May be possible to stay slim and eat what you want

Imagine being able to throw away those diet books and eat whatever you want without becoming fat, and – as a bonus – not develop diabetes and live longer as well. A new study led by Joslin Diabetes Center researchers and published in the Jan. 24 issue of the journal Science brings scientists one step closer to turning this scenario – no doubt the dream of the estimated 60 million overweight American adults – into a reality.

The study, conducted in laboratory animals, raises the possibility that new drugs can be developed to make fat cells in the body less sensitive to insulin. Perhaps one day humans, like the genetically altered mice studied, may be able to eat whatever they want and still stay slim – and live longer.

The researchers, headed by C. Ronald Kahn at the Joslin Diabetes Center, reported on their experiments with mice that have been genetically altered to have no insulin receptor in fat. These so-called FIRKO mice were able to eat all they wanted and remain lean. In fact, even when they were stimulated to overeat, they failed to gain any extra weight. What’s even more important is that these mice live longer than brother/sister controls that ate the same amount of food but did not have this genetic knockout.

Matthias Bluher of Joslin, and Barbara B. Kahn of Boston’s Beth Israel Deaconess Medical Center’s Department of Medicine, also participated in the study. Both institutions are affiliated with Harvard Medical School, where C. Ronald Kahn is the Mary K. Iacocca Professor of Medicine, Barbara B. Kahn is professor of medicine, and Matthias Bluher is a research fellow in medicine.

Why did the mice stay slim? The mice in the study had fat that could not respond to insulin. “Since insulin is needed to help fat cells store fat, these animals had less fat and were protected against the obesity that occurs with aging or overeating. They also were protected against the metabolic abnormalities associated with obesity, including type 2 diabetes,” C. Ronald Kahn said.

“In this interesting mouse model, a reduction in fat mass, achieved without caloric restriction, significantly extends life span. These exciting results demonstrate how the National Institutes of Health investment in fundamental research continues to generate new insights with major implications for preventing and treating diabetes and obesity,” said Judith Fradkin. Fradkin heads the endocrinology and metabolic diseases divisions of the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health, which funded the study.

Scientists know that how long an organism lives depends on many factors, including genetics, hormone signaling, body weight, body fat content, and environmental factors such as food or caloric intake. It also has been known for some time that caloric restriction increases longevity in various organisms, ranging from yeast to mammals. What was not clear was if diet restriction increased longevity directly or whether the longevity was due to the associated leanness.

In the current study, the researchers found FIRKO mice at all ages had a 50 to 70 percent reduction in fat mass, despite the fact that they ate normally or even more than the controls. Moreover, they were protected against obesity and its related metabolic disorders, including type 2 diabetes, which affects at least 17 million Americans and is associated with obesity in at least 80 percent of cases.

The researchers found both male and female FIRKO mice on average had a life span increase of 18 percent, or 134 days – from 753 to 887 days. Furthermore, the researchers found that at 30 months of age – when 45 to 54 percent of control mice had died – more than 80 percent of FIRKO mice were still alive.

While the researchers do not know if the same outcome would occur in other mammals or humans, the findings in the FIRKO mice study provide hope. “Perhaps one day if we are able to find a drug to reduce or block insulin action in fat cells in humans, we might be able to prevent obesity, as well as type 2 diabetes and other metabolic diseases,” C. Ronald Kahn said. “And who knows, they might also live longer too.”