Just about everyone by now knows the importance of limiting fat intake. But for a few individuals,
a scarcity of fat is the real problem. Researchers in the Center for Human Nutrition have been awarded a $1.6 million grant from the National Institutes of Health to study a rare disorder characterized by a partial or complete lack of body fat; research that may expand understanding of common forms of obesity.
The four-year grant from the National Institute of Diabetes and Digestive and Kidney Diseases will allow investigation of the genetic and metabolic basis of inherited forms of lipodystrophy. Researchers will look for the genes responsible for two conditions -- congenital generalized lipodystrophy and familial partial lipodystrophy-Dunnigan (FPLD).
Individuals with congenital lipodystrophy are born with almost no body fat. Those with FPLD lose subcutaneous fat from their extremities and trunk at the onset of puberty but gain excess fat in the head, neck and abdomen. Both groups appear extremely muscular yet suffer the same complications as obese people: insulin resistance, glucose intolerance, diabetes and high blood lipids.
British teen age siblings Melanie and Renaldo Watt have been treated by Dr. Abhimanyu Garg, center researcher and principal study investigator of the project. Melanie has been unable to attend school for almost two years because of the uncontrollable diabetes brought on by congenital generalized lipodystrophy.
"When Melanie was born, we noticed that she'd eat a lot but not gain weight," said her mother, Jean Watt. "She was not chubby like babies get. She was really thin but muscular. It was strange for a baby to look so strong." After a two-week stay in UT Southwestern's Clinical and Translational Research Center (CTRC) at Parkland Memorial Hospital, Dr. Garg prescribed a low-fat diet and strict control of her diabetes with highly concentrated insulin.
"Some fat is essential. Too much is bad, but too little is probably worse," Dr. Garg said. "People used to think of fat as an inert tissue -- that it didn't perform any function. But we know that it definitely performs vital functions. "The most important function of fat is to store energy. But it also is involved in the conversion of male hormones, or androgens to estrogens; stores fat-soluble vitamins; and provides thermal protection.
Last year Dr. Garg and colleagues pinpointed the location of the gene that causes FPLD on chromosome 1, but they have not yet isolated the gene. Studies are underway to find the location of the gene that causes congenital lipodystrophy.
"If we can find out why these genetic defects cause loss of fat and also cause complications associated with insulin resistance, hopefully we will learn more about common types of obesity," said Dr. Garg, an associate professor internal medicine.
The disorders are extremely rare, with congenital lipodystrophy affecting roughly one in 12.5 million people, and FPLD affecting roughly one in 25 million. Obesity, on the other hand, affects more than half the population in some countries. About 97 million American adults are overweight or obese. "The identification of genetic defects will allow us to define the normal role of these genes in the growth and development of body fat during embryonic life and at the start of puberty," said Dr. Garg. "We will also elucidate how these genes affect the action of insulin on the fat cells, which will lead to a better understanding of how common obesity causes insulin resistance and other metabolic complications."
Researchers will study dozens of families in the CTRC, testing them for glucose and fat metabolism. Whole-body magnetic resonance imaging will be employed to characterize the extent and location of fat loss -- a technique developed at UT Southwestern. DNA samples from family members will be used to find genes responsible for these disorders.
Other investigators on the project include: Dr. Ronald Peshock, professor of radiology and internal medicine; and Dr. Peter Snell, assistant professor of internal medicine.
