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Humans: the next frontier
One could now search for the human equivalent of the mouse double mutant, Hotamisligil realized. "It could turn out to be one of those rare but highly annoying people you might know--someone who eats all the junk and doesn't exercise, but remains slim and healthy," he says.

Hotamisligil wondered next whether people with an inherited aP2 deficiency might be protected against metabolic disease. So he joined forces with an old friend, HSPH Associate Professor Eric Rimm, an epidemiologist, and together they planned a major study in humans.

Research by Rimm, an expert on obesity and heart disease in human populations, ran parallel to Hotamisligil's work in mice. What's more, Rimm had access to samples from the NHS and HPFS cohorts. "We saw this as a perfect match in terms of uniting basic science and human epidemiology," Rimm says.

OF MICE AND HUMANS Research Associate Gurol Tuncman (left) and Associate Professor in the Department of Epidemiology Immaculata De Vivo have helped identify a natural variation in a gene in mice and humans that lowers the risk of obesity and other metabolic disorders. Photo by Kent Dayton/HSPH

In a pilot project using 96 NHS blood samples, Rimm, Hotamisligil, and others at Harvard--including HSPH Vincent L. Gregory Professor of Cancer Prevention David Hunter, director of the Program in Molecular and Genetic Epidemiology, and Associate Professor of Epidemiology Immaculata De Vivo--sequenced the human gene for the aP2 protein and found five variations. One in particular, T-87C, looked especially promising. It was identified chiefly by HSPH Research Associate Gurol Tuncman, who confirmed its aP2-blocking properties in the lab. His work led the team to predict that humans with the T-87C variant would be partially protected from diets high in unhealthy fats, just as the knockout mice were.

They were right. Drawing on nearly 8,000 NHS and HPFS blood samples, the scientists found that people with the T-87C variant were far less likely to have metabolic syndrome than people without it. Tuncman, lead author of the PNAS paper, says that relative risks for heart disease among T-87C carriers dropped by 34 percent. For type 2 diabetes, the risk fell by 48 percent among highly vulnerable obese participants. The variant was also associated with a 12 percent decline in blood triglycerides, fats known to exacerbate heart-disease and stroke risk.

"The really lovely thing is, we found a variant in humans that was an exact replica of the variant in mice. Then, we were able to assign a function to that variant in terms of metabolic protection," Tuncman says. "In other words, we were able to complete that loop."

A simple blood test?
The work has impressed one of the world's leading experts on the genetics of obesity. Rudy Leibel, head of the Division of Molecular Genetics at Columbia University College of Physicians and Surgeons, says the study "reflects a paradigm of animal-to-human research that many of us hope will reveal disease pathways of great interest."

The discovery does have its limitations. Because the NHS and HPFS cohorts are mainly Caucasian, "we don't know if the results will be applicable to other ethnic and racial populations," Hotamisligil cautions. Beyond that, the findings have "huge implications," he asserts. Studies are emerging to show that the aP2 gene can be chemically modified, suggesting its expression could be blocked with drugs as a way of tempering patients' metabolic problems. Moreover, as Tuncman noted, aP2 leaks from fat cells into the bloodstream. Already Rimm and Hotamisligil are on their way to another exciting goal: a simple blood test for metabolic disease.

Moving forward, the HSPH group will explore the aP2 gene variant's power to protect against another obesity-related disease: asthma. Data recently published in the Journal of Clinical Investigation by Hotamisligil and collaborators show aP2 knockout mice are resistant to this respiratory disorder. Might human carriers of the aP2 variant be similarly protected? "This story," Hotamisligil says, "just gets more interesting with time."

Charlie Schmidt writes about health, science, and the environment for the Washington Post, Environmental Health Perspectives, and National Geographic Online.

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Illustration: Peter Horvath

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