Fatty findings: Genes that regulate fat may affect a variety of diseases.

America's battle of the bulge is not going well. A recent report suggests that 61 percent of U.S. adults--almost 108 million people--are overweight and, therefore, are at greater risk for heart disease, diabetes, and cancer.

These diseases are chronic and complex, and they're leading causes of death in the developed world. Imagine, then, how exciting it has been in recent years for researchers--and drug companies--as they have discovered a single family of proteins with pivotal roles in obesity, diabetes, heart disease, and cancer. These molecules have become attractive targets for drug development.

The proteins are called peroxisome proliferator activated receptors, or PPARs. They're found directly on DNA molecules in the cell. Other proteins, as well as smaller molecules, then associate with these PPARs and form complexes that initiate a wide range of cellular actions. In short, PPARs are part of the molecular switching machinery that controls genes that regulate how cells take in and break down fat.

Understanding the role of PPARs in this process may help researchers come to grips with why heart disease, diabetes, and obesity so often emerge in the same person. PPARs may also point toward improved treatments for those diseases, says Ronald M. Evans of the Salk Institute for Biological Studies in La Jolla, Calif. Researchers note that they'll have to proceed with caution since tinkering with PPARs can trigger both beneficial and deleterious effects.

Perhaps the most intensely studied member of the PPAR family is PPAR-gamma, which regulates fat storage. It's found primarily in fatty tissue and to a lesser extent in the colon, white blood cells, the lining of blood vessels, and the retina. PPAR-alpha is linked to the breakdown of fat for energy. Less clear is the role of the third known PPAR, most commonly called PPAR-delta but sometimes called PPAR-beta.

In the mid-1990s, researchers realized that maturing fat cells depend on cascades of biochemical signals initiated by PPAR-gamma. In addition, they learned that gene-controlling actions orchestrated by PPAR-gamma influence the storage of fatty acids in mature cells. At around the same time, researchers showed that troglitazone, or Rezulin, a new diabetes drug that increases a person's ability to respond to insulin, binds to PPAR-gamma and turns it on. That, in turn, leads either to activation or deactivation of the gene or genes that the PPAR molecules attach to.

This discovery that drugs can regulate PPAR-gamma has been a boon for researchers aiming to uncover this protein's function. "PPARs in general, and PPAR-gamma in particular, have become one of the hottest molecular targets for basic and biomedical research, because they are at the nexus of all these [obesity-related] diseases," Evans adds.

Consider diabetes. Several drugs that turn on PPAR-gamma, called thiazolidinediones, are already in widespread use for treating the disease. Although troglitazone itself was pulled from the market last year because of side effects, such as liver damage. Several related drugs remain on the market.

Researchers know that PPAR-gamma activation is a key part of the insulin-sensitizing effect of these drugs. Still, they remain uncertain about exactly which genes and biochemical pathways are modified.

Some investigators have proposed that fat cells stimulated by PPAR-gamma release as-yet-unknown compounds that trigger muscle cells to respond to insulin. Muscle cells are especially affected by the inability to respond to insulin, the hormone that enables the cells to tap into the energy of sugar molecules. This inability to take up sugar is the hallmark of type II, or adult-onset, diabetes.

Another explanation for the thiazolidinedione's ability to help diabetics respond to insulin better is that PPAR-gamma governs whether cells get their energy from fat or sugar. According to this theory, as PPAR-gamma spurs fat cells to grow and pull in fat molecules from the blood, the lower concentration of circulating fat prompts muscle, liver, and other tissues to get more of their energy from sugar. The result is lower blood sugar concentrations.

There are also now genetic leads for PPAR-gamma's specific roles in diabetes. In an analysis of more than 3,000 people, researchers last year linked a common variant of the gene for PPAR-gamma to a slight increase in diabetes risk. Because the gene variant is so common, it may contribute to as much as 25 percent of type II diabetes patients in the general population, says Eric S. Lander of the Whitehead Institute/MIT Center for Genome Research in Cambridge, Mass. On the other hand, another variant of the PPAR-gamma gene actually protects people against diabetes, Lander's team reported in the September 2000 NATURE GENETICS.

Mutations in the PPAR-gamma gene have also been linked to insulin resistance and a precursor to high blood pressure in which people don't respond well to insulin but can still control their blood sugar. In studies of PPAR genes, volunteers with such mutations weren't overweight, which is the case for most people with insulin resistance. The implication is that drugs affecting PPAR-gamma could break the link between obesity and diabetes, Evans says.

The role of PPAR-gamma in heart disease also has many facets. Evidence is emerging that the protein has an important role in one of the earliest signs of heart disease, atherosclerosis. This is the gradual buildup of fats along the lining of blood vessels into plaques, which can gradually obstruct blood flow or suddenly rupture into pieces that jam arteries and veins.

PPAR-gamma may have an important role in clearing destructive cholesterol--low-density-lipoprotein (LDL) cholesterol--from the bloodstream, suggests Evans. But the protein may also help pack that cholesterol into plaques. "It's a Dr. Jekyll-Mr. Hyde problem, where you clear out the bad stuff but you are storing it in a dangerous location," Evans says.

Based on research over the past few years, some scientists think PPAR-gamma regulates fat transport in the white blood cells called macrophages, the vacuum cleaners of the immune system. Once a macrophage encounters LDL cholesterol, it calls other macrophages to the attack. Stimulated by PPAR-gamma, the macrophages scoop up LDL cholesterol from the bloodstream. However, in the process these cholesterol-filled macrophages accumulate in the fatty plaques lining arteries.

The picture gets even more complicated. Thousands of people with diabetes have been taking thiazolidinediones over the past few years, and they seem less likely to develop atherosclerosis than diabetic people who are not taking the drugs.

