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How Obesity is Connected to Changes in Small Artery Function

An Investigator in the Center for Cancer Cell Biology, Immunology and Infection is homing in on the cellular and molecular mechanisms of obesity.

The United States leads developed nations in obesity with the rate of disease at 40 percent for adults and nearly 20 percent for children and adolescents, according to the Centers for Disease Control. Medical care costs for the many chronic conditions associated with obesity, including Type 2 diabetes, high blood pressure, cardiovascular disease and cancer, were estimated at $147 billion in 2008 dollars. The CDC adds to that estimate annual losses of productivity between $3 billion and $6 billion.

While the nation searches for prevention, treatment and policy solutions to the public health crisis, RFU Associate Professor of Physiology and Biophysics Carl White, PhD, is searching at the molecular level to discover how obesity, and the chronic inflammation it unleashes, may strangle the body’s smallest blood vessels, causing a cascade of serious health issues.

“I’m always struck that one of the first pathological manifestations of obesity is dysfunction in tiny blood vessels — the arterioles of the microvasculature,” Dr. White said. “This can be seen in obese children, well before we see any other of the more familiar pathological signs of disease like insulin resistance or hypertension. Right up front, we see a change in how small blood vessels function. So our big question is: How is obesity connected to changes in arteriolar function?

“Once we understand the mechanisms involved in how obesity makes us sick, we will be in a better position to target, manage, mitigate or reverse diseases at different stages in the process.”

Dr. White’s research team, which relies on the expertise of co-investigator Assistant Professor Joseph Reynolds, PhD, an immunologist, is focusing on the layer of fat tissue that shrouds most blood vessels in the body, with the exception of the brain. Called perivascular adipose tissue (PVAT), the fat was initially thought to act like padding to support and protect arteries. But a new understanding has developed over the past decade.

“We now know that there are signals coming out of this fat and going into the vessel to help it maintain its function,” Dr. White said. “In obesity, there are changes in the fat, so maybe something’s going on within the PVAT that is contributing to this microvascular dysfunction that we see so early on.”

Cells of the innate immune system called macrophages accumulate in the PVAT during obesity, recruited through chemotaxis, a process Dr. White likens to “following a chemical trail of breadcrumbs.” The cells sense and move toward signals released from adipocytes. Dr. White’s mentee, MD/PhD candidate Adriana Fresquez, developed a microscopy technique that captures macrophages undergoing chemotaxis.

“See these three little guys crawling, reaching out — extending what looks like tentacles and kind of feeling around,” Dr. White narrates a snippet of video. “They’re sampling the environment as they move to where they’re needed. And with obesity, when they get to where they’re going, they have their work cut out for them. They need to mop up free fatty acids and debris from dead and dying adipocytes. But we don’t know if they ever finish, because the problem is always there. It’s never resolved. And that contributes to the chronic inflammatory response we see in obesity.”

Dr. White postulates that it is these “cleanup” macrophages that change the function of the microvasculature. He points to an in vivo image of a constricted arteriole.

“They’re impairing the ability to dilate,” he said. “The arterioles are constantly constricted. They don’t relax. And that ability to relax is very important for normal functioning.”

It’s been known for years that artery function is impaired in many disease states, including obesity, Type 2 diabetes and in aging.

“Obesity changes the physiology of the fat tissue, which brings in the macrophages, which promote inflammation,” Dr. White said. “Whatever they’re releasing in the process we hypothesize drives the microvascular dysfunction that we think could contribute to more serious complications of obesity. If that is true, it opens the possibility of targeting macrophages as a way of preventing these complications.”

Dr. White grew up in Northern Ireland, where he earned a doctorate in physiology from Queen’s University Belfast. Ireland has one of the highest obesity rates in Europe, a trend he notices on visits home.

“It’s devastating to see it in younger people, especially with the insight of what it’s doing to their microvasculature and long-term health prospects,” he said. “Obesity presents a really intriguing problem. You take the human and you change one thing — increase the adipocyte size — and now you have what is a very complex, global problem.”

Posted August 20
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