In search of a lean gene

Independent research groups have discovered novel therapeutic targets in the battle of the bulge


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.

Living longer, weighing less

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.

Targeting obesity and diabetes

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.

Dr. Roger Davis and colleagues in the Howard Hughes Medical Institute at UMASS Medical School focused their research effort on the JNK (pronounced “junk”) family of kinase enzymes. JNK acts as an intracellular signaling molecule, and is known to contribute to insulin insensitivity during obesity. However, rather than concentrate on JNK, itself, which is involved in a number of physiological processes (and thereby constitutes a more complicated therapeutic target), Dr. Davis’ team centered upon JIP1, a scaffolding protein that interacts with components of the JNK signaling module and facilitates its activation in adipose (fat) tissue.

“The JIP1 scaffold protein is implicated in the effects of stroke to cause brain damage, but whether JIP1 plays a more general role in the response of the body to stress is unclear. One form of stress that may be relevant to JIP1 is obesity. The goal of this study was to test whether JIP1 contributes to the effects of obesity on the body,” explains Dr. Davis.

To investigate the role of JIP1 in obesity and insulin resistance, the researchers used a strain of mice in which both copies of the gene encoding JIP1 (Jip1) had been mutated. These Jip1-deficient mice (or knock-out mice as they are known) fail to activate JNK in adipose cells. As a result, they gained 40% less weight than their genetically normal (wild-type) counterparts when fed a high fat, high calorie diet, and displayed increased sensitivity to insulin. Thus, Jip1 inactivation effectively protects against obesity and the development of insulin resistance.

This finding posits Jip1 as a novel target for the rational design of drugs to combat obesity and Type 2 diabetes. Dr. Davis emphasizes that “Our study demonstrates that JIP1 plays a critical role in the response of the body to the stress caused by obesity. Drugs that target the function of JIP1 to regulate JNK activity may therefore be useful for the treatment of obesity and insulin resistance. Our study provides a proof-of-concept that validates this approach using a model organism. An exciting future possibility is the application of this strategy to the treatment of human obesity.”

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