The research team led by Gary Ruvkun, PhD, of the MGH Department of Molecular Biology, and postdoctoral fellow Kaveh Ashrafi, PhD, identified about 400 genes encompassing a wide range of biochemical activities that control fat storage. These studies were conducted using the tiny roundworm Caenorhabditis elegans, an organism that shares many genes with humans and has helped researchers gain insights into diseases as diverse as cancer, diabetes, and Alzheimer's disease.
Many of the fat regulatory genes identified in this study have counterparts in humans and other mammals. "This study is a major step in pinpointing fat regulators in the human genome," says Ruvkun, who is a professor of Genetics at Harvard Medical School. "Of the estimated 30,000 human genes, our study highlights about 100 genes as likely to play key roles in regulation of fat levels," he continued. Most of these human genes had not previously been predicted to regulate fat storage. This prediction will be tested as obese people are surveyed for mutations in the genes highlighted by this systematic study of fat in worms.
In addition, this study points to new potential therapies for obesity. Inactivation of about 300 worm genes causes worms to store much less fat than normal. Several of the human counterparts of these genes encode proteins that are attractive for the development of drugs. Thus, the researchers suggest that some of the genes identified could point the way for designing drugs to treat obesity and its associated diseases such as diabetes.
To discover this treasure trove of fat regulators, the researchers inactivated genes one at a time and looked for increased or decreased fat content in the worms. Through this time-consuming process, they identified about 300 worm genes that, when inactivated, cause reduced body fat and about 100 genes that cause increased fat storage when turned off. The identified genes were very diverse and included both the expected genes involved in fat and cholesterol metabolism as well as new candidates, some that are expected to function in the central nervous system.
About 200 of the 400 fat regulatory worm genes have counterparts in the human genome. "A number of these worm genes are related to mammalian genes that had already been shown to be important in body weight regulation. But more importantly, we identified many new worm fat regulatory genes, and we believe that their human counterparts will play key roles in human fat regulation as well," says lead author Ashrafi. "The work was done in worms because you can study genetics faster in worms than in other animal models, such as mice," says Ashrafi. "The model is a great tool for discovering genes."
About 600 million years ago the common ancestor to worms and humans also stored fat and regulated its feeding and metabolism based on communication between its stored fat and the brain centers that control feeding. Both the worm and humans have inherited this complex system from that ancestor. It is likely, the researchers say, that failure of these circuits within our bodies is one of the underlying causes of obesity and that drugs can be developed to correct these missing circuits of metabolic communication. The challenge now is for scientists to unravel these regulatory pathways and prioritize the relevant genes in animal models, such as the worm and the mouse.
The researchers also found that some of the identified genes were effective at regulating fat levels in all strains of C. elegans but others could only regulate fat in certain worm obesity syndromes caused by brain defects. The brain also is an important player in the regulation of human fat. Some human obesity syndromes are due to defective assessment of fat levels by the brain that lead to a continuous voracious appetite. Some of the newly identified worm fat regulatory genes are predicted to function in its nervous system, as are the human counterparts to these worm genes.
The work was dependent on the use of an RNA-mediated interference (RNAi) library constructed by the MGH team's collaborators at the Wellcome/Cancer Research Institute in England. The library consists of individual genetic components that each disrupt the expression of one particular gene. With this tool, the researchers were able to systematically screen almost 17,000 worm genes for their potential roles in fat storage.
The other members of the research team are Francesca Chang of the MGH, Jennifer Watts, PhD, of the Institute of Biological Chemistry at Washington State University, and Andrew Fraser, PhD, Ravi Kamath and Julie Ahringer, PhD, of the Wellcome/Cancer Research UK Institute. The study was supported by funds from the National Institutes of Health, the Damon Runyon/Walter Winchell Cancer Research Fund, the U.S. Army, Howard Hughes Medical Institute, and the Wellcome/Cancer Research UK Institute.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $300 million and major research centers in AIDS, cardiovascular research, cancer, cutaneous biology, transplantation biology and photomedicine. In 1994, the MGH joined with Brigham and Women's Hospital to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups and nonacute and home health services.
Journal
Nature