Elevated Free Fatty Acids: Detrimental?

As many of my readers know, I've been challenged lately on my beliefs on NEFA.  So I thought I would summarize my thinking on this in a post rather than having several comments scattered amongst a few threads.   I'm not going to be referencing my post here at this time (it's too time consuming to do so at the moment).  If/when I have the opportunity to do so in the future, I'll do a bumped update.  

These are my thoughts based on extensive research of the peer review literature on this topic, in almost all cases, considered review of full text articles including reading as many supporting citations in major reviews as possible.  Over the past year I have read at least a hundred such articles.

Elevated non-esterified or free fatty acids (NEFA/FFA) are a symptom associated with insulin resistance, Metabolic Syndrome (aka Syndrome X) and Type II diabetes.  The overwhelming evidence in the literature points to elevated NEFA being more than just associated with these conditions, but rather the initiating step in their development..   

It seems that each of us, lean and obese, have a limit to our fat storage capacity, and there is evidence to support the theory that it is more the limits of our visceral adipose tissue (VAT) than our subcutaneous adipose tissue (SCAT) that cause us trouble.  The reasons for this are twofold:

1.  Adipocyte Turnover & Insulin Sensitivity v. Adipocyte Size:  Although the number of fat cells we have seems to be determined by the time we reach adulthood, there is still turnover of fat cells where pre-adipocytes are differentiated into mature adipocytes and old adipocytes die off.  There is a distinct difference between the behavior of VAT and  SCAT in  this regard.  Adipogenesis (formation of new fat cells by differentiation of pre-adipocytes) is greater in SCAT than VAT.   It has also been established that as fat cells are filled and grow larger, they lose their sensitivity to the action of insulin on hormone sensitive lipase (HSL) which regulates NEFA release.  Although at least one study I read showed larger cells in SCAT vs. VAT, the ability of SCAT to produce young insulin-sensitive cells is protective against excess NEFA release.  Indeed, one effective diabetes drug does just that:  stimulates adipogenesis generally accompanied by weight gain, but improved metabolic function.

2.  Lipolytic Rates:   The process of lipolysis (breaking down triglycerides into glycerol + fatty acids) occurs at higher rates in VAT.  Elevated NEFA are the result of increased or excessive lipolysis without a concurrent increase in energy needs.   One encouraging thing about this characteristic of VAT is that, when we lose fat, we tend to lose proportionally more from VAT.  This phenomenon is often cited as the reason why only modest weight reduction (10%) even in the severely obese is often accompanied by significant amelioration of MetS/IR/T2.

Fat cells, regardless of location, become less sensitive to insulin as they get bigger.  When they do, insulin is unable to properly suppress HSL resulting in increased mobilization of fatty acids from it's appropriate storage depots.  This condition is called adiposopathy, or "sick fat" by some.  At the risk of being repetitive, we each seem to have our own individual threshold for this condition to develop.  Lean or those suffering from some degree of lipodystrophy can have insufficient fat to buffer dietary intake or store much before getting over-full.  In such a person, a little paunch can be all that's required to set things in motion.  The gynoid, "female pattern" obese, aka "pears", who have large amounts of below-the-waist SCAT in hips and thighs tend to have lower rates of MetS.  Thigh/butt SCAT in particular, however we feel about it aesthetically, is generally considered protective for this reason.  The android, "male pattern", centrally obese, aka "apples" lack this buffer, tend to have exceeded their threshold and exhibit MetS.

Regardless of if a person is lean or obese, chronic/pathological insulin resistance initiates in the fat cells.   And the initial factor is the excessive release of fatty acid resulting in increased/elevated levels of circulating NEFA.    It should be pointed out that Type 1 diabetics also have elevated NEFA because of lacking basal insulin.  Even those who believe in the carb/insulin hypothesis can accept this.  Just go ahead and blame the carb-induced postprandial insulin for fat accumulating in your body, the result is the same.  Once you've reached your storage limit, your fat becomes insulin resistant, HSL is insufficiently suppressed and NEFA flow out.  

