"By looking at your genes, we can tell how fat you are and how your body fat will be distributed," said lead researcher C. Ronald Kahn, M.D., President of Joslin and the Mary K. Iacocca Professor of Medicine at Harvard Medical School. In lower animals, he added, it's long been known that genes play an important role in the body's development. "Genes tell the body where the head goes and where the tail goes, what goes on the front and what goes on the back. In insects, genes determine if the wings go on the front or back and whether they will be large or small. So it's not surprising that in humans, genes may determine how many fat cells we have and where they are located," he said.
Together with Joslin post-doctoral fellow Stephane Gesta, Ph.D., and colleagues at the University of Leipzig in Germany, the researchers for the first time used gene chips as a tool to understand what genes might control the development of fat inside the abdomen versus fat under the skin. The resulting study will be published online today, April 10, in the journal Proceedings of the National Academy of Sciences.
When it comes to obesity, the location of body fat can significantly impact one's risk for developing serious chronic diseases. Obesity, which is reaching worldwide epidemic proportions, is a major risk factor for type 2 diabetes, cardiovascular disease, cancer and other metabolic disorders. Doctors have long recognized that people who are "apple-shaped" -- with their fat concentrated in the abdomen -- are much higher risk for diabetes and metabolic syndrome than those whose fat is mainly subcutaneous, i.e., distributed beneath the skin primarily in the buttocks and thighs.
While recent studies at Joslin and elsewhere have shed light on the role of appetite and energy expenditure (physical activity) in obesity, little has been known about the role of genes in fat distribution or the association of genes in metabolic disorders like type 2 diabetes.
To investigate this question the researchers examined the genetic makeup of fat samples from around internal organs and under the skin of both mice and almost 200 human subjects ranging from normal to very obese, and including people with mostly abdominal obesity and people with subcutaneous and intra-abdominal obesity. Theorizing that fat distribution patterns -- and perhaps obesity itself -- may originate in the genes involved in control of development, the researchers found that as many as 12 developmental genes may play a role in different fat depots and that at least three of these seemed to be especially important in obesity.
The researchers compared levels of activity for these three genes --Tbx15, Gpc4, and HoxA5 -- in intra-abdominal and subcutaneous fat taken from individuals of normal weight versus overweight or obese individuals. "The differences we found in gene expression were so distinct," said Dr. Gesta, "that we could identify the body mass index (level of obesity) and the waist/hip ratio (whether the fat is in the abdomen or under the skin) in the overweight population by the expression level of these genes. This finding suggests that the expression of these genes could be related to the pathogenesis of obesity."
These results also suggest that different fat cell precursors are responsible for where the body stores fat. "While we don?t know yet whether this genetic activity is a cause or an effect of obesity," said Dr. Gesta, "these data do suggest that different forms of obesity could be a developmental problem that begins very early in life."
Can people outsmart their fat genes to alter the outcome? "Now that's the big question," said Dr. Kahn. "While we now can predict the fat pattern, we have no magic bullet to alter the outcome. But with these new findings, we have identified potential targets for perhaps one day changing body shape. We don't have drugs to alter the pattern now, but perhaps in the future we will."
Other Joslin researchers participating in the study were Yuji Yamamoto, Andrew W. Norris, M.D., Ph. D., Jeremie Boucher, Ph.D., and Choy Lewis. Researchers from the Department of Internal Medicine of the University of Leipzig were Matthias Blüher, M.D., Janin Berndt, and Susan Kralisch.
Funding for the study was provided by the National Institutes of Health, the American Diabetes Association, the Diabetes Genome Anatomy Project (DGAP), and the Deutsche Forschungsgeminschaft.
About Joslin Diabetes Center
Joslin Diabetes Center, dedicated to conquering diabetes in all of its forms, is the global leader in diabetes research, care and education. Founded in 1898, Joslin is an independent nonprofit institution affiliated with Harvard Medical School. Joslin research is a team of more than 300 people at the forefront of discovery aimed at preventing and curing diabetes. Joslin Clinic, affiliated with Beth Israel Deaconess Medical Center in Boston, the nationwide network of Joslin Affiliated Programs, and the hundreds of Joslin educational programs offered each year for clinicians, researchers and patients, enable Joslin to develop, implement and share innovations that immeasurably improve the lives of people with diabetes. As a nonprofit, Joslin benefits from the generosity of donors in advancing its mission. For more information on Joslin, call 1-800-JOSLIN-1 or visit www.joslin.org
Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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