UF Researchers Show Mice Live Longer When They Slim Down After Gene Therapy

October 25, 2004

GAINESVILLE, Fla. — Doctors have said it for years: Maintaining a healthy weight can help you live longer.

Now, a University of Florida gene therapy study provides further proof that doctors are right, say researchers who measured the lifespans of mice that were twice as heavy as their normal counterparts.

The mice lacked a crucial weight-control gene, and when the gene was restored to some of the mice they not only slimmed down, two-thirds of them also outlived every mouse in an untreated group, said Satya Kalra, a UF professor of neuroscience. The results of the National Institutes of Health-funded study, presented today at the Society for Neuroscience annual meeting in San Diego, suggest it’s never too late to benefit from proper diet and exercise.

“Our study very clearly demonstrates for the first time that if you can reduce obesity or the fat load, you have a greater chance of living longer,” said Kalra, who also is a member of UF’s McKnight Brain Institute. “Clinical reports are abundant that obesity produces metabolic diseases that shorten the lifespan of obese people.”

Obesity is defined using a formula called body mass index, which compares weight with height. People with a body mass index of 30 or more are considered obese, and have increased risks for ailments such as high blood pressure, type 2 diabetes, heart disease, stroke and some forms of cancer, according to the U.S. Centers for Disease Control and Prevention.

Funding for the study was provided by a five-year, $1.9 million grant from the National Institutes of Health.

UF researchers put the missing gene where it was needed most: into cells in a part of the brain called the hypothalamus, which controls many basic body functions, Kalra said. The gene controls production of a protein called leptin, which signals the hypothalamus to reduce appetite and increase metabolism.

Leptin is produced in the fat tissue of all mammals, including people, he said. It is normally released when a mammal eats, traveling to the hypothalamus through the bloodstream. Without adequate leptin, mammals overeat and gain weight, Kalra said.

Some people may carry excess weight because their bodies don’t produce enough leptin, a theory that could be demonstrated by future research, he said.

“If it is demonstrated, then there’s a good chance that leptin gene therapy may also be beneficial clinically,” Kalra said. He emphasized that clinical trials for human patients would be years away and that for now, the best way for people to stay slim is through proper diet and exercise.

The study involved several breakthroughs for researchers, Kalra said.

Most important, the treatment involved a single application of gene therapy, yet produced beneficial results that lasted for the remainder of the animals’ lives, which was more than a year, he said. Because many human diseases are caused by missing or faulty genes, the study offers hope that similar treatments may eventually provide long-lasting results in people.

“It’s also never been shown that by replacing one gene you can prolong life,” said Kalra, who conducted the study with his wife and longtime research partner Pushpa Kalra, a UF professor of physiology and functional genomics, and UF postdoctoral fellows Naohiko Ueno, and Stephane Boghossian.

In the study, 24 male mice 8 weeks to 10 weeks old were separated into two groups of 12. All the mice lacked the gene that controls leptin production, so they weighed between 40 grams and 50 grams, about double the weight of a typical mouse.

Mice in the treated group were injected with a harmless virus modified to carry a gene that controls production of leptin. The untreated group received the same virus, but it carried a gene that produces a protein that glows bright green but has no therapeutic effect.

After the injections, body weight and food intake were monitored weekly for each mouse. The mice treated with leptin ate an average of 15 percent less than the other mice and eventually returned to normal weight. The untreated mice continued to gain weight and began to show increased mortality after 315 days.

In addition, after 595 days, two-thirds of the mice treated with leptin remained alive, but all the untreated mice had died.

The UF study is important because it demonstrates that weight-loss research can be accomplished using animals that voluntarily reduce their food intake instead of being forced to diet by food restriction, said leptin researcher M. Susan Smith, director of the Oregon National Primate Research Center in Portland, Ore.

“Feeling hungry is stressful,” Smith said. “So whenever you have stress on top of other factors it makes it much more difficult to understand what is really going on.”