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Obesity heightens the risk of type 2 diabetes and coronary heart disease, but not everyone who becomes obese gets sick. Why is it that a few lucky individuals who gain weight on potato chips, Big Macs and ice cream escape these diseases, while most others suffer heart attacks and other grievous complications?

New research at the Harvard School of Public Health (HSPH) offers insight. In part owing to a simple change in the DNA code that make up one gene, a fortunate few who consume high-fat diets can put on pounds without the expected risk of skyrocketing blood sugar, atherosclerosis, heart attack, and more. That's because a rare, subtle variation in the gene's normal makeup makes them partly immune to metabolic syndrome—a cluster of coronary and diabetic risk factors that include insulin resistance, hypertension, and high levels of LDL ("bad") cholesterol.

obese mouse and normal mouseUnderstanding how the rare variant works could signal a breakthrough in treating metabolic diseases, according to Gökhan Hotamisligil, the James Stevens Simmons Professor of Genetics and Metabolism at HSPH. Mimic its effects with the right drug, he says, and millions of people could reap the benefits. Meanwhile, one could devise a simple blood test useful for screening people for susceptibility to metabolic problems early in life, then take aggressive steps to mitigate their disease risk.

More than a milestone for research on metabolism, the new finding showcases how discoveries in laboratory animals can be applied to human populations. It was evidence in mice that led Hotamisligil and his collaborators to investigate the gene variant’s protective effects in two of the largest human studies in the world: the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS), both administered jointly by the Harvard School of Public Health and Brigham and Women's Hospital, in Boston.

With a combined sample size of about 160,000, these studies match health-status and lifestyle data with molecular information extracted from blood samples and other biological specimens, with the aim of identifying factors that promote diseases or protect people from them. The studies' ample cache of data allowed scientists to tie the gene variant to metabolism in humans. This variant, which turned up in just under four percent of subjects, might never have been found in a smaller cohort.

Making knockout mice
The HSPH findings were announced in the Proceedings of the National Academy of Sciences (PNAS) on May 2, 2006. But the story begins at the Dana-Farber Cancer Institute in the mid-1990s, when Hotamisligil, now chair of HSPH's Department of Genetics and Complex Diseases, was a PhD student.

In a quest to learn how young cells mature into fully-functioning adult cells (or don't, as in some cancers), he and other researchers were studying a mysterious lipid (fat) binding protein called aP2 and its role in fat cell metabolism. Previous studies had shown that mature fat cells made high levels of aP2, while in the younger, precursor cells, the protein was scarcely detectable. Suspecting that aP2 helped fat cells mature, the scientists produced a strain of mice whose aP2 gene was genetically disabled, or "knocked out."

Given the aP2 protein's abundance in normal fat cells, the team expected their knockout mice to be in big trouble, with high lipid levels and other hallmarks of metabolic disruption. To the contrary, the mice appeared perfectly normal. “They couldn’t have cared less, they had no problems whatsoever,” Hotamisligil recalls with a chuckle.

Was there more to these mice than met the eye? Knowing that aP2's only known role was to bind lipids, Hotamisligil fed the mice a high-fat diet, betting that lipid overload might fail to trigger metabolic abnormalities.

That hunch proved dead right. Though the mice grew plump, they did not develop the telltale signs of metabolic syndrome that would have appeared in animals with a functioning aP2 gene. In fact, as reported in Science in 1996, the rodents were remarkably healthy, with reduced insulin resistance, the precursor to type 2 diabetes.

When Hotamisligil moved to HSPH to take a job as assistant professor, he started tackling the collective biology of lipid-binding proteins in body metabolism. In collaboration with Linton McRae from Vanderbilt University, he made a startling discovery: these proteins also played a big role in macrophage cells of the immune system. As described in Nature Medicine in 2001, the proteins’ function turned out to be critical in atherosclerosis: aP2-deficient mice were dramatically protected from heart disease, even on diets that shot their cholesterol sky-high.

This work prompted Hotamisligil’s next step: He blocked both aP2 and a sister lipid-binding protein from fat cells and macrophages called mal1, creating a new knockout mouse strain. These double mutants, he says, were "metabolic supermice." No matter how much fat they ate, or how high their cholesterol levels were, these mice were protected from insulin resistance, atherosclerosis, diabetes, liver disease—even obesity. "You couldn’t kill those animals," says Hotamisligil, whose lab described the findings in Cell Metabolism. "They were unbelievable."

Where did the protection come from? Hotamisligil surmises that the proteins--aP2 in particular--help drive inflammatory processes that, in turn, fuel metabolic disorders, which range from type 2 diabetes to atherosclerosis to asthma. Somehow, he says, the cellular machinery in the second knockout mouse strain became "blind" to dietary fat overload and harmlessly burned off the extra energy.

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Illustration: Peter Horvath

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