The technique detects fat accumulation in cells of the beating heart in a way no other clinical method can, the researchers said, and may provide a way to screen patients for early signs of heart disease in diabetes. Hearts beat; people breathe; and magnetic resonance imaging is very sensitive to motion, so we had to find a way to electronically freeze' the image of the heart, said Dr. Lidia Szczepaniak, assistant professor of internal medicine at UT Southwestern and senior author of a study appearing in the Sept. 4 issue of Circulation. We wanted a noninvasive method to study the beating human heart, Dr.  Szczepaniak said. Dr. Szczepaniak and her colleagues developed a technique that captures the signal from a beating heart as a person lies in an ordinary magnet used for MRI scanning. The researchers knew that fat builds up in the hearts of people with heart failure or non-insulin-dependent diabetes (type 2) from earlier studies involving patients undergoing heart transplants, but they didn't know if this fatty buildup occurred before or after the diabetic conditions developed.   There is currently no way to clinically evaluate the fatty heart, Dr. Szczepaniak said. Using this technique, which analyzes magnetic signals, we might be able to determine if people are prone to heart disease very early before the disease progresses. This method might also allow us to measure the effectiveness of medical treatments targeted toward lowering fat in the heart. In the new study, the UT Southwestern researchers used an ordinary MRI system, but added the newly developed computer software to convert the signals from a moving heart into a single image. They looked at lean and obese people with normal blood sugar, obese people beginning to show abnormal sugar metabolism, and obese people with full-blown type 2 diabetes. Their most important finding, Dr. Szczepaniak said, was that fat buildup in the heart develops before the onset of diabetes. They also found that the amount of fat in the heart of people with abnormal sugar metabolism was significantly higher than in those with normal blood sugar, whether obese or lean. The amount of fat in the heart was unrelated to the amount of fat in the bloodstream or liver, indicating that measuring any of those factors could not predict accumulation of fat in the heart. Fat in the heart did correspond to the amount of fat in the stomach region, however. The researchers recruited some participants from the Dallas Heart Study ” a multi-ethnic, population-based study of more than 6,000 patients in Dallas County designed to examine cardiovascular disease. Detecting fat in heart cells is especially important because once a heart cell dies, it is not replaced by a new one, as happens in many other tissues, said Dr. Roger Unger, professor of internal medicine at UT Southwestern and a co-author of the paper. When you lose a heart cell, that's it ” you can't get it back. Some researchers, including those at UT Southwestern, believe that as a person becomes over-weight, fat accumulates in normal fat cells, but eventually fat cells can't store fat any more. Eventually the excess of fat kills other cells ” a hypothesis supported by a recent study by Dr. Unger in mice. Dr. Szczepaniak is translating our rodent studies into humans, and that is a huge technological breakthrough, Dr. Unger said. But Dr. Unger also cautioned that no sophisticated test can replace common sense in fighting obesity: You don't need a fancy test to tell a patient not to eat too much. Other UT Southwestern researchers involved in the study were Dr. Jonathan McGavock, former postdoctoral fellow in internal medicine; Dr. Ildiko Lingvay, assistant professor of internal medicine; Dr. Ivana Zib, former medical fellow; Tommy Tillery, magnetic resonance imaging technician; Naomi Salas, former research assistant; Dr. Benjamin Levine, professor of internal medicine; Dr. Philip Raskin, professor of internal medicine; and Dr. Ronald Victor, professor of internal medicine. The work was supported by the Heart and Stroke Foundation of Canada, the Canadian Institutes for Health Research, the Canadian Diabetes Association, the National Institutes of Health, the American Diabetes Association, the Donald W. Reynolds Foundation and Takeda Pharmaceuticals North America Inc.

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The gene, called adipose, was discovered in fat fruit flies more than 50 years ago by a graduate student at Yale University, but few people knew about it. Its mechanism was unknown, and whether it's important in other genes was a mystery. In the current study, the UT Southwestern researchers examined how adipose works by analyzing fruit flies, tiny worms called C. elegans, cultured cells, and genetically engineered mice, as well as by exploiting sophisticated molecular techniques. Using several methods, they manipulated adipose in the various animals, turning the gene on and off at different stages in the animals' lives and in various parts of their bodies. It was discovered that the gene, which is also present in humans, is likely to be a high-level master switch that tells the body whether to accumulate or burn fat. In the mice, the researchers found that increasing adipose activity improved the animals' health in many ways. Mice with experimentally increased adipose activityate as much or more than normal mice; however, they were leaner, had diabetes-resistant fat cells, and were better able to control insulin and blood-sugar metabolism. In contrast, animals with reduced adipose activity were fatter, less healthy and had diabetes. The researchers' work on flies showed that the gene is dose-sensitive ” that is, the various combinations of the gene's variants lead to a range of body types from slim to medium to obese.  This is good news for potential obesity treatments, because it's like a volume control instead of a light switch; it can be turned up or down, not just on or off, Dr. Graff said. Eventually, of course, the idea is to develop drugs to target this system, but that's in the years to come. This genetic mechanism makes survival sense, he said, because if a population has many versions of the gene scattered among many different individuals, at least some will survive in different conditions. For instance, a fat fruit fly may be able to survive famine, but a sleeker model might be better at evading predators. Dr. Graff said the next step is to understand better the exact mechanisms by which adipose exerts its control. Although the current study finally identifies the adipose gene's function, the gene was discovered more than 50 years ago when Winifred Doane, now a professor emeritus at Arizona State University, was studying fruit flies and noticed that some contained more fat than others. She linked this trait to a gene she named adipose and hypothesized that this natural variation gave the chubbier flies an evolutionary advantage; they could hoard more fat on the same amount of food as their skinnier counterparts, allowing them to survive times of famine. But for people in developed countries, this trait has backfired. It's all feast and no famine, so the fat builds and builds. Even a pound a year adds up over a lifetime, Dr. Graff said. Other UT Southwestern researchers involved in the study were Dr. Jae Myoung Suh, postdoctoral researcher in developmental biology; Daniel Zeve, Robert Li and Michael Wang, students in the Medical Scientist Training Program; Dr. Renee McKay, instructor of developmental biology; Dr. Jin Seo, postdoctoral researcher in developmental biology; and Zack Salo, undergraduate at UT Arlington. The work was supported by the National Institutes of Health.

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