Fat-Making Gene Found

Could become target for obesity treatments, says expert

WEDNESDAY, Jan. 2, 2002 (HealthDayNews) -- Two sets of researchers have each pinpointed a gene that puts the finishing touch on turning cells into fat.

Researchers from Harvard Medical School and the drug company Pfizer, working independently, identified the gene that creates PPARgamma as being crucial to making fat cells. According to an expert in obesity and diabetes research, targeting this gene could lead to new therapies against obesity.

The findings appear in the Jan. 1 issue of Genes & Development.

Obesity is a disease that affects at least 39 million Americans, and public health experts are increasingly using the term "epidemic" to describe the problem. One in five Americans is obese and more than half are overweight, according to government figures. Being fat raises the risk of many potentially fatal health conditions, including heart disease and diabetes, and it's believed that obesity is linked to at least 300,000 deaths in the Unitred States annually.

In the Harvard study, cell biologist Bruce Spiegelman led a team that examined the role of the PPARgamma gene and another gene called C/EBPbeta, which is also involved in the process of fat cell development. Creating fat cells is a two-step process: generalized cells first turn into transitional fat cells, then PPARgamma helps turn those transitional cells into fat-filled ones.

Previous studies have shown that in cells where the C/EBPbeta gene has been genetically removed, fat cells will develop if PPARgamma is present.

In this study, Spiegelman tested the opposite scenario: His team created a line of fibroblast cells that lacked PPARgamma but did have the C/EBPbeta gene.

The cells didn't develop into fat cells, which, according to Spiegelman, suggests that while C/EBPbeta and PPARgamma play a role in the same pathway that leads to fat cell development, PPARgamma's function occurs earlier in the process.

"It's the dominant regulator of adipose differentiation," says Spiegelman, meaning it controls whether precursor cells specialize to become fat cells. "It's a gene control factor, and it looks like it's very important."

In the Pfizer study, Heidi Camp and researchers at Pfizer Global Research and Development in Ann Arbor, Mich., took the findings a step further.

The PPARgamma gene actually produces two forms of its protein, called PPARgamma1 and PPARgamma2. The forms are very similar, except that PPARgamma2 has an extra clump of amino acids on one end. But Camp, a research associate in molecular science, says that little research exists into what the differences are between the two forms.

Using a new technique, the team inhibited roughly 50 percent of the production of the PPARgamma2 form, and Camp found that this reduced fat cell development by 50 percent.

Adding a solution of PPARgamma2 protein to the cells restored fat cell development, but adding a solution of PPARgamma1 protein had no such effect, she says.

"It hinted to us that reduction in [fat cell development] appears to correlate with the PPARgamma2 expression level, and not necessarily with the PPARgamma1," says Camp. "We think that PPARgamma2 is the main regulator."

The function of PPARgamma1 remains less clear, and Camp says that future research needs to look into it.

Dr. Mitchell Lazar, the director of the Penn Diabetes Center at the University of Pennsylvania in Philadelphia, says that these findings place PPARgamma, and specifically PPARgamma 2, above C/EBPbeta in the fat cell development hierarchy.

"It stands to reason that if we understand how you make fat cells, then we might be able to more intelligently figure out how to stop making fat cells," Lazar says. "That might be useful information as we try to supplement dietary treatments of obesity with, hopefully, a generation of drugs that can specifically prevent people from making fat cells."

"If scientists can target -- very specifically -- the PPARgamma2 form, which turns out is only found in fat cells, then it might be possible to come up with new ways to prevent people from making more fat cells without harming other parts of the body," he adds.

Compounds that activate both PPARgamma forms are currently used as anti-diabetic drugs because they help sensitize the body to the effect of insulin. The compounds cause weight gain.

This raises the question of whether drugs that block PPARgamma might have the opposite effect.

Although Camp says it's an interesting question, she cautions that it creates a paradox: Activating PPARgamma sensitizes the body to insulin but increases weight, which is a risk factor for Type II diabetes. Blocking PPARgamma, although it might reduce weight, could increase insulin resistance and raise the risk of Type II diabetes.

"At this point, it's very premature to say that blocking PPARgamma would be a good anti-obesity approach," Camp says.

Spiegelman stresses that diet and exercise are a better way to battle a weight problem.

"Obesity is a problem of energy imbalance, not a problem of fat cells," he says. "It's not a good idea to treat obesity by directly regulating fat cell differentiation."

"You wind up making an animal sick," he adds, pointing out that people with defective fat cell metabolism end up with lipodystrophy, an insulin-resistant condition that causes loss of fat in the arms, legs and face and abnormal deposits of fat scattered around the body.

What To Do

For information on obesity, check out the National Institutes of Health or the American Obesity Association.

You can also check out the Guidance for Treatment of Adult Obesity publication from Shape Up America! (You'll need Adobe Acrobat Reader to open this file.)

SOURCES: Interviews with Bruce M. Spiegelman, Ph.D., professor, department of cell biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Mass.; Heidi S. Camp, Ph.D., research associate, department of molecular science and technology, Pfizer Global Research and Development, Ann Arbor, Mich.; Mitchell A. Lazar, M.D., Ph.D., professor, division of endocrinology, diabetes and metabolism, departments of medicine and genetics, and director, Penn Diabetes Center, University of Pennsylvania, Pa.; Jan. 1, 2002, Genes & Development
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