Critical Visceral Adipose Tissue Theory

I found this article almost a year ago, posted it on an LC discussion board, and was mostly greeted with silence so I had sort of forgotten about it.  In any case, I was reminded of the article while recently reading LynMarie's latest post on her blog:  Fat Fails First?  (Incidentally, that post corresponds well with my own recent offering on the topic:  The Progression of Insulin Resistance ).  

There are likely many scenarios and pathways that can lead to metabolic syndrome. This paper reviews mechanisms by which the accumulation of visceral adipose tissue (VAT) may contribute to the metabolic syndrome, and explores the paradigm of a critical VAT threshold (CVATT). Exceeding the CVATT may result in a number of metabolic disturbances such as insulin resistance to glucose uptake by cells. Metabolic profiles of patients with visceral obesity may substantially improve after only modest weight loss. This could reflect a significant reduction in the amount of VAT relative to peripheral or subcutaneous fat depots, thereby maintaining VAT below the CVATT. The CVATT may be unique for each individual. This may help explain the phenomena of apparently lean individuals with metabolic syndrome, the so-called metabolically normal weight (MONW), as well as the obese with normal metabolic profiles, i.e., metabolically normal obese (MNO), and those who are "fit and fat." The concept of CVATT may have implications for prevention and treatment of metabolic syndrome, which may include controlling dietary carbohydrates. The identification of the CVATT is admittedly difficult and its anatomical boundaries are not well-defined. Thus, the CVATT will continue to be a work in progress.
This hypothesis is consistent with men having historically higher risks of CVD while women seem to be catching up as obesity becomes more prevalent.  On average, women have more adipose tissue, and more SCAT so it seems we tend to have more metabolically benign "depots" in which to store excesses before it wreaks metabolic havoc in our VAT.  Men, OTOH, tend towards central fat deposition from the get go.

I have expressed this same theory as each of us having an individual "fill line" for our fat depots -- the metabolic derangement seems to manifest itself when we near and/or exceed that level.  
Figure 1.  Critical Visceral Adipose Tissue Threshold (CVATT). According to the hypothesis, there is an individual range for accumulating a critical amount of visceral adipose tissue (VAT). Insulin sensitivity is important for weight gain and accumulation of VAT. Once the critical VAT threshold (CVATT) is reached, insulin resistance occurs, which may be protective initially and impair further weight and fat gain. Continuation of VAT accumulation can lead to metabolic syndrome. However, only a modest weight loss (5–10 percent) with accompanying VAT loss can reverse the process.
Adipose Tissue, Adipocyte Size and MetS:  As discussed in my blog post referenced above, elevated NEFA levels precede the other derangements of MetS.   It is also well known that VAT is the more metabolically active fat vs. SCAT.  Fat mass increases by a combination of two processes -- filling pre-existing cells therefore increasing size and/or creating new cells by differentiating pre-adipocytes.  In the section titled "Implications of fat mass expansion" we learn that it is the "stuffed full" (hypertrophy) fat cells that become dysfunctional leading to metabolic derangement.  SCAT is more efficient at creating new, smaller (therefore properly functioning) adipocytes that readily take up free fatty acids and triglycerides to sequester them from circulation.  VAT is apparently less so, so when these adipocytes reach capacity they become insulin resistant.  It doesn't say so in the article, but as I've blogged on several times, perhaps the most key role of insulin in our bodies is to regulate NEFA levels by inhibiting release from fat cells.  When an adipocyte becomes insulin resistant, the insulin is less able to inhibit lipolysis, thus free fatty acids are released.

So chronic positive caloric balance --> fat deposition in SCAT (some in VAT) --> more and bigger SCAT cells until you near capacity --> SCAT-IR --> diversion of fat to more metabolically active VAT -->  increase in VAT cell size --> VAT cell dysfunction --> Metabolic Syndrome.   This seems to agree with the discussion in the article indicating VAT is usually the first fat to go with weight loss and why improvements in biomarkers are seen with the first 5-10% weight loss but not correlated much more with further weight loss.  I find this to be good news.  If one is obese but not able to maintain a significant amount of weight loss, maintaining a modest one may be all that's required to at least reduce risk of developing T2, etc.  It may be impossible to predict an individual's CVATT, but if we can monitor NEFA levels in the overweight, a threshold weight for CVD risk could be established early.  If NEFA are normal, this person's fat cells are functioning normally and keeping excesses where they are supposed to be.  If NEFA are elevated, this is the first indication of adipocyte dysfunction -- the person has reached their "fill line".


Helen said…
Thanks for posting this. I've skimmed it and will look at it more in-depth soon. As always, my filter is looking for explanations for my own hyperglycemia, which isn't accompanied by any usually-tested-for markers of metabolic syndrome. I don't know if I have "thin-person's diabetes" - as written about in the recent book, Sugar Nation (which I haven't yet read), or if I have a MODY-like form, or something else. My A1c did get to diabetic range when I got just a little chubby, but has only come down by 0.4 since - on low carb as well as on low fat (though my home meter tests show low fat to do me better).

