fatty acids from both endogenous (release from fat) and exogenous (dietary) sources in both lean (BMI 19-25) and abdominally obese men (BMI 27-32).  
RESULTS- Abdominally obese men had substantially (2.5-fold) greater adipose tissue mass than lean control subjects, but the rates of delivery of nonesterified fatty acids (NEFA) were downregulated, resulting in normal systemic NEFA concentrations over a 24-h period. However, adipose tissue fat storage after meals was substantially depressed in the obese men. This was especially so for chylomicron-derived fatty acids, representing the direct storage pathway for dietary fat. 
Note: Subjects with elevated fasting glucose or triglycerides were excluded, e.g. the obese were "normal". So in normal abdominally obese men it appears the physiological adaptation is to reduce the rate of NEFA release from fat tissue so that total NEFA release is not elevated due to increased "supply" (fat). However adipose tissue dysfunction in these normal obese men was observed on the intake side of the cycle. Chylomicrons are the circulating particles comprised of dietary fats. Lipoprotein lipase, LPL, acts on the triglycerides in chylo to release fatty acids in the capillaries of adipose tissue intended for uptake into adipocytes for storage. This study demonstrated that this part of the process seems to break down first in the obese.
Adipose tissue from the obese men showed a transcriptional signature consistent with this impaired fat storage function.
This was assessed by looking at 12 mRNA's involved in fatty acid trafficking where 11 showed downregulation.  They also looked at markers for macrophage infiltration that were all increased for the obese.

From the Discussion:
Upper-body subcutaneous adipose tissue is the main site of storage and release of fatty acid to the systemic circulation (27) and by comparing lean healthy men with moderately abdominally obese men, we describe a remarkable adaptation of the expanded adipose tissue. In terms of delivery of NEFA from the tissue, this adaptation appears to be entirely appropriate, resulting in normal diurnal regulation of NEFA concentrations in abdominally obese men, which is brought about by significantly diminished NEFA release rates per unit of adipose tissue. The storage of fatty acids from plasma TG was correspondingly reduced in subjects with abdominal obesity and in this pathway there were also clear signs of maladaptation;  there was an inability to induce fat storage with sequential meals combined with a failure to effectively store the chylomicron-TG–derived fatty acids originating from the most recent meal. We propose that this is the pathophysiological basis for diversion of fatty acid to be stored in organs not dedicated for fat storage, i.e., ectopic fat deposition.
There's a lot more to the discussion here but I don't see the point in repeating it all here.  This is why I shared the full text so we can discuss what additional info in the study may be of interest to you in the comments.
CONCLUSIONS—Enlargement of adipose tissue mass leads to an appropriate downregulation of systemic NEFA delivery with maintained plasma NEFA concentrations. However the implicit reduction in adipose tissue fatty acid uptake goes beyond this and shows a maladaptive response with a severely impaired pathway for direct dietary fat storage. This adipose tissue response to obesity may provide the pathophysiological basis for ectopic fat deposition and lipotoxicity.
OK ... some thoughts ... in no particular order:
  • The obese are LESS able to efficiently trap (aka deposit, accumulate, fix) fat than lean.  How come so many of us continue to gain weight despite a breakdown in the efficient trapping if fat accumulation drives caloric surplus not the other way around?
  • Insulin resistance in the fat tissue seems to "bear its ugly head" sooner on the "in" side compared to the "out" side of the fat cell according to this study.  IOW, these metabolically normal obese men still exhibited proper suppression of NEFA release - e.g. they were not insulin resistant to the extent of HSL not being properly suppressed by insulin.  
  • However it might not be IR at all -- A "full up" fat cell presents a much less favorable concentration gradient for the flow of fatty acids into the cell.  ASP's effectiveness may be gradient dependent.  Could be this simple? ← please note the question mark!!
  • Would be interesting to see how this is impacted by meal size/frequency for a given intake.  The effect was more pronounced with sequential meals, but what if the meals were smaller?
  • Elevated NEFA - regardless of source - are a driving force for ectopic lipid accumulation.  If we're "fat burners" this may be benign in skeletal muscle.  But what of other cells/tissues?
Some more thoughts specific to low carbing
  • If you are lean, eat low carb and don't gain weight, the impaired post prandial NEFA uptake issue is probably not applicable to you.    But ...
  • If you are obese and remain significantly so eating a low carb diet, this study may be cause for concern over the healthfulness of this approach.   
  • Might there be special concern, as well, for the abdominally obese?  I tend towards thinking so.
  • VLC can add to the mix by the *failure* to suppress NEFA release from adipose tissue.  This is a characteristic of adipose tissue that has traveled further down the road to pathology.  If diet mimics a pathological state, can your ectopic tissues tell the difference?
  • Low carbers have been shown to be able to clear postprandial triglycerides more quickly ... but ... is there a balancing act at maintenance levels of fat intake especially in those who eat a very high fat version of this diet?


Paul Jaminet said…
Very nice post, CarbSane.

I'm very interested in what tissues and pathways break first, and the order in which the pathology progresses.

It's fairly obvious that if the fat cells are no longer storing excess fat properly, the excess of fat elsewhere will induce insulin resistance by pathways we've discussed previously.

