Independent research groups have discovered novel therapeutic targets in the battle of the bulge. By altering the expression of a single -- albeit different – gene, Drs. Roger Davis (UMASS Medical School, USA) and Ying-Hue Lee (Academia Sinica, Taiwan) have succeeded in creating two different strains of transgenic mice that don't gain weight, even when fed fat-laden, high calorie diets.
Their reports will be published in the August 15th edition of Genes & Development.
Dr. Ying-Hue Lee and colleagues at Academia Sinica took a different approach towards the obesity epidemic, analyzing the effects of C/EBP gene replacement in mice. The C/EBP protein family consists of 5 members, 3 of which (alpha, beta, and delta) have established roles in promoting adipogenesis (fat cell differentiation). The researchers were specifically interested in determining the physiological impact of replacing the C/EBPalpha gene with the C/EBPbeta gene.
"No doubt, C/EBPalpha is very important for life as indicated by many excellent studies related to its physiological function. Still, we wondered that its cousin, C/EBPbeta, might do the job well as well if given a chance," explains Dr. Lee.
Dr. Lee and colleagues utilized an existing strain of mice that contains the alpha-to-beta gene substitution, referred to in the paper 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 markably leaner, apparently burning fat at a much higher rate than normal mice.
Dr. Lee and colleagues observed that despite their svelte appearance, beta/beta mice actually eat more food and are no more active than their genetically normal littermates. In search of the cause of this revved-up metabolism, Dr. Lee's team found that the white adipose tissue, which is normally reserved for fat storage, had actually been converted into fat burning cells in beta/beta mice. The researchers believe that this remarkable conversion in tissue function (from fat storage to fat burning) may be due to the increased expression of yet another gene, Galphas, in the white adipose tissue of beta/beta mice.
To further investigate the effectiveness of C/EBP gene replacement in preventing obesity, Dr. Lee and colleagues introduced the beta/beta alleles into two different mouse models of obesity: Cpefat/fat mice, which are obese due to a suppressed metabolism, and Lepob/ob mice, which are obese due to overeating. Amazingly, this gene modification was able to dramatically decrease weight gain in both strains of mice, illustrating that C/EBP gene replacement can overcome both hereditary and dietary forms of obesity.
Dr. Lee is hopeful that the activation of Galphas may prove useful as a potential therapeutic target in the fight against human obesity, helping to jump-start metabolism in fat storage cells and thereby 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 says.
As the rate of obesity continues to rise, so does the number of people developing Type 2 diabetes (formerly known as adult-onset or insulin-independent diabetes). In fact, obesity is believed to be one of the most important risk factors for Type 2 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.