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First Link Found Between Obesity, Inflammation and Vascular Disease

Researchers find human fat cells produce C-reactive protein

HOUSTON, TX -- September 16, 2005 -- Researchers at The University of Texas M.D. Anderson Cancer Center and The University of Texas Health Science Center at Houston have found that human fat cells produce a protein that is linked to both inflammation and an increased risk of heart disease and stroke.

They say the discovery, reported in Journal of the American College of Cardiology, goes a long way to explain why people who are overweight generally have higher levels of the molecule, known as C-reactive protein (CRP), which is now used diagnostically to predict future cardiovascular events.

And they also report some good news: the researchers found that aspirin and statin drugs, now commonly used to treat heart diseases, effectively damp down production of CRP from fat cells.

"This study is the first to show how body fat participates in the inflammatory process that leads to cardiovascular disease, but also demonstrates that this process can be blocked by drugs now on the market," said study leader Edward T. H. Yeh, MD, who is both chairman of the Department of Cardiology at M.D. Anderson and director of the Research Center for Cardiovascular Disease at the Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases at the UT Health Science Center at Houston.

UT Health Science Center at Houston President James T. Willerson, MD, is a co-author of the study.

Adipose tissue has been lately regarded as a separate body organ that produce a number of different biologically active molecules -- such as cytokine proteins that are associated with inflammation, and the hormone resistin, which is linked to insulin resistance and the development of type two diabetes.

Even if they are healthy, people with more adipose tissue also tend to have higher levels of CRP. Previous research, however, had only found CRP to be produced in liver tissue, although Drs. Yeh, Willerson and Paolo Calabro, MD, discovered in 2003 that the protein also is manufactured in the walls of blood vessels.

"But that didn't explain obesity's connection to high levels of CRP and it also was not clear why CRP is higher in patients who have metabolic disorders," Dr. Yeh said.

So the research team decided to see whether fat cells themselves could be stimulated by inflammatory cytokines or resistin to produce CRP. To help find out, plastic surgery patients at M.D. Anderson donated adipose tissue that would have been discarded, and the research team then isolated fat cells, cultured them and stimulated them under a number of different conditions.

They found the cells produced cytokines that resulted in inflammation and that this process triggered production of high levels of C-reactive proteins.

The researchers also discovered that resistin, the hormone associated with diabetes and insulin resistance, could stimulate production of CRP proteins. "And this is interesting because it is known that resistin is itself produced by fat cells," Dr. Yeh said.

"We know that patients with metabolic syndromes have higher levels of CRPs, as well as a higher risk of developing heart disease and stroke, but no one understands why that is," Yeh said. "If fat cells by themselves produce inflammatory signals that trigger cells to produce CRPs, and if CRPs also produce biological effects on vascular walls, that could explain the higher risk of cardiovascular disease."

The investigators then solved the other part of the puzzle -- why it is that aspirin, statin drugs and an agent known as troglitazone, used to treat diabetes, can reduce CRP levels. They exposed the cultured fat cells that were producing high levels of CRPs to these drugs, and found production of the proteins declined. "We knew from studying patients that these drugs can reduce C-reactive proteins, but now we have direct proof of their benefit."

Even as the CRP picture becomes clearer, there is still much that is not known, the researchers say, including the reason why fat tissue produces an inflammatory response, and just precisely how CRP participates in that process.

"Inflammation is a very complicated phenomenon, but at least we now have a few more clues as to what it does and how the damage it produces can be prevented," Dr. Yeh noted.

Co-authors include Calabro, an Italian cardiology fellow at the UT Health Science Center at Houston, and David Chang, MD, a plastic surgeon at M. D. Anderson Cancer Center. Co-author Willerson also is president-elect, medical director and director of research for the Texas Heart Institute at St. Luke's Episcopal Hospital.


SOURCE: The University of Texas Health Science Center at Houston

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