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Cloning of the mouse coat color gene, agouti, in the early 1990s revealed the basis for the obesity of mice with the yellow mutation in the agouti gene and led to the demonstration that actions at the melanocortin receptors in skin and the hypothalamic region of the brain accounted for the dual effects on coat color and body fatness.

Now, research from Dr. Rudolph Leibel's laboratory—the cloning of another coat color gene, called mahoganoid—has led to the identification of a new gene involved in weight regulation in the animal. The mutation produces a reddish brown coat and a leaner mouse. The gene, which seems to code for a ubiquitin ligase, could offer a novel mechanism of action for the regulation of body weight compared with the nearly 40 other genes in mice and humans implicated in aspects of energy intake and expenditure related to body weight. The gene also might prove to be a target for future weight-reduction therapies if it's involved in weight regulation in humans. The research was published in the November Journal of Clinical Investigation.

The lab began looking at the mahoganoid mouse because the offspring from a mahoganoid crossed with the obese yellow mouse are lean. Dr. Leibel, professor of pediatrics and medicine and co-director of the Naomi Berrie Diabetes Center, says the absence of obesity in the offspring suggested the mutation that causes the mahoganoid coat color is also implicated in the melanocortin pathway related to body weight. His graduate student, Loan Phan, working with Dr. Wendy Chung, assistant professor of pediatrics; Feng Lin, staff associate; and Dr. Charles LeDuc, associate research scientist, set out to find which gene contained the mutation.

The team used a combination of classical genetics and bioinformatics to pinpoint the mutation to a gene in the mouse's 16th chromosome. Further analysis showed that large retroviral insertions in the mahoganoid gene result in the loss of the gene's normal function in the brain and in the skin. Because these retroviral mutations in the mahoganoid gene can prevent the usually obese yellow mice from gaining weight, Dr. Leibel and Ms. Phan believe the mahoganoid gene's normal function is to increase food intake or reduce energy expenditure.

The normal mahoganoid protein probably increases food intake by decreasing signaling through the melanocortin pathway in the hypothalamus. When the receptor is blocked, food intake goes up. The protein in the skin also decreases signaling through similar receptors, accounting for the mahoganoid coat color.

Based on sequence analysis of the protein encoded by mahoganoid, the researchers believe that the gene product is a ubiquitin ligase—an enzyme that attaches ubiquitin molecules to other proteins. Ubiquitin molecules can mark proteins for degradation, indicate the protein needs to be moved to another location, or regulate transcription of genes into messenger RNA. Dr. Leibel's lab is trying to identify what protein the ubiquitin ligase targets and whether the ligase also plays a role in regulating weight in humans.

As an enzyme that promotes weight gain, the ligase makes a potentially attractive target for drug-based obesity therapies. "The protein is apparently an enzyme, and drug companies like enzymes that can be inactivated by a small molecule," says Dr. Leibel, who also is head of the Division of Molecular Genetics and deputy director of the New York Obesity Research Center.

The researchers are interested in how the mahoganoid gene, if it also controls weight in humans, works with a number of other human genes that regulate body weight and energy expenditure. "We believe that human obesity is the result of the joint influence of several genes," Dr. Leibel says. "Subtle variations in subgroups of these genes may account for the control of human body weight, and in any one person, degree of fatness could reflect the aggregate effect of interactions among several of these genes with powerful environmental influences." The most relevant genes could vary among ethnic groups.

Dr. Leibel's lab now is working on finding genetic variations in weight-regulating genes in a variety of human populations, to try to identify the five or six genes that may be major determinants in most people. But finding these genes will take statistical tools that are still in development, and he and Dr. Chung are collaborating on that with Dr. David Allison, professor of biostatics at the University of Alabama in Birmingham. "We're trying to work out strategies for interpreting DNA variations in multiple genes simultaneously in large numbers of individuals," Dr. Leibel says. "The effort to understand obesity is probably paradigmatic of how we're going to understand the genetics of other complex diseases in which a number of genes interact powerfully with the environment."

The research was funded by the National Institutes of Health.