Activated PPAR-gamma also starts a cascade of biochemical reactions that pumps the cholesterol back out of the plaques, but now in the form of high-density-lipoprotein (HDL) cholesterol. This so-called good cholesterol is then metabolized or otherwise eliminated from the body. Evans and his colleagues reported these findings in the January MOLECULAR CELL. Similar results were reported by other researchers in the January NATURE MEDICINE. The PPAR-gamma system, Evans says, seems to be "a way of transforming a toxic particle [LDL cholesterol] into a good cholesterol."

If researchers can manipulate the PPAR-gamma system in macrophages, they may find ways to convert more LDL cholesterol into HDL cholesterol. A drug that could do that would be even more beneficial than current anticholesterol medications are, which simply reduce LDL cholesterol concentrations, Evans says.

The medical exploitation of PPAR-gamma by using drugs that activate it may have other positive effects on the cardiovascular system. Some research has suggested that thiazolidinediones lower blood pressure in people. Theoretically, they do this by spurring PPAR-gamma to trigger the release of compounds that make blood vessels more flexible, says Evans. Stiff arteries tend to create higher blood pressure and cause heart disease.

Learning more about PPAR-gamma's effects on cancer is also on scientists' to-do list. Researchers started to look at the effects of PPAR-gamma on cancer largely because of the protein's role in the maturation of fat cells, says Bruce M. Spiegelman of the Dana-Farber Cancer Institute in Boston.

Mature cells rarely divide, in contrast to the uncontrolled cell division that marks cancer. In fact, typical cancer cells appear to be in a less-than-mature, or dedifferentiated, state.

Spiegelman and his colleagues have shown that in people with cancers of fatty tissues, known as liposarcomas, the PPAR-gamma activator troglitazone appears to force the cancer cells to mature and stop dividing. Spiegelman expects this to improve the survival of these patients.

Perhaps even more significant are results from lab tests showing that PPAR-gamma slows the division of cells taken from breast, prostate, and colon tumors. All of these cancers, it turns out, are more likely in people who are obese.

In the Sept. 26, 2000 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, Spiegelman and his colleagues reported that giving troglitazone to men with prostate cancer stabilized amounts of a blood protein, called prostate-specific antigen, that ordinarily increases as the cancer grows. Patients receiving the drug experienced longer periods without new symptoms or signs that their cancer was spreading, the researchers say.

Earlier this year at a meeting on PPAR-gamma, Spiegelman and his colleagues reported that mice genetically engineered to produce about half the normal amount of PPAR-gamma are more likely than unaltered lab mice to develop colon cancer after being treated with a cancer-causing agent.

Complicating that promising news, however, is evidence that drugs that turn on PPAR-gamma might promote colon cancer. Evans and his colleagues gave thiazolidinediones to animals with a cancer that serves as a model for familial colon cancer.

Surprisingly, those animals "don't get less colon cancer, they get more," says Evans. "If I were a patient," he says, "I wouldn't want to be treated [with drugs that turn on PPAR-gamma] until we know more."

While acknowledging that more research into the potential downsides of PPAR use is required, Spiegelman says "there's very good reason to think that [thiazolidinediones] will have a role in the cancer clinic. And if they do, they are much more benign than most cancer drugs."

PPAR-gamma may have an even more complicated role in obesity. Some researchers speculate that PPAR-gamma evolved because it helps the body store energy--in the form of fat-storing cells--when food is scarce. Now that most people in developed countries have plenty of high-fat food available, the context has changed for PPAR-gamma. It may be triggering harmful processes instead, says Theodore W. Kurtz of the University of California, San Francisco.

One of the problems in obesity is that once fat cells are created, they stick around. Even if a dieter gets the fat out, the depleted cells stand ready for a refill. Rebound weight gain is hard to avoid, in part, because these cells can quickly fill with any extra fat the body takes in.

Roger H. Unger of the University of Texas Southwestern Medical Center in Dallas and his colleagues have shown that exposing a fat cell to very high amounts of a hormone that dramatically reduces the concentration of PPAR-gamma causes a fat cell to stop holding fat. As a consequence, Unger says, drugs that turn off PPAR-gamma may hold promise for reducing rebound weight gain.

There's another problem with PPAR-gamma, says Unger. When it gets turned on more than usual, fat can accumulate where it doesn't belong. Abnormal fat buildup in the heart, liver, and other organs may trigger some of the diseases linked to obesity, he points out.

No one yet knows the mechanism behind this misplaced fat accumulation. It's a tough problem, says Unger, because the PPARs themselves lie within tremendously complicated pathways of metabolism, which remain poorly understood.

PPAR-gamma research is still in early stages, but it's becoming a field unto itself. Already this year, scientists have convened at two international conferences devoted to PPAR research.

Theses scientists are already studying PPARs' effects on yet other diseases. The proteins' ability to affect cell division, for example, may give them a role in psoriasis, in which skin cells grow abnormally. Also, preliminary studies suggesting that PPAR-gamma reduces inflammation have encouraged researchers to look into whether the protein plays a role in diseases like arthritis or inflammatory bowel disease.

Investigators studying PPARs are hoping to develop compounds that turn on the substances' effects in some tissues but block their activation in others. There's already evidence that the different thiazolidinediones may be somewhat selective: The genes induced or repressed by troglitazone aren't the same as those induced or repressed by two other thiazolidinediones.

A better understanding of the nuances of PPAR-gamma's effects in the body may reveal some of the ways diseases like obesity, heart disease, diabetes, and cancer are related. That knowledge in turn could point the way to better drugs to treat these ailments.

"It's going to be difficult to come up with the perfect drug," says Daniel P. Kelly of Washington University School of Medicine in St. Louis. "There will be a lot of growing pains in trying to understand PPARs, but in the process ... we're finding out that the biology is really cool."