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A Big Fat Problem
The Basic Science of Obesity

by Jeff Worley

Photo of Eric Smart and Haining ZhuEric Smart (left) in UK's Department of Pediatrics and Haining Zhu in the Department of Biochemistry are collaborating to identify "obesity proteins." The basic science of obesity is the first step, Smart says, on the road toward human clinical trials.

Eric Smart's research is focused on our body's housekeeper and frontline defender—macrophages. When these cells spot an unwanted intruder, they reach out with a pseudopod, ensnare it, and gobble it up. Macrophages are the Good Guys.

Well, not always, says Eric Smart, a UK professor of pediatrics and Barnstable-Brown Chair in Diabetes. "Basically, bad nutrition can do them in. When people eat a lot of bad things, macrophages do their best at damage control by disposing of some of these things, but if they eat too much they become bad things themselves. Poor eating habits can change the function of macrophages," Smart explains, "and obesity plays a clear role in turning macrophages bad."

When someone is obese for a long time, he continues, macrophages begin to participate in an inflammatory process. Long-term activation of macrophages will kill the pancreas, cause plaques to form in the aorta, and increase the risk of heart attack and stroke. Smart knew that macrophages were an important piece of the obesity puzzle, and three years ago he began a study to find out exactly what roles these natural scavengers play.

Illustration of macrophagesWhen macrophages, the body's frontline defenders, spot unwanted intruders such as these bacteria, the cells reach out with a pseudopod, ensnare the intruders and gobble them up.

In his lab at UK's Sanders-Brown Center on Aging, Smart and his staff began by isolating macrophages from normal-weight mice, which is easily done through a blood sample. Next, the researchers fattened up the mice and took another blood sample, again isolating the macrophages. Then the mice were put on strict diets and exercised so they would return to their original weight. A third blood sample was taken.

"What we've been interested in all along is proteins that change at these different stages," Smart explains, "not genes, but proteins. Lots of genes change, but that doesn't have any direct effect on function. If proteins change, that usually causes a direct functional effect."

Smart and his group are looking specifically at a special piece of the macrophage membrane, called a lipid raft, which functions like an air traffic control tower. This raft moves within the membrane—it actually floats—which is how it got its name. Basically, Smart explains, a lipid raft controls signals from outside and inside the membrane, and directs them to where they should go.

"We already know that fat and cholesterol directly affect the lipid rafts," says Smart, "and that diet will change them. What we're doing now is looking more intensely at the functions of these rafts."

The researchers are isolating these pieces of membrane to do a protein search. "Lipid rafts in normal animals contain around 250 proteins," says Smart. "What we're looking for is protein change after the mice are obese. What proteins are present now that weren't before? What proteins disappeared?" Proteins unique to the raft when the animal is obese could possibly be harmful, which is why they are the focus of interest. The flip side of the question is also important: What proteins have disappeared? These may have been contributing to good health, so it's important to identify them if, now, they are missing in action.

Then there's the third stage of weight control, when the mice are returned to normal. "It's interesting that when the animals are brought back to their original weight, the protein complex is not the same as it was initially. The difference in the proteins that show up in this stage is something very important to look at because it has important clinical implications," Smart says. "We know, for example, that there's a residual effect when obese people go back to normal weight; they don't really get back to baseline 'normal.' They still tend to have some health problems related to their previous obesity."

If Smart and his staff discover that certain proteins don't "come back" in the post-obesity phase in humans, these proteins could be targeted and replaced with a drug or a treatment. And Smart's lab is already out in front of this.

"Part of my team is working to understand the why and how of these protein changes. The other part of my lab is looking at different drugs that are known to affect particular proteins."

Smart says that he couldn't even attempt a project like this without the postdocs and grad students who work long hours in the lab. In addition to this team effort, there's another "essential player" in the mix.

"Our lab does all the biology—it's very intensive work, collecting the macrophages and going through the analysis. Then our partner, Dr. Haining Zhu in molecular and cellular biochemistry, does the chemical analysis." Zhu is an expert in proteomics—the identification, characterization and quantification of all proteins involved in a particular pathway, cell or tissue. In his work with Smart, he characterizes the proteins found in the lipid rafts in each stage of mouse weight. "It's a great partnership," Smart says.

Photo of boy with his father's arm around him

So what about clinical trials with humans? Is that part of Smart's game plan?

"Yes, absolutely. What our animal studies will do is give us good candidates for drugs that can be used in therapy, and then we need to set up our own human study to see if what we've discovered is applicable to kids," he says, clearly excited by this prospect. "And because we have people here like Joan Griffith, Jody Clasey and Jim Anderson, we can do that, right here at UK.

"What's crucial is to get kids to lose excess weight as quickly as possible, because the shorter the time you're obese, the less damaging the long-term effects are."

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