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.

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