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Fat cells have taken the blame for obesity-related conditions like Type 2 diabetes and hypertension, but new research suggests a cell more commonly associated with inflammation may be an equally important contributor.

The new study found that macrophages, cells that are known to promote and regulate inflammation by releasing a slew of inflammatory molecules, infiltrate the fat tissue of obese mice and humans. In the most obese mice, macrophages make up an astounding 50 percent of all cells in fat tissue. The macrophages also appear to secrete the majority of diabetes-related pro-inflammatory molecules produced by fat tissue. Previously, researchers thought the tissue's fat storage cells, adipocytes, produced the molecules. The research, along with similar work by a group at Millennium Pharmaceuticals, appeared in the Dec. 15 issue of the Journal of Clinical Investigation.

"One exciting thing is this observation moves the target of potential therapies away from the fat cell to the macrophage," says the study's leader, Dr. Tony Ferrante, assistant professor of medicine. "Pharmaceutical companies have lots of experience developing anti-inflammatory drugs directed at these types of cells. They may be able to develop therapies that affect the fat's macrophages specifically."

In the last decade, scientists have come to view obesity as a low-grade inflammatory state. As animals grow fatter, fat tissue releases more and more inflammatory molecules that stoke conditions associated with obesity, including Type 2 diabetes, high blood pressure, and atherosclerosis.

Fat storage cells have been blamed for producing these molecules, but analysis of GeneChip studies of fat tissue in the laboratories of Dr. Ferrante and Dr. Rudolph Leibel, professor of pediatrics and medicine at P&S suggested that macrophages also had a role. The GeneChip analysis compared fat tissue from a variety of mice, ranging from lean to extremely obese, and looked for changes in gene activity that correlated with degree of obesity. "Amazingly, out of the 100 most tightly correlated genes, 30 percent are characteristically produced by macrophages," Dr. Ferrante says. "And all of these increased activity as fat increased, which suggested to us that the number of macrophages were going up."

Macrophages were known to exist in fat tissue, but were considered rare outposts of the immune system, guarding against infections. But when Stuart Weisberg, an MD-PhD student, looked at fat tissue from severely obese mice, he found that macrophages constituted half of the tissue's cells and noted unusual clusters of fused, multinucleated macrophages. These fused macrophages resembled giant cells typically found in the disease Wegener's granulomatosis and other chronic inflammatory states. He also observed in obese animals that macrophages surrounded fat cells and contained large lipid droplets. In contrast, macrophages in fat tissue from lean mice were rare, isolated and not lipid-laden.

In humans, the trends were similar. The numbers of macrophages increased with body mass index (BMI), with macrophages making up 40 percent of all adipose tissue cells in severely obese people with BMIs around 50.

Because macrophages are adept at secreting inflammatory molecules, Dr. Ferrante and Mr. Weisberg then asked whether these cells were the culprits responsible for the inflammatory molecules released from fat. It appeared that they were. They examined the expression of several molecules previously associated with obesity and diabetes and found that macrophages, and not fat cells, were responsible for their production.

"Since several molecules are likely responsible for obesity-associated diabetes, targeting a single molecule may not significantly improve insulin sensitivity," Dr. Ferrante says. "But if macrophages are producing the majority of these molecules, we may be able to take aim at just the macrophages."

Before macrophages are seriously considered as targets, though, Dr. Ferrante says they still need to show, in vivo, that adipose tissue macrophages contribute to insulin resistance or other obesity complications like atherosclerosis and high blood pressure. Macrophages produce many of the molecules associated with these conditions, though not all. A factor associated with insulin resistance, adiponectin, for example, is secreted by fat storage cells.

Why do macrophages accumulate in the fat tissue of overweight mice and people? Dr. Ferrante's team also hypothesizes that as fat cells in adipose tissue get larger they release factors that attract macrophages from bone marrow. They are sifting through several possibilities to find which ones are responsible. Blocking the factors may inhibit macrophage migration and be therapeutic.

"We haven't been very successful at getting people to reduce fat cells," Dr. Ferrante says. "Maybe we'll be more successful with therapies that target macrophages."

The work was supported by the NIDDK, the Russell Berrie Foundation, and the Fawcett Foundation.

–Susan Conova


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