Mutation In Mice That Keeps Them Thin May Point The Way To A New Type Of Drug Treatment For Obesity

August 15, 1996

Treatment of Obesity
Contact: Laurie McHale, 206-543-3620

Genetic Mutation Keeps Lab Mice Thin

Scientists have produced a genetic mutation that keeps laboratory mice thin even on a very high-fat diet. The discovery by University of Washington researchers provides an important clue for development of a new type of drug to treat obesity.

"On a diet with 50 percent of its calories from fat, something akin to the typical fast-food meal, the mice stay thin," said Dr. G. Stanley McKnight, professor of pharmacology in the UW School of Medicine and principal investigator on the study, which is published in the Aug. 15 issue of the journal Nature.

McKnight says the knowledge gained from the research may give pharmaceutical companies a new direction in the search for effective drugs to control obesity: drugs that will work within fat cells, unlike current drugs that bind to the surfaces of cells.

McKnight and his pharmacology colleagues, Dr. David Cummings, Eugene Brandon, Dr. Josep Planas, Dr. Kouros Motamed and Dr. Rejean Idzerda, induced a genetic mutation that resulted in mice lacking a subunit of protein kinase A (PKA), an enzyme that helps regulate cellular metabolism. The subunit, called RII, is expressed predominantly in white adipose (fat) tissue, brown adipose tissue and the brain.

(The enzyme is the same one discovered by UW scientists Dr. Edwin Krebs and Dr. Edmond Fischer, who received the Nobel Prize in 1992.)

White fat stores energy but does not produce heat. Brown fat also stores energy, but is regulated by the brain through the sympathetic nervous system. It produces heat and, for example, allows hibernating animals to stay warm. By using the mutation to lower the setpoint at which the brown fat produces heat and forces breakdown of fat in the white adipose tissue, the UW researchers created mice that stay lean. "The mutation resets their thermostats," said McKnight. "They run a slight fever and have a slightly higher metabolism."

The experimental mice have only about one-fourth as much white fat as regular mice when both are fed a high-fat diet, said McKnight. On a standard low-fat laboratory diet, they remain slightly thinner than normal mice. They appear to be healthy and their appetites are as good or better than the appetites of normal mice.

Mice with the mutation avoid some of the adverse effects of a high- fat diet, such as insulin resistance (a precursor of diabetes) and accumulation of fat in organs like the liver. Despite their higher metabolic rate, they do not become hyperactive.

The research has implications for new directions in development of drugs to control obesity, said McKnight. "Several drugs now being developed target receptors on the surfaces of fat cells," he said. "We have targeted intracellular (inside-the-cell) signaling with this mutation. While we can't create mutations in humans to achieve these effects, it may be possible to create small-molecule drugs that, like the mutation, would act within fat cells. The challenge is to find a drug that targets the kinases in the fat cells, but not in cells elsewhere in the body."

The same subunit of PKA is expressed in brain cells, said McKnight, so another challenge is to develop a drug that cannot pass into those cells.

While the subunit is also found in other tissues such as the ovaries and testes, the mutation does not affect the reproductive capacity of the mice.

University of Washington

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