Wednesday, March 26, 2008

Visceral Fat

This week, I stumbled upon a very interesting series of articles from the lab of Dr. Nir Barzilai.

The first article I came across showed that surgical removal of the visceral fat deposit of rats increased their lifespan. Visceral fat (VF) is the "beer belly", and consists of the perinephratic fat around the kidneys and the omental fat in front of the intestines. It doesn't include subcutaneous fat, the fat layer under the skin.

VF is tightly associated with the metabolic syndrome, the quintessential "disease of civilization" that affects 24% of Americans (NHANES III). It's defined by three or more of the following criteria: high blood pressure, large waist circumference, low HDL cholesterol, high triglycerides, and high fasting glucose. The metabolic syndrome is associated with a 3-4-fold increase in the risk of death from cardiovascular disease, and a 6-fold increase in the risk of developing type II diabetes. From a review on the metabolic syndrome (parentheses mine):


The most common alteration related to the impaired glucose metabolism with aging is the progressively increased fasting and postprandial [post-meal] plasma insulin levels, suggesting an insulin-resistant state.

This is all well and good, but who cares? What's to say VF plays any role other than as a simple marker for overweight?


The longevity paper led me to Dr. Barzilai's previous papers, which answered this question rather thoroughly. Rats raised on standard rat chow, which is a sad little compressed pellet made of grains and added nutrients, develop elevated insulin and insulin resistance with age, just like humans. Unless they don't have VF. Rats that had their VF surgically removed did not develop insulin resistance or elevated insulin with age, despite rebounding to their original total fat mass rather quickly (VF accounts for ~18% of total fat in these rats). These parameters are unaffected by removing an equal amount of subcutaneous fat, which has been shown in human liposuction patients as well.

Removing VF also improved diabetes-prone Zucker rats, which are profoundly insulin-resistant (leptin receptor loss-of-function). It kept wild-type rats just as insulin-sensitive as calorically restricted controls, which had a small amount of VF. This shows that VF isn't just a passive player; it's essential for the development of insulin resistance. It also shows, along with human studies, that insulin resistance is not an inevitable consequence of aging.

Adipose (fat) tissue is being increasingly recognized as an important endocrine (hormone-secreting) organ. It produces many different hormones that affect insulin sensitivity and appetite regulation, among other things. These hormones are collectively known as fat-derived peptides (FDPs). At least one of these FDPs, TNF-alpha, promotes insulin resistance.

Dr. Barzilai's group went on to explore the mechanism of VF contributing to insulin resistance. They increased the rate of glucose flux into the fat tissue of rats by infusing either glucose or insulin into the bloodstream. These treatments both cause increased glucose uptake by fat cells. What they saw when they dissected the rats was striking. The VF had ramped up its production of FDPs from 2- to 15-fold, while the subcutaneous fat had barely changed. Incidentally, insulin increased glucose uptake by VF twice as much as subcutaneous fat.

I'll say this again, because it's important. They forced glucose into VF cells, and those cells dramatically upregulated FDP production. And again, no visceral fat, no FDPs.

In earlier papers, he also showed that the removal of VF dramatically reduces the expression of TNF-alpha and leptin (two FDPs) in subcutaneous fat on a longer timescale, showing that VF and subcutaneous fat communicate to alter the metabolism. Again, TNF-alpha promotes insulin resistance, making it a possible link between the fat tissue and peripheral effects. VF removal had no effect on triglycerides, suggesting that they're only a marker of insulin dysfunction rather than a cause.

Now to take this research to its logical conclusion. Here's a plausible sequence of events leading up to the metabolic syndrome:
  • A meal high in quickly digested carbohydrate elevates blood glucose. OR, excessive fructose causes insulin resistance in the liver which leads to high fasting glucose.
  • Visceral fat responds by increasing production of FDPs.
  • FDPs, directly and/or indirectly, cause insulin resistance in the liver, muscle and other tissue. Liver insulin resistance causes alterations in lipoprotein ("cholesterol") profile (more on this in another post). Fat tissue remains insulin-sensitive.
  • The vicious cycle continues, with increased visceral fat size and glucose uptake increasing FDP production, which makes the liver more insulin resistant, which increases glucose production by the liver, etc.

8 comments:

Charles R. said...

That's probably the most interesting and important piece of research of read in a long, long time. And you summarized it beautifully.

This explains so much. How people get fat, and why, when you are fat, it's so difficult to get un-fat. The VF is basically turning your body into a little VF factory.

This dovetails nicely with the research that's just coming out indicating that if you have belly fat in your 40s, you're much more likely to get dementia.

Stephan said...

Thanks Charles. I agree the implications are really interesting. I'm still trying to wrap my brain around it. It sounds like it creates a positive feedback loop.

It actually took me a while to believe VF was an active player in insulin resistance and not just a marker.

reid said...

Another strong argument for a low carb diet (and a reminder that I need to cut down on beer)! It's scary how many Americans have VF, especially as we get older.

Ross said...

so... liposuction a cure for type 2 diabetes?

Stephan said...

Liposuction doesn't work because it targets subcutaneous fat. Removing the omental fat in conjunction with bariatric surgery improves insulin sensitivity better than bariatric surgery alone, but it's hard to dissociate the two possible causes.

rnikoley said...

Stephan:

Just found your blog a few days ago and it's right up there with Peter's and Art's in my book.

This was a very interesting post for me. It made me think of an analogy I formed back when I saw Taube's Berkely lecture. It seemed to me that he was describing fat as one would describe a tumor. Here's what I wrote:

http://www.honestylog.com/root/2008/01/180-degree-erro.html

"I think the tumor analogy is an interesting one, at least in the way I understand Taubes at present. What do you often hear expressed about tumors, short of outright removing them? Well, sometimes they're "small," such that the risk of surgery isn't called for. So, you try to keep them small. Why? Well, because when they're small their effect is minimal. They aren't cannibalizing good tissue sufficiently to cause a large effect. How about shrinking a tumor? Same thing. And what happens when a tumor gets to be of sufficient size? Does it not then become a self-sustaining cannibalistic parasite, sacrificing healthy bodily tissue for its own sake in a positive-feedback mechanism, such that the bigger it gets, the bigger and more parasitic its influence on the rest of the body until eventually its pathological selfishness kills the very host that feeds it?"

This has been an amazing journey and I'm just amazed there are guys like you out there blasting away at the nonsense.

Oh, BTW, I linked to all your lard posts in my breakfast entry this morning:

http://www.honestylog.com/root/2008/03/chili-verde.html

Try the chile verde. You'll be glad you did.

Stephan said...

Thanks Richard. Your blog is interesting as well.

I like the tumor analogy. I have to wonder if there's not an adaptive function to the VF's behavior though. Maybe when carbohydrate was more plentiful in the fall (starchy tubers and berries), VF created peripheral insulin resistance to increase fat mass for the winter?

trinkwasser said...

Brilliant summation!

I'll keep this post up to link to as part of my diabetes resources.

I was just looking at the same thing from a different point of view

http://trinkwasser.wordpress.com/2009/09/16/crossing-the-sahara/

Did you not spot the irony of this following your "lard" posts? Surgically remove the visceral fat from patient #1 and sell it to patients #2 -#10 as lard, treat them all. Soylent Green.