In search of a lean gene

This findings pinpoint novel targets for the rational design of drugs to combat obesity and Type 2 diabetes, regulating protein activity for the treatment of obesity and insulin resistance. An exciting future possibility is the application of this strategy to the treatment of human obesity on a genetic level.

As the rate of obesity continues to rise, so does the number of people developing diabetes. Obesity is believed to be one of the most important risk factors for diabetes, in which muscle, liver and fat cells become resistant to insulin, causing blood glucose levels to rise and eventually damage nerves and blood vessels.

In the first of two independent research groups, Dr. Ying-Hue Lee and colleagues creating two different strains of transgenic mice that don't gain weight, even when fed fat-laden, high calorie diets. Their novel approach consisted of replacing the C/EBP alpha gene with the C/EBPbeta gene which both have established roles in promoting adipogenesis (fat cell differentiation).

Dr. Lee and colleagues utilized an existing strain of mice that contains the alpha-to-beta gene substitution, referred to as "beta/beta mice."​ They found that beta/beta mice not only live an average of 5 months longer than wild-type mice, but are also markedly leaner, apparently burning fat at a much higher rate than normal mice.

Despite their slim appearance, beta/beta mice ate more food and are no more active than their genetically normal littermates. In search of the cause of this revved-up metabolism, the team found white adipose tissue, normally reserved for fat storage, had been converted into fat burning cells in beta/beta mice.

Dr. Lee said this discovery, made at the Academia Sinica, Taiwan, may prove useful as a potential therapeutic target in the fight against human obesity, helping to jump-start metabolism in fat storage cells and prevent fat accumulation.

"It would be wonderful, if fat cells can be programmed to be more wary of their own size and take good care of it themselves,"​ he said.

Targeting obesity and diabetes​

In related research, scientists from the University of Massachusetts Medical School​ have been working with the JNK family of enzymes, which are known to contribute to insulin insensitivity during obesity.

Dr. Roger Davis and colleagues also focused their efforts on JIP1, a scaffolding protein that interacts with components of the JNK signalling module and facilitates its activation in adipose tissue.

Dr. Davis explained: "We think JIP1 may play a role in the response of the body to stress. This study was to test whether JIP1 contributes to the effects of obesity on the body."​

The researchers used a strain of mice in which both copies of the gene encoding JIP1 had been mutated thus failing to activate JNK in adipose cells. As a result, they gained 40 per cent less weight than their genetically normal (wild-type) counterparts when fed a high fat, high calorie diet, and displayed increased sensitivity to insulin. Essentially JIP1 inactivation effectively protects against obesity and the development of insulin resistance.

Despite major progress in the understanding of the molecular mechanisms behind it, no safe and effective treatment has yet been found.

Current treatments, while effective, also suffer from nasty side effects. Xenical (Orlistat), inhibits the activity of enzymes required for digestion of dietary fats. The undigested fat cannot be absorbed and is excreted in the faeces. Full doses of the drug reduce fat absorption by about 30 per cent.

However, its side effects include changes in bowel movement (BM) habits, gas with discharge, oily or fatty stools and an inability to control BMs

Obesity has reached epidemic proportions globally, with more than 1 billion adults overweight - at least 300 million of them clinically obese -and is a major contributor to the global burden of chronic disease and disability, according to the World Health Organization.

In the US, obesity related deaths rose 33 per cent between 1990 and 2000 to an estimated 400,000. And, according to a recent Rand study, by 2020, approximately one in five healthcare dollars spent on people aged 50 to 70 will be due to obesity- related disabilities, if the current trend of overeating and inactivity continues.