Fatty acid flow is essentially a one-way street for all cells in the body except for fat and the liver.  Fatty acids are transported into cells by diffusion so that the higher the concentration in circulation, the more flow into non-adipose tissue (ectopic) cells.  Once in, they are either oxidized for energy or esterified and stored as triglycerides in lipid droplets.  This lipid content in muscle cells is often called intra myocellular lipid or triglyceride (IMCL or IMCT) and high levels cause insulin resistance in most cases.  When do they not?  There is a paradox whereby insulin resistant obese and insulin sensitive trained athletes both exhibit high levels of IMCT, so it can't be the lipid itself that is the culprit here.  The evidence points to metabolic intermediaries in lipid oxidation - diacylglycerols, ceramides - building up in cells when oxidation rates aren't sufficiently high.  These interfere with overall cell metabolism, and increase reactive oxidative species (ROS) formation.  The ROS are the "toxic" culprits in lipotoxicity and the effects can range from functional impairment to cell death.   So the athlete may have high IMCL/T levels, but the turnover is sufficiently rapid so that the molecules aren't hanging around long enough to form ROS, whereas the obese person has lipid intermediary metabolites hanging around, forming ROS and causing insulin resistance.

Now, IMCL/T accumulation is also associated with a high fat Western style diets.   So, unfortunately, the introductions and discussions in much of the "lipotoxicity" studies is littered with statements indicating bias or adherence to the lipid hypothesis.  I see that too, but I read past it and look at the actual results.  IOW if they infuse free fatty acids into circulation and those disproportionately infiltrate ectopic tissues instead of being taken up and stored in adipose tissue, I don't care if the investigator is biased.  It shows me that the concentration of fatty acids alone, coupled with an inability of the fat tissue to properly sequester the excesses CAN lead to accumulation of IMCL/T in ectopic tissues, which CAN, in turn lead to disruption of cell function that may or may not be associated with insulin resistance.  Please note my qualifiers here.  

In this regard I have come across too many studies implicating either absolute NEFA levels, NEFA turnover rates or both directly interfering with proper cell function/insulin action in pancreatic beta cells, vascular endothelium (blood vessel lining), liver cells, etc.   The progression/causality of what we might refer to as chronic, metabolic or pathological IR (as opposed to transient IR due to dietary state) is pretty clearly established in the literature:  NEFA --> (a)Muscle IR & (b) Liver IR --> (a) reduced clearance of glucose from blood & (b) increased glucose production - gluconeogenesis --> hyperglycemia.

VLC diets seem to cause fat cells to behave like those that start this whole progression above.  NEFA levels rise to fasting levels and stay close for the entire day.  Both the T2 and the IR individual, fasting NEFA and postprandial NEFA release is elevated.   By keeping exogenous glucose (dietary carb) low to non-existent, hyperglycemia is ameliorated.   But if dietary carb were the only contributing factor to hyperglycemia, this control should be immediate but it's not.  Yes, postprandial glucose excursions are reduced, but elevated fasting BG is reduced much more slowly.  On the bright side, even elevated fasting levels are below levels normally implicated in glycation or under the umbrella term glucotoxicity.  But on the other hand, in exchange for this improvement, the other circulating energy substrate - NEFA - is released.  Now folks often point to the elevated ppBG lasting longer, essentially overlapping = chronic hyperglycemia.  This is fair enough for someone who is in what I would call advanced stage IR or full-blown T2.   

