Genes in Overweight Mice, Rats Carry Instructions for Leptin Receptor

The diabetes (db) gene in mice and the fatty (fa) gene in rats are not only the same genes, they also carry instructions to make the receptor for the protein called leptin, which is known to signal the body’s fat, report scientists at The Rockefeller University and Millennium Pharmaceuticals Inc., in the Feb. 16 Science.

Using genetic mapping techniques and gene analysis, the scientists, led by Streamson C. Chua Jr., M.D., Ph.D., assistant professor and Rudolph L. Leibel, M.D., associate professor and codirector of the Laboratory of Human Behavior and Metabolism, identified similarities in the two genes. Previous research at Rockefeller and elsewhere showed that mice and rats with mutated versions of the db and fa genes are overweight and usually develop diabetes. They also have high levels of leptin, yet remain fat.

“Finding mutations in the gene that makes the receptor for the obese gene product in two different mammals, mice and rats, increases the likelihood that we will find mutations in the gene in humans and other mammals as well,” Leibel says. “We suspect that because of the relationships between rodent and human genes, a similar gene is likely to reside on the human chromosome 1.”

In 1995, a receptor for leptin was cloned by Louis Tartaglia, Ph.D., of Millennium Pharmaceuticals in Cambridge, Mass. In the work reported in the current paper, the Rockefeller investigators and Tartaglia precisely located the leptin receptor gene in the mouse and rat genetic material and demonstrated thatdb and fa are mutations of this receptor. The db gene is on the mouse chromosome 4 and the fa gene is on the rat chromosome 5.

At least five mutations have been identified in the db gene and two in the fa gene. In the specific db gene mutation examined by the investigators at Rockefeller, the mutation appears to be a duplication of DNA within the gene. In the rats with faulty fa genes, the mutation appears to be a deletion of some of the gene’s DNA.

“The db gene is quite large, which allows for a greater chance of mutations,” Leibel says. “By detecting how such mutations affect the receptor made by the db gene, we should learn more about the receptor’s structure and how it binds, responds to and processes the obese gene product.”

Leibel and his team continue their work to determine the molecular structures of the db and fa genes, the characteristics of their activities and the exact nature of the mutations in mice and rats with defectivedb and fa genes.

In addition, the research team plans to search for the human gene equivalent to db and fa by screening blood samples from adults who are 300 or more pounds. Interested individuals are asked to write to Dr. Leibel at The Rockefeller University, 1230 York Avenue, Box 309, New York, N.Y. 10021. People interested in participating must write “Obesity Study” on their envelope and include information about their age, weight, height, address and day and evening phone numbers.

The mice with defective obese gene were identified in 1950 and db mice in 1966, both at the Jackson Laboratory in Bar Harbor, Me. Lois M. Zucker and Theodore F. Zucker, Ph.D., of the Laboratory of Comparative Pathology in Stow, Mass., found the fa gene in rats in 1961.

In 1973, Douglas Coleman, Ph.D., discoverer of the ob gene, conducted a series of experiments that suggested db codes for a receptor for the obese gene’s product, although neither gene had been cloned nor had their products been identified. In 1994, Rockefeller’s Jeffrey Friedman, M.D., Ph.D., professor and Howard Hughes Medical Institute associate investigator, and his colleagues cloned the obese gene and, in 1995, they identified the gene’s product, naming it leptin. Friedman’s studies showed that when overweight mice with defective ob genes, who cannot make leptin, responded to injections of leptin by losing up to 30 percent of their body weight in two weeks.

Chua, Leibel and Tartaglia’s coauthors include Wendy K. Chung, B.S., Sharon Wu-Peng, M.D., Ph.D., Yiying Zhang, Ph.D., and Shun-Mei Liu, M.D., all at Rockefeller.

The National Institute of Child Health and Human Development, the National Institute of Diabetes and Digestive and Kidney Diseases and the Irma T. Hirschl Trust provided support for the study. Chua also received an International Life Sciences Institute Future Leaders Award.