If I have thin-person's diabetes, this is of great relevance to me. And it could be so. My hip-waist ratio has always been higher than it should be regardless of my weight, including now, at BMI 20 - I've lost 30 pounds, but my hip-waist ratio hasn't budged - and even when I was a skinny 14-year-old (measured in Home Ec class). This could point to more VAT. If so, I'd point to chronic stress, starting in infancy, as playing a role in VAT accumulation. I'm sure this statement could apply to many people.
CarbSane said…
Hi Helen, I have a related post/study dealing with birthweight and IR. Were you a low birthweight baby?
Margaret said…
Hi Evelyn, this post reminds me of a talk I heard at the 2010 World Congress on Insulin Resistance, by Sam Klein, a respected expert from the University of Washington St. Louis (probably one of Stephan Guyenet's colleagues/mentors?) He said that when you surgically remove the visceral fat tissue from type 2 diabetics, their insulin resistance does not change (although the paper you analyse here quotes 2 references that say removal of omental fat DOES improve IR). If I remember correctly, his argument was that it is the accumulation of liver fat that drives insulin resistance as well as some visceral fat accumulation, which also explains the lean metabolic syndrome person who has liver fat but is not necessarily overweight. He also says that weight loss in general of course improves IR, but probably via reduction of NAFLD. IOW, visceral fat loss is a by-product of overall weight loss but the metabolic benefits are a result of liver fat loss. What do you think?
Helen said…
Hi Evelyn,

Almost - 5 lbs, 9 oz. Less than either of my twins!

I was adopted and can only imagine my birth mother was under some stress. For me, more stress followed.
CarbSane said…
@Margaret: That sounds plausible, and I would add pancreatic fat accumulation to the mix as well, especially for IR progressing to frank diabetes.

I think it is fair to summarize my thoughts on this as follows. I do not believe IR leads to obesity/disease, I believe the evidence is clear that excess fat accumulation (above some individual threshold in whatever location/type ends up being the culprit) leads to IR/disease. However one can be developmentally predisposed to IR. It is the inability to store fatty acids leading to elevated NEFA and non-adipose tissue buildup of fats -> dysfunction & toxicity -> metabolic shit-storm. Not the other way around.

Oh .... thanks for making me think! I found the paper/post I was referring to for Helen:
Funny you were the last comment on that one ;

I've got some thoughts now that I didn't have at the time, on how this all might intertwine in a consistent manner. FattiER babies are associated with IR, but are predisposed to obesity b/c of starvation adaptation. This would be much like the 5% calorie-restricted mice getting fattiER but not heavier in total mass due to a downregulated metabolic rate. So the LBW baby is predisposed to gain more weight and if the predisposition is for central fat, perhaps their threshold has already been exceeded.
Margaret said…
Yes, all my reading would also confirm that it's the non-adipose (liver, pancreas, etc) buildup of fat where it's not supposed to be that is the most dangerous metabolically. As you say, insulin resistance doesn't cause obesity, it's the other way around. I believe a certain amount of visceral fat buildup is an evolutionary adaptation to having fat stores where they can be most readily mobilized, especially in men - womens' higher estrogen levels tend to protect against visceral fat as their evolutionary tendency is to store fat where it's most appropriate for nurturing/protecting a child. But in a long term excess caloric intake situation, the "normal" fat distribution reaches capacity and starts to overflow to the organs, leading to metabolic dysregulation.

Great work, Evelyn - this is such a great resource and you have so much energy and enthusiasm for this subject - I always learn something coming here!
Mirrorball said…
When I read your post, it reminded me of this study:
Sam Klein is the last author.
M. said…
A lot of it seems to keep going back to the liver, and I still get the feeling that the Chris Masterjohn posts about adequate choline basically giving the liver immunity to fatty liver disease is probably one of the most important things I have read since I started reading health blogs.
Sanjeev said…
Margaret wrote ...
non-adipose (liver, pancreas, etc) buildup of fat where it's not supposed to be
Chicken & egg, squire[0] ... chicken & egg.

see these entries down the right hand sidebar

The reason the fat ends up other places is, the fat's poisoning/poisoned the adipocytes.

[0] is it squire for both men & women? A Brit must tell
CarbSane said…
Thanks Margaret!

@M - thanks for reminding me of that series. I was made aware of it back during a really busy time and need to read it sometime. The liver plays a key role in the distribution of insulin as well as glucose too. Something I hope to get around to blogging on. It's something that makes insulin replacement therapy so much more difficult than the mere injections. We've come a long way with that.
lightcan said…
Hi Evelyn,

ditto, thanks for the interesting posts
I know two 'normal' diabetics and one overweight one (my mother) (visible fat at the moment of the diagnosis) One of the 'normal'looking diabetics was a doctor (They're all in their late sixties now). He obviously didn't understand the mechanism of this disease.
There was a BBC Horizon programme on that hypothesis, seemingly proven by the population of India. malnutrition of the mother - low birth baby- insulin resistance in childhood - diabetes in later life, with no obesity. So that might be one of the causes. The other overeating/excess fat in reserves (based on individual threshold)?
Can you explain then, how can somebody put on more fat after being diabetic for a while? It seems, due to medication the initial situation changed and more fat cells could be created, or they accepted more fat.
CarbSane said…
Hi lightcan, thanks :)
I don't recall the specific class of drugs at the moment, but one for T2 improves glycemic control by causing weight gain. Apparently it stimulates differentiation of preadipocytes -> adipocytes and small young adipocytes are insulin sensitive.