By David N. Leff

Nicotine and alcohol aren't the only strictly legal substances that are addictive. So is food.

Overweight people who try to slim down find out how hard it is to override their appetite - the brain's engine that drives overeating addiction.

"Anyone who has tried to lose weight by dieting," observed mammalian developmental biologist Kiran Chada, "knows that making permanent changes in eating behavior can be difficult. Even though obesity is the second leading cause of preventable death in the U.S. - smoking is first - the development of safe and effective drugs to fight obesity have so far proven to be elusive."

Chada, a professor of biochemistry at the University of Medicine and Dentistry of New Jersey in Piscataway, directs the university's Genomics Center.

He said, "There's a great concentration of opinion in the obesity field that in order to control excessive weight, one has to modify behavior, such that at the end of the day you'd eat less, and therefore have less fat to store.

"The problem with that brain-centered approach as far as I can see," Chada continued, "is that controlling feeding behavior means you have to have drugs that affect the central nervous system [CNS]. To my knowledge, that's a very difficult pursuit, because you can't get precise and specific compounds to modify one specific behavior. Consequently, you always end up with adverse side effects."

For the past five or six years, Chada's research has endeavored to shift the obesity arena from appetite behavior in the brain to the actual buildup of adipose tissue and fat-cell deposits in the body's periphery - its abs, buns and limbs.

Putting his mouse where his message is, Chada reports progress in the April issue of Nature Genetics, under the title: "In vivo modulation of Hmgic reduces obesity."

"So what I hope," he told BioWorld Today, "is that our paper will stimulate scientists to move away from CNS control of obesity, by trying to change feeding behavior, and look at the periphery - like the adipose tissue where the actual fat is stored. In other words, try to control the amount of adipose tissue that you make in response to an obesity-reducing stimulus."

That stimulus resides in a long-known but little-noticed gene called Hmgic, and its protein, HMGI-C. Chada explained: "When the gene was identified a quarter-century ago, its discoverers named it HMG, standing for 'high-mobility group.' HMG genes," he noted, "are spread throughout the mammalian genome."

'Architectural' Gene Designs Obesity-Linked Protein

"In humans," he went on, "the Hmgic gene - of specific interest here - sits on the long arm of chromosome 12; in mice, on the distal portion of chromosome 10. The protein it expresses, HMGI-C, is a genomic architectural factor. That is, it has the ability to unbend or bend the structure of DNA, whereby the gene will be activated and transcribed.

"The cell biology function, which links HMGI-C to obesity," Chada continued, "seems to be its involvement in mesenchyme, a specialized cell type in the body, of which adipose and fat cells are derivatives. The embryonic mesenchymal cell is one of three primary cell layers - ectoderm, endoderm and mesenchyme - from which all of our cells are derived. The mesenchyme proliferates and differentiates to form bone, skin, cartilage, fibroblasts - in fact it's present within every single tissue and organ that we have as adults.

"Since adipose cells are mesenchymal cells," Chada recounted, "we wanted to know if the HMGI-C protein plays a role in obesity, because in obesity there is proliferation and differentiation of fat cells. When we made a knockout mouse lacking HMGI-C, and placed that animal on a high-fat American diet, it did not get fat, did not gain weight. Because it lacked HMGI-C, its cells did not proliferate like those of a normal mouse."

In a second in vivo experiment, Chada and his co-authors crossbred their fat-defying HMGI-C-minus mice with leptin-deficient animals, as a way of inducing obesity in those knockouts. They tried to make them fat on the high-fat diet. "Even under the severe leptin stimulus to eat more, and lower their metabolic rate," Chada recalled, "they did not become fat. They indirectly overcame the effects of leptin deficiency."

Chada observed, "Since mice and humans are genetically similar - their HMGI-C protein sequences are 98 percent identical - we expect to find that fat tissue in humans also has undifferentiated cells that mature into adipose cells under conditions, such as a high-fat diet, that promote obesity. For us, the next step is to identify a pharmacological agent that can inhibit the expression of HMGI-C."

On this score, he recalled, "One of the most exciting results of our study is that if the expression of the Hmgic gene is inhibited by only 50 percent, weight gain does not occur. And this fractional efficacy has important implications for drug development."

'Extreme Scenario' Sets Virtual Stage

That finding leads to what he calls his "extreme scenario." Chada elaborated: "The extreme scenario is that you can eat whatever you like, but if you're taking an inhibitor of HMGI-C function it won't matter; you're not going to make any fat cells to store the fat. Of course," he hedged, "that extreme scenario will not turn out to be the case, but I think it paints the picture."

To implement actual therapeutic application, Chada related, "We are now attempting to isolate such an inhibitor. That project," he pointed out, "is more appropriate for a company than an academic lab. So about a year ago, the university and my laboratory set up HMGene Inc., in Piscataway, which is now trying to identify such an inhibitor to block HMGI-C. But this is an extremely expensive undertaking, so we are looking for a collaboration with a major pharmaceutical company, which would have the financial resources.

"Finding an inhibitor will take a couple of years," he predicted, "and once it's isolated, then obviously it has to go through clinical trials, to make sure there aren't any adverse side effects. That could take anywhere from five to 10 years."

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