Apr. 23, 2003 La Jolla, Calif. -- A cellular receptor that balances the accumulation of fat and fat burning in the body may be a new target for anti-obesity and cholesterol-fighting drugs, according to a Salk Institute study.
The study, published in the April 18 issue of Cell, identified the function of this key receptor for the first time. The receptor, called PPARd, was found to regulate how fat is used and could point the way to new treatments for obesity as well as its associated lethal medical complications: type II diabetes, cardiovascular disease, hypertension and atherosclerosis.
Professor Ronald M. Evans, the March of Dimes Chair in Developmental and Molecular Biology at the Salk Institute and Howard Hughes Medical Institute investigator, and his team found that stimulating PPARd -- short for peroxisome proliferators-activated receptor -- depleted fat deposits in mice, while mice deficient in PPARd were prone to obesity.
PPARd was shown to regulate the rate by which fat is burned to produce heat or is used to maintain normal cell functions. The process of uncoupling energy from work production to heat generation, known as adaptive thermogenesis, is generally regarded as a physiological defense against obesity.
"We have long known that excess calories are warehoused in fat tissue for future use," said Evans. "We also know that fat is released and consumed in times when energy is needed, such as from exercise or shivering from cold exposure. This study shows us that PPARd is an important regulator of this function. By exploiting PPARd, we hope to design drugs that can control how much fat is stored in the body."
The team found that mice with an activated PPARd gene weighed about 20 percent less than normal mice, even though both groups received the same food at the same rate. Once the mice were a year old, the difference in weight widened, to 35 percent less for the genetically active PPARd mice.
At the same time, activated PPARd protects mice against diet-induced obesity. Mice that had the active PPARd gene did not show significant weight gain over a month's time, despite having a high-calorie, high-fat diet. Mice without the active gene, however, became obese. In addition, a short-term treatment of the obese mice with a molecule that activated PPARd caused a dramatic reduction in fat in their tissues.
"PPARd activates an array of genes that are required for fatty acid combustion and uncoupling, but does not activate genes that are involved in the formation and storage of fats," said Evans. "We show then, that PPARd coordinates fatty acid oxidation (burning) and energy uncoupling to regulate the use of fat."
Obesity is now considered an epidemic in the United States. About 65 percent of Americans are considered overweight, and some states report an obesity rate of over 20 percent of their populations. The condition is strongly linked to some of the leading causes of death in the United States, including high blood pressure, heart disease and diabetes. Deaths due to overweight conditions kill more than 300,000 people a year, second only to tobacco-related diseases, according to the U.S. Centers for Disease Control.
The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and conditions, and the training of future generations of researchers. The institute was founded in 1960 by Jonas Salk, M.D., with a gift of land from the City of San Diego and the financial support of the March of Dimes Birth Defects Foundation.
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