A mutant rat that mimics a 400-pound human is helping scientists understand early vascular changes that make walking a pain for more than 2 million Americans.

"Everybody knows that obesity eventually causes diabetes and that when you have complications of the disease, you may even die," says Dr. David W. Stepp, cardiovascular researcher in the Medical College of Georgia Vascular Biology Center. "What is underappreciated … is that there are vascular changes and cardiovascular effects of obesity well before you become diabetic."

The Obese Zucker rat model shares the symptoms of obesity with a growing number of Americans. "For example, these animals are glucose intolerent, slightly hypertensive and showing protein in their urine. They have kidney dysfunction even though they are not yet diabetic," he says.

That is because small blood vessels in their kidneys already have begun to fail. All the fat rats eventually will get diabetes, but these ailing animals still have the same blood glucose levels as their lean peers. "When they go into frank diabetes, that pushes their kidneys over the edge. The goal of our lab is to use this model to examine vascular disease in other organs, especially the limbs."

Dr. Stepp recently received a $1.4 million grant from the National Heart, Lung and Blood Institute to study these early vascular changes, called peripheral vascular disease, that can result from obesity, smoking and inactivity.

His goal is to prevent a common condition with significant quality-of-life consequences. "The reason peripheral vascular disease is of interest to us is not because it kills but because patients with it often have quality of life indices worse than those of terminal cancer," Dr. Stepp says. "They can't walk. They don't have any mobility. They are not free. They feel humiliated and miserable."

Causes are multifaceted. "One of the things that goes on is the number of vessels shrinks," says Dr. Stepp, leaving legs, for example, starved for blood and oxygen. "What we think happens is the sympathethic nervous system, which makes blood pressure go up, is cranked up in obese individuals."

To make matters worse, obesity also changes energy use in the body, creating a state called insulin-resistance, a precursor for diabetes, that in the shorter term dumps more fat, or lipid, in the blood. Changed blood content affects sensitive blood vessel lining so vessels don't dilate well. That increased pressure decreases blood flow which gives surrounding tissue the wrong idea. "The dilator signal is not getting through, the constrictor signal is too high so blood pressure goes up and blood flow goes down," says Dr. Stepp. "If your blood flow is chronically low, your local organs say, 'Oh the flow is low. I must not need this vessel,' and it goes away. Anything you don't use atrophies."

Interestingly, lost vessels may not be missed until the person tries to be more active and the deprived tissue protests with pain.

"As long as you don't do that much, low blood flow is fine; you can function," says Dr. Stepp. "But now let's say you have a clot in one of your arteries and you need to increase blood flow to get around it. You can't do it. Now let's say you want to exercise. You can't do it. All the blood supply, all the reserve you think you are supposed to have, is gone."

He sees this in his Zucker rats. Lean rats love to run fast but the fat rats have dramatically reduced capacity for such sport.

"One of the things we would like to find out is, if we train the animals, can we get that capacity back? That we don't know. Nobody has done that."

Another key question is how much the revved-up sympathetic nervous system, reduced ability to dilate and structural changes in blood vessel linings each contribute to peripheral vascular disease. And, if you take one away, say with vasodilators to improve dilatation, does it fix the problem?

"One of the questions we are asking is how much of vascular disease is metabolic changes and how much is just from being obese? They go hand-in-hand, but which one is causing the disease? What if you subtract one of them out? Will you get it slower, or not at all or some mixed portion of it? If we can identify the root cause of the end-stage disease, we can design therapies to intervene early and develop better diagnostic tools," Dr. Stepp says.

So he looks at what happens to exercise capacity when the sympathetic nervous system is blocked or a nitrate patch is used to improve impaired dilation.

"The holy grail of all this is if you can figure out how obesity impairs vascular fucntion and how exercise makes it better and bottle it," he says, acknowledging obvious questions about why obese people can't just exercise. "While it's easy to say 'go exercise,' people who are genetically obese (about 50 percent of the obese population) or who have been obese all their lives may have trouble exercising intensely enough to improve vascular function. By indentifying ways to mimic the positive effects of exercise in an obese population, we may come up with new ways to treat all patients who have peripheral vascular disease."