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Obesity-related Gene in Mouse Discovered at ORNL

See Related Articles: Searching for Mouse Models of Human Disorders,
Mouse Models for the Human Disease of Chronic Hereditary Tyrosinemia

Some mice born at ORNL have grown dangerously fat, even though they have been on a low-fat diet since birth. Although they do not appear overweight, these mice have a mutated gene that plays a strong role in causing obesity in the form of internal fat deposits that are hazardous to their health. The gene was discovered by Madhu Dhar, postdoctoral fellow from the University of Tennessee who works in the laboratory of Life Sciences Division's Dabney Johnson. Dhar's research was funded by the National Institutes of Health, and the findings were published in a paper in a recent issue of Physiological Genomics.

Mice

"We have found that the normal mouse has a gene on chromosome 7 that probably plays a role in the transport of fat from the blood into fat cells, where fat is stored as a source of energy to keep the body healthy," Johnson says. "If a mutant form of this gene is inherited from the mother in certain genetic backgrounds, the offspring grow 35 to 50 percent fatter by middle age than does a normal mouse, even though they are eating food low in fat."

Unlike some known mouse obesity genes that can act all alone to cause excessive body fat, the ORNL researchers have shown that the chromosome 7 gene must act in concert with other genes involved in maintaining the body's energy balance. If female mice possessing this mutated gene are mated with males having different genetic backgrounds, the offspring may not become obese, suggesting they have genes that code for proteins that suppress fat accumulation. Humans and mice are genetically similar and produce similar proteins. In humans, chromosome 15 is similar to chromosome 7 in the mouse.

Madhu Dhar shows how a mouse is placed in a MicroCAT X-ray  computerized tomography system
Madhu Dhar shows how a mouse is placed in a MicroCAT X-ray computerized tomography system. This device has been used to produce images showing the locations of life-threatening fat deposits in the body of a mouse with the newly discovered obesity-related gene. Mice with this gene have fat pads in known regions of the body. Thanks to biomedical imaging using the MicroCAT scanner, it is no longer necessary to sacrifice fat mice and dissect them to measure the size and weight of fat pads. (Photo by Curtis Boles, enhanced by Gail Sweeden.)

The ORNL group has been focusing on chromosome 7 in the mouse for some time. In the 1950s ORNL geneticists Bill and Liane Russell irradiated mice and observed that some of their offspring who survived had a pinkish coat and pink eyes instead of normal gray-brown fur pigmentation and dark eyes. It was later determined that the radiation knocked out DNA from a coat-color gene, called the pink-eye marker (p), on mouse chromosome 7. Neighboring genes also were deleted or altered in some irradiated mice, and the defects were passed on.

Thanks to the availability of improved technologies, ORNL researchers have defined the small region on mouse chromosome 7 that contains the p gene and its neighbors. Using recombinant DNA techniques, they identified and characterized genes from this small region in the normal mouse. And in mutant mice they have identified behavioral oddities, internal defects, and disorders such as epilepsy and obesity caused by the absence or alteration of certain neighboring genes on chromosome 7. From this information on genetic material gone awry, they can determine the function of the normal genes in this chromosome region.

MicroCAT images showing fat deposits in a normal mouse and a mouse with the obesity gene on chromosome 7.

Johnson says that, like humans, mice deposit fat in their bodies in different patterns that are genetically controlled. The distribution of fat deposits in mice with the obesity-related gene has been observed in three dimensions by Mike Paulus and Shaun Gleason in ORNL's Instrumentation and Controls Division (see MicroCAT "Sees" Hidden Mouse Defects). They have imaged internal fat deposits in mice using the MicroCAT miniature X-ray computerized tomography system they developed. Using special software, they have determined the size and weight of those fat deposits.

 

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Related Web sites

ORNL Life Sciences Division
ORNL Instrumentation and Controls Division
Physiological Genomics Online
National Institutes of Health

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