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Investigating the Perils of Obesity

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  • Title: Assistant Professor, University of Michigan
  • Education: MD/PhD, University of Michigan, 2000
  • Recommended by: Alan Saltiel

As a pediatrician, the University of Michigan's Carey Lumeng has been watching the rise of obesity among children. Along with obesity come diseases such as asthma and diabetes, among others, but exactly why too much fat is so bad for people is still not known. Lumeng suspects it has something to do with inflammation. "There have been a wide variety of genomic studies that have also validated the idea that inflammatory markers are strongly associated with obesity as well as diabetes," Lumeng says.

Some of those screens found that macrophages are a component of the inflammatory response, and other studies have shown that macrophages invade fat tissue. "I think the bulk of the literature now has demonstrated pretty strongly that … these macrophages actually [are] required to generate inflammation with obesity and, in fact, if you get rid of them or block their function, the mice don't get diabetes," he says.

But macrophages are also found in other, normal tissues where they do not cause problems. The question there, Lumeng says, is: "Why is one in one context maybe OK and in the other context maybe bad for you?" Indeed, there are different types of macrophages, M1 and M2, as Lumeng and his colleagues published a little more than a year ago. Lean mice, he says, have M2 macrophages and obese ones have M1 types, but what triggers the switch between the types is not yet known, nor is it clear whether the findings in mice will be smoothly translated to people.

"My lab's going to be looking at this in human tissue and, in addition, we're going to be trying to understand what regulates one type of macrophage, the good macrophage for example the M2s, and what regulates the bad guys, the M1s," Lumeng says.

One method that his lab is already using to study these macrophages is a new imaging approach. Fat, Lumeng says, is difficult to cut and tends to auto-fluoresce. To get a better look, his team has been using confocal microscopy on whole pieces of tissue. "It just lets us get a depth of imaging that looks at all the different cells in three dimensions at a much higher resolution," he says. As his lab gets up and running and starts collecting samples from patients — including those who have undergone bariatric surgery — and from different types of fat tissue, Lumeng hopes to be able to use high-throughput drug screening and genomics.

Publications of note

It was in the January 2007 issue of the Journal of Clinical Investigation that Lumeng and his colleagues first proposed their model of different types of macrophage activation and how that activation is altered in obesity. In a Diabetes paper published online in October, Lumeng starts to address the mechanisms behind this by using flow cytometry, immuno-fluorescence, and expression analysis.

Looking ahead

Lumeng says that the next few years will accelerate how people understand the role of inflammation in obesity, especially in diabetes. Already, Lumeng says that some diabetes drugs that were thought to target fat cells have been found to actually focus on macrophages. He also says there are more diabetes drugs in the pipeline that target inflammation.

And the Nobel goes to …

If Lumeng were to win, he hopes it would be because he found a way to stop the negative effects of obesity by addressing inflammatory changes. "Clearly this is going to be a huge issue in the next decades because all the obese children are going to become obese adults," Lumeng says.

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