February 2001

From Whitehead Institute for Biomedical Research

Researchers discover weight-loss compound that doesn’t affect food intake

Researchers from the Whitehead Institute and Genset Corporation have found a new compound that controls weight gain in obese mice without affecting their food intake. The compound, called gAcrp30 and administered in daily low doses, caused profound and sustained weight loss in chubby mice eating a cafeteria diet—meals high in fat and sugar and available in unlimited quantities. Continuing the low daily doses allowed the mice to keep the weight off over a sustained period of time despite their fattening diet. The results will be published in the Proceedings of the National Academies of Science on February 6 on the web and on February 13 in print.

"The human gAcrp30 protein was used in these mouse studies," says Harvey Lodish, Member of the Whitehead Institute for Biomedical Research and lead author of the paper, "but much further research is needed to determine whether this substance can be used in man as an aid in weight loss. Such a therapy is urgently needed by the many thousands of obese patients who suffer from many related health problems such as diabetes,"

Humans have developed a very efficient mechanism to store fat—a survival mechanism that allowed our hunter-gatherer ancestors to withstand long periods of time without food. However, this boon has become a curse for us in modern times, with our constant, abundant food supply. Food is broken down in our intestines to form free fatty acids, which are then absorbed by the body and circulate in the blood. When we don’t expend energy the free fatty acids can be stored for the long term as fat or converted to sugar and stored for short-term use as glycogen About five years ago, researchers from Harvey Lodish’s lab cloned a protein secreted only by fat cells. Called Acrp30, this protein was suspected to be a hormone, but not much was known about its function. The protein was patented by Whitehead Institute and licensed to Genset in 1999. Over the past year, researchers at Whitehead Institute and Genset discovered that one particular fragment of Acrp30, called gAcrp30, is naturally produced by the body and works in a completely different manner compared to most available weight-loss agents.

Most weight-loss drugs work by either preventing the body from absorbing fatty acids in the intestine or inhibiting the break down of fatty acids so they are excreted from the body rather than get stored as fat. In contrast, the gAcrp30 circulates in blood and causes muscle to burn fatty acids faster so they are not stored as fat. The result is weight-loss without the complications of having fatty acid pass through the body. This is especially significant since 25% of our weight is muscle, making muscle quantitatively the most important tissue to remove fatty acid from the blood circulation and use it for energy.

The mice treated with gAcrp30 showed significantly reduced levels of free fatty acids as well as decreased glucose and triglyceride levels in their blood despite their high-fat diet. Even treated mice that were directly injected with fat showed these lowered levels indicating that the protein rids the body of fatty acids without interfering with intestinal absorption.

The title of the paper is "A Proteolytic Cleavage Product of ACRP30 Increases Fatty Acid Oxidation in Muscle and Causes Weight Loss in Mice." The Authors are:
Joachim Fruebis, Genset Corporation
Tsu-Shuen Tsao, Whitehead Institute
Sandrine Jvorschi, Genset Corporation
Dana Ebbets-Reed, Genset Corporation
Mary Ruth S. Erickson, Genset Corporation
Frances T. Yes, Genset Corporation
Bernard E. Bihain, Genset Corporation
Harvey Lodish, Whitehead Institute












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