The vicious circle idea where increased obesity leads to reduced ASP effectiveness leads to lipotoxicity-induced insulin resistance leads to increased obesity could be a factor, but it leaves unexplained how the process gets started.

Best, Paul
Melchior Meijer said…
Hi CarbSane,

Very interesting post. I have (again) a very naive question. How can it be that most people with severe visceral obesity become so much healthier after adopting a 'paleo' or low carb diet? Following your logic they would flood their system with NEFA and become very insulin resistant and hyperinsulinaemic and suffer all the consequences. In reality, this just doesn't seem to happen. On a theoretical level - as far as I am able to grasp it - your logic holds water, in clinical practice however, quite the opposite seems to happen.

Considering the enormous health improvements I have seen in very sick people after they adopted a lower carb, paleoish way of eating (and we have all seen them), I have a hard time it (the adoption of a paleoish diet) really induces the lipotoxicity we should indeed be afraid of.
CarbSane said…
@Melchior: I look at Mark Sisson's diet and compare it to the SAD, and it's a no brainer to me. Weight loss ensues and this man is eating enough carbs to keep insulin SENSITIVITY.

Since we lose visceral fat more quickly, this may well restore the fatty acid traffic to normal especially in calorie deficit.

But what then. I think the jury is still in deliberations over the long term implications of the extremes some take his dietary prescription. What happens after the weight loss for those starting out obese?

In many ways I can't seem to get a handle on what exactly paleo really is. Many of the most vocal proponents advocate VLC/VHF versions while most studies looking at it employ a higher carbohydrate lower fat version. Sisson's ratios come out to 55% fat, but looking at his foods - 3 eggs fried in a pat of butter with 1c. cooked veggies. His salad? Over 1/4c vinegar to 2T oil on his Big Ass (5c veggies) salad with 6oz salmon. We're not talking a whole lot of fat on an absolute level. This is in stark contrast with the 75% on up fat diets promoted by many who cannot even eat a few bites of potato w/o soaring blood glucose.

Sisson is also just plain active as are many paleo advocates far more than they seem to express. Don't give me the primal cardio shunning exercise nonsense - he's moving it. Chris Kresser posted once on the ineffectiveness of cardio, laid out a rather meager plan of what he does, then rounded out the post with how he walks or bikes (memory fuzzy) to work and hikes, etc. Ummmmm...

The paleoish folks who eat some higher carb seem to be much better off than most of the long time "high fat, moderate protein, low carb" folks. I'd say they have normal fatty acid traffic and storage.
CarbSane said…
Hi Paul: it leaves unexplained how the process gets started.

True! I'm inclined to think there are many many different ways in which this gets started, and the causes are highly variable between individuals. And I believe strongly that there is no one lynch pin even for most single individuals - likely several factors there too.

For me it all got started by gaining a few pounds eating fast food for lunch while going through puberty and developing a body type that wasn't "in" at the time. Even the start was multifactorial!

I'll be posting on a companion piece to this article soon.
CarbSane said…
BTW Melchior: I would love to find a study where ectopic lipid content is measured directly for VHF/VLC consumers. I don't see that such exists. Even if elevated, we still can't assume it to be deleterious, but might at least let us know if high peripheral fatty acid usage (e.g. increased fraction of energy derived from lipid oxidation in skeletal muscle) "protects" infiltration of other tissues.
Bill said…
@Paul, "I'm very interested in what tissues and pathways break first, and the order in which the pathology progresses."
me too! more specifically, is IR in one tissue always the cause of IR in another tissue? which one comes first, and is diet composition involved?
Melchior Meijer said…
CarbSane, I realise that I'm not directly responding to ypur answer now, but have you listened to Jimmy's interview with Gregory Ellis? A fascinating mix of insights (insulin is evil, calories do count, exercise is paramount and can even supress appetite, most cells prefer fat as an energy source...). One idea that I got out of this mixed bag is that a low carb diet improves mitochondrial function, which per definition reduces the risk of lipotoxicity.
Melchior Meijer said…

I just read that many players of the Norwegian national soccer team have switched to a low carb high fat diet. They say they perform a lot better on it, don’t feel the need to take a nap after a hard training, are more clear headed, etc. Now the interesting thing, I find, is that the medical staff meassured what substrate these guys run on. They used some fancy technique, which is without doubt very accurate. The result: they do burn much more fat, even at higher intensities, than their high carb fed peers. So they oxidize all the circulating NEFA and then some. Their low insulin promotes lipoysis, yes, but the fat is used at a higher rate too. Doesn’t this suggest that they do not have excess NEFA hanging around and perhaps even less (than the average SAD eating Knud)?
CarbSane said…
@Melchior: Never heard of Ellis. I've bookmarked the podcast and will give a listen this weekend. I did find this interview with him and ... well ... he's a carb/sugar turns to fat guy. That just bugs me at this point ;-)

That is interesting about the soccer team. I used to play soccer - LOTSA cardio! - and Norwegian? Was the diet based on lutefisk?

I've no doubt that an active fat-burning metabolism spares skeletal muscle from lipotoxicity. It seems more the "backlog" of DAGs and ceramides that cause the problem there. However I wonder if uptake of NEFA by skeletal muscle protects the other organs and cells (like vascular endothelium) from taking up too many merely as a function of concentration. I hope not.