Big Difference Emerges Between Body Fats

The beer belly. The apple shape. The high waist-to-hip ratio. All of these indicate an increased risk of metabolic and cardiovascular disease. The culprit? Visceral fat. The accumulation of white fat around the internal organs has long been associated with insulin resistance, type 2 diabetes, and atherosclerosis.

While the prime focus of health care providers has been on the location of the fat, new research from C. Ronald Kahn’s lab at Joslin Diabetes Center suggests that location is not the only factor.

“Our hypothesis was that it isn’t just where the fat is but that the fat in different areas is intrinsically different,” said Kahn, the Mary K. Iacocca professor of medicine at HMS, Brigham and Women’s Hospital, and Joslin.

This hypothesis came from hints in other studies that visceral fat was not the end of the story. For instance, one study that categorized 1,356 individuals aged 60 to 85 years based on their ratio of subcutaneous to visceral fat showed that those with higher proportions of subcutaneous fat had lower levels of insulin resistance. Another study showed that patients with type 2 diabetes who were treated with thiazolidinedione drugs, diabetes drugs known as glitazones, had decreased insulin resistance despite a concurrent increase in subcutaneous fat.

Kahn began to test his hypothesis several years ago, with two recent studies showing that visceral fat and subcutaneous fat, though they are both white adipose tissue, have fundamentally different cellular properties. While visceral fat seems to have ill effects on health, subcutaneous fat plays a protective role against metabolic disease.

In the earlier study, published in 2006 in Proceedings of the National Academy of Sciences, first author Stephane Gesta, HMS instructor in medicine at Joslin, used genetic profiling data to show that visceral and subcutaneous fats mature through very different developmental pathways.

For the second study, reported in the May 2008 Cell Metabolism, first author Thien Tran, HMS research fellow at Joslin, took a physiological approach, asking, “If we put subcutaneous or visceral fat into a different location, will this affect its properties?”

To explore this question, Tran performed an array of fat transplants between wild-type laboratory mice. In each case she transplanted 1 gram of subcutaneous (SC) or visceral (VIS) fat (about 20 percent of a mouse’s total fat content) from a donor mouse into either the SC flank area or the intra-abdominal VIS cavity of a recipient mouse. A fifth group of mice underwent sham transplant surgery.

The two sets of mice with added subcutaneous fat showed marked changes. Twelve weeks after the transplants, these mice gained significantly less weight than the other mice and had less total body fat, conditions not attributable to differences in diet or activity levels. The added subcutaneous fat “made a difference that was in a good direction and that was further enhanced when it was inside the abdomen, the place visceral fat would normally be,” said Kahn. In contrast, mice with added visceral fat closely resembled the sham surgery control group. The lack of whole body changes in all except those with added subcutaneous fat confirmed that subcutaneous fat had specific intrinsic effects.

“Everyone before has focused on removing visceral fat,” said Phillip Gorden, senior investigator and director emeritus of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. “The novelty of this study is to show that if you take fat from an area that has less metabolic negativity and actually put it in the visceral anatomic area, it confers a benefit.”

These dramatic whole body changes led the team to try to understand the cause. The mice with added subcutaneous fat showed improved insulin sensitivity and lowered glucose levels. These changes are typically associated with weight loss, which these mice did experience. Kahn speculates that the changes may be directly caused by increased subcutaneous fat.

Moreover, the mice with added subcutaneous fat also showed a significant drop in glucose production in the liver when exposed to high insulin levels during a gold-standard test of insulin sensitivity. In the mice with subcutaneous fat transplanted into the abdomen, the effect on the liver was more pronounced, suggesting “cross-talk between subcutaneous fat and the liver,” said Tran.

“The model suggests that we should look hard for some secreted substance [from subcutaneous fat] that may confer this beneficial effect,” said Gorden.

That substance is likely a hormone, according to Kahn. He speculates that subcutaneous fat embedded in the visceral cavity secretes this hormone, which enters the liver through the portal vein and packs a punch. The effect of that same hormone when secreted from subcutaneous fat stored peripherally has a more subdued effect, possibly because it is degraded or diluted as it travels through the circulatory system before it reaches the liver.

Kahn points out that the difference in potency of the effect of the subcutaneous fat could also be a side effect of the transplant. If the visceral transplant “took better,” he said, perhaps more of the transplant survived there than in the periphery, causing a “kind of dose response.” The team was not able to measure the fat stores with fine enough detail to rule out this possibility.

The researchers have, however, ruled out well-known cytokines and adipokines in a first pass at a search for the beneficial secreted factor or factors. According to their analyses of plasma as well as genetic expression of these proteins in the fat tissues, none of them varied in a way that would explain the observed whole body effects in their mouse model. The team is focusing its future work on a search for novel secreted factors.

In a parallel effort, the team is also trying to understand the intrinsic characteristics of fat in all of its varied depots. It is well accepted that fat is an endocrine organ. Some even venture to call visceral fat its own “unofficial” organ. According to Kahn, “there is fat everywhere. We have fat in our joints, fat behind our eyeballs,” he said. “We don’t know how many different ‘organs’ it may be.”