For a goodly portion of people, especially the very obese, VLC leads to substantial rapid weight loss coinciding with significant caloric deficit.  The combination of glycogen depletion and caloric deficit ameliorates insulin resistance as measured by glucose disposal.  Adding the glycogen depletion to the equation, one might expect the improvements to be better for VLC vs. conventional calorie restricted diets (CRD) in the short run because of the extra "sink".  But what of the long run?  What of those who lose weight but remain obese or significantly overweight?  What of those who do not lose much doing low carb?   There are many whose diabetes progresses on low carb diets.  They become more and more intolerant of any carbohydrate.  These people will even see their blood glucose levels soar after eating low carb bread products and fasting FBG's slowly rise over time.  If someone can't eat a cup of white rice with a pat of butter and a splash of soy sauce without their blood sugar levels going all out of whack they simply have not re-established normal metabolic control.   

The lipid profile of IR/MetS/T2 is characterized by high triglyceride levels.  These are usually attributed to carbs and DNL (that do contribute), but a goodly portion of the fatty acids the liver packages up and exports as triglycerides (VLDL) are *excess* NEFA the liver "filters" from circulation!  In a low carb state triglycerides tend to go down rather dramatically.  The reasons for this may well relate to lower insulin 24-hour exposure, but this means NEFA is not being properly removed from circulation.   The fasting triglycerides as major biomarker for CVD are likely associated with elevated NEFA (that is not commonly  measured and reported unfortunately) for those consuming sufficient carb (say >100g/day).  On VLC inefficient esterification means fewer circulating trigs but more NEFA.  

Whatever folks think about my treatment of  a certain author, this blog remains largely a labor of love for me born out of my desire to assure myself that my diet is a healthy one for me.  That's why I started looking into this stuff and why so much of my research (yes, folks, by definition what I do fits well within the definition of that word) has ended up focusing on NEFA.  The cluster of metabolic diseases seem to all point to one culprit:  resistance to the appropriate action of insulin by various tissues.  And, to repeat, the evidence strongly supports that this process initiates in the adipocytes with excessive release and/or inefficient trapping of NEFA/FFA leading to elevated circulating levels of free fatty acids.  Just as the concentration of glucose in blood is directly linked to deleterious consequences, so, too, are NEFA levels.  Not just a "biomarker associated with" (although there are those indications too), but a direct effect. 

So, does VLC cause a detrimental NEFA level?  Well, I compare some of the levels reported following a single large meal as well as the consistent levels reported after 6 weeks of VLC reducing diet, and they are comparable to those exhibited by those with active diabetes and such.  And sustained far more than abnormal  blood glucose incursions I might add.  The chance of a diabetic who has a heart attack (myocardial infarction) subsequently going into sudden cardiac arrest and dying (SCD) is about 3X higher and this is attributable to circulating NEFA concentrations.   So at least in this instance, it matters not what elevates the NEFA, only that they are high.  I'm going to inject a little sarcasm here:  This is, of course, nothing any of us have anything to worry over if we've been extremely overweight, eating a crappy diet, and possibly been diabetic for years.  Because we know none of us have even a risk, let alone an elevated one, of having a heart attack or any issues with hypertension  or arrhythmia or racing hearts.  Right? 

Control hyperglycemia through removing exogenous glucose, and you still don't address the risks of NEFA.  My personal advice for the long term (and take it for what you will based on your assessment of what I write here, I'm not a medical doctor!):  Focus, instead, on long term improvements in sensitivity to insulin and controlling the NEFA, and the hyperglycemia will fix itself.  Provided your beta cells haven't sustained permanent damage (and the diabetes cure rate with gastric bypass provides reason to be optimistic that this is actually not the case for some 85% of morbidly obese diabetics)  this should ultimately be reversible with lifestyle change.  I mean reversible to the point that you CAN enjoy moderate carbohydrate consumption (of whole fruits and "safe starches") with normal glycemic control.  Couple this approach with eliminating foods you can identify an intolerance to and avoiding/cutting back on foods that are potentially toxic, and get healthy.

I am planning a series on IR that will include an installment on why I think VLC diets are so effective for weight loss in so many with some significant degree of this condition.  I have no idea when that will be.  In retrospect, I have reservations on the safety of this approach, but if one can reduce and MAINTAIN weight, the benefits do definitely, in my considered opinion, outweigh the risks.