Even on a “supersize” diet, mice bred to lack a certain enzyme remained more svelte than mice with the enzyme, according to a study by Yale scientists in the July 2006 issue of the journal Cell Metabolism. Moreover, in a finding that surprised the research team, the mice’s blood sugar levels remained under control.

The study’s senior author cautioned against premature talk of an elixir that prevents diabetes or does away with the need for exercise. “The long-term goal, I think, would be to figure out how this enzyme is working under normal circumstances,” said Anton M. Bennett, Ph.D., associate professor of pharmacology. “But I think we’re a long ways away from this as an obesity target.”

Bennett’s laboratory studies mitogen-activated protein kinase phosphatases (MKPs), important players that have been implicated in numerous cellular functions such as cell growth and cell survival. For a better understanding of these enzymes, mice were bred to lack one of them, MKP-1. “There was no preconceived hypothesis that it would necessarily be involved in regulating body mass,” Bennett explained.

At first there appeared to be no obvious differences between the mice lacking MKP-1 and the control mice. “If you looked in the cage and had the mice side by side, they would be indistinguishable,” Bennett said. Both groups ate a typical chow diet—“the equivalent of three squares a day.” Soon, the knockout mice showed that they were less likely to put on the ounces.

“Then we put them on a McDonald’s ‘supersize’ equivalent, where 55 percent of the calories was from carbohydrates,” he continued. “The differences in weight were extremely pronounced.” The mice without the enzyme were, on average, 15 to 20 percent leaner than the control group. “The enzyme seems to act as a brake on how fast you burn energy. When you remove that enzyme, energy expenditure seems to go up dramatically.”

The mice without the enzyme were also better able to control their glucose levels. Because they were leaner, they also should have exhibited signs of increased insulin sensitivity. “But it was normal,” Bennett said. “That was somewhat of an unexpected result.” The knockout mice also were less likely to show signs of metabolic syndrome, a constellation of risk factors for heart disease and diabetes. One of the hallmarks of metabolic syndrome is a fatty liver, and the mice without the enzyme were resistant to that symptom.

While the study shows that MKP-1 “may contribute to obesity and diabetes,” it is far from certain whether turning it off will prevent or ameliorate those conditions. There is also concern about the overall effect of turning off the enzyme in the body. Bennett said studies have found knockout mice to be more susceptible to infection. “That’s not a good thing,” he said. “Everything is connected.”