Direct evidence has been found that links inflammation around visceral fat deposits with development and progression of atherosclerosis, according to an article published online January 21 by Circulation.

The researchers at University of Michigan Cardiovascular Center, led by Daniel Eitzman, MD, also reported that a medication often given to people with diabetes can be used to calm that inflammation and protect against progression of arterial damage.

The team had been studying mice that lack the gene for leptin. In an effort to get the obese mice to produce some leptin, the team developed a technique to transplant clusters of fat cells from normal mice of the same strain into the leptin-deficient mice.

"In addition to producing leptin and preventing obesity, the fat transplants became inflamed, attracting immune cells called macrophages," Eitzman said. "Since the mice were genetically identical except for leptin, this shouldn't have happened. But the inflammation was there, and it was chronic."

The inflammation occurred around individual adipocytes. Further tests showed it was regulated by the same factors that regulate the inflammation that other researchers have seen in the naturally occurring fat deposits of obese mice -specifically a chemokine called MCP-1.

They were especially interested to see if there might be any link between the inflammation and atherosclerosis. Because normal mice do not develop atherosclerosis, the team obtained a strain that had been developed to be prone to high cholesterol and atherosclerosis. These ApoE-negative mice, were divided into three groups: two that received fat transplants from normal mice and one that underwent sham surgery.

Some of the fat-transplant ApoE-negative mice received transplants of visceral fat, whereas others received transplants of subcutaneous fat. Mice that received the visceral fat transplants developed atherosclerosis at a much accelerated rate and showed the same type of inflammation as the leptin-deficient mice had. Meanwhile, mice that received subcutaneous fat did not experience an increase in atherosclerosis despite having increased inflammation. The mice that had the sham operations developed neither inflammation nor increased atherosclerosis.

"There appeared to be an interaction between the macrophages causing the inflammation in the visceral fat and the process of atherosclerosis," said Eitzman, who noted that blood vessels far from the site of the fat transplant developed increased atherosclerosis.

As a final experiment, the team treated the mice with pioglitazone - a member of the class of drugs called thiazolidinediones or TZDs that are often used to treat diabetes. While these drugs have an impact on metabolism, which makes them useful in diabetes, they also have been discovered to have an anti-inflammatory effect.

Pioglitazone reduced both concentration of macrophages and MCP-1 and atherosclerosis in mice that received transplants of visceral fat. However, the drug had no effect in the other mice.

Now the investigators are looking for factors that might trigger macrophages to invade the area and bring on inflammation and for blood-borne biomarkers that might be used as a way to identify early warning signs of atherosclerosis.