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Major research grant targets inflammation in battle against obesity and disease

Story Date: Tue, 24 Jan 2012 10:42:00 EST

If you are obese, you are at great risk of developing heart disease and diabetes. But research now underway at Eastern Virginia Medical School could drastically improve your odds of avoiding these serious diseases.

EVMS has secured a major, five-year research grant from the National Institutes of Health that may lead to ways to prevent the development of these diseases linked to obesity. The $1.8 million grant supports a multidisciplinary study of how to safely thwart chronic inflammation; scientists believe that inflammation triggers disease in people who are overweight.

"Inflammation is key to why central 'belly' fat leads to high risks for diabetes, heart disease and maybe even some forms of cancer," says Jerry L. Nadler, MD, director of the EVMS Strelitz Diabetes Center and principal investigator on the grant.

Inflammation is vital to our health. The immune system uses acute inflammation to battle certain infections and heal wounds; it subsides when no longer needed. But chronic inflammation can cause problems. It is this long-term inflammation that Dr. Nadler and his colleagues are targeting.

Obesity — now at epidemic levels in the United Sates — represents a major public-health challenge for the nation. The risk of having a heart attack triples during obesity. Nearly 80 percent of people who develop type 2 diabetes (often as a result of obesity) also develop heart disease.

To help limit the potentially deadly impacts of these diseases, the scientists are examining a particular chemical pathway in the body involved in chronic inflammation. Obesity activates the protein Interleukin-12 (IL-12) that then signals a gene "switch" called STAT-4 to initiate inflammation.

"As IL-12 goes up, it activates the gene switch, and we think when that is unregulated or not regulated correctly, it leads to excessive inflammation around the blood vessels and in the body. That can lead to heart disease, insulin resistance and potentially to diabetes," Dr. Nadler says.

Dr. Nadler, who also is professor and chair of the Department of Internal Medicine, is leading a team of scientists on the research. Also from EVMS are Anca D. Dobrian, PhD, assistant professor of physiological sciences and co-investigator on the grant, and Elena Galkina, PhD, assistant professor of microbiology and molecular cell biology. The EVMS team is collaborating with other well-known scientists in the field, including Alan Chait, MD, from the University of Washington, and Mark Kaplan, PhD, at Indiana University.

The team already has strong evidence to demonstrate that by controlling STAT-4, they can prevent long-term inflammation and the diseases that often follow.

Preliminary studies over the last two years show that when certain mice are fed a high-fat diet, they develop insulin resistance (a precursor to diabetes) and atherosclerosis (hardening of the arteries that is a hallmark of heart disease). But when scientists eliminate the STAT-4 gene, the mice do not develop disease and otherwise appear normal.

"You can't take out the gene in people, but you can develop drugs that work the same way," Dr. Nadler says. "We're not preventing obesity. That has to be a lifestyle change. But what we are able to do is help prevent some of the damaging effects."

The team will test their theory that the fat around the blood vessels can act as a reservoir of inflammation, feeding the vessel wall with inflammatory cells and leading to the development of vascular disease such as atherosclerosis.

"We have preliminary evidence showing that excess visceral fat can increase inflammation in the fat surrounding the blood vessels," Dr. Dobrian says. "The cross-talk between visceral fat, vascular fat and blood vessels is an exciting, novel concept that may explain better the complex relationship between obesity, diabetes and heart disease."

The researchers will use mice and donated human tissue — including blood vessels and fat cells — to determine if controlling the STAT-4 switch is safe and effective in preventing the development of disease. They also hope to better understand how IL-12 and STAT-4 work so they can identify targets for drugs that would control the inflammation.

"Right now we don't have any treatments like this. Nothing is on the market to target that kind of inflammation," Dr. Nadler says. "If this works, it will open up a whole new idea of how to treat people with obesity, with heart disease and maybe even prevent diabetes."