The last link in the chain from food to fat has been found. Deep in human cells sits the master regulator of fat cells, a gene with the awkward name PPAR-gamma. When activated, this gene and the protein it produces drive the formation of fat cells that are part of the epidemic of obesity now sweeping the United States.
That new knowledge isn’t going to lead to an anti-obesity pill, at least not directly, but PPAR also plays a role in fighting cancer. Researchers at Dana-Farber Cancer Institute in Boston are testing a drug that they expect will activate PPAR-gamma in prostate cancer patients, thereby suppressing tumor growth.
“We don’t know what the odds are that it’s going to work, but we’re very enthusiastic about the possibilities,” says Bruce Spiegelman, a professor of cell biology at Harvard Medical School.
Spiegelman and his colleagues first uncovered the role of PPAR-gamma in fat production in 1994. But scientists were not sure it worked alone. They believed that two routes could lead to production of new fat cells, one went though PPAR-gamma and another through a different gene-protein combination called C/EBP. Then Spiegelman and his colleagues showed that you could knock out the C/EBP path in cells and PPAR could still make fat cells. In the latest edition of the journal Genes and Development, Spiegelman reports on experiments showing that, in the absence of PPAR, C/EBP does not produce fat cells on its own.
“Although many factors affect fat genesis, it ultimately comes down to the amount and activity of PPAR-gamma, Spiegelman comments. “You can call it the master regulator of turning uncommitted or unspecialized cells into fat cells.”
About 60 percent of adults and 13 percent of children in the United States are overweight or obese, according to Surgeon General David Satcher. Spiegelman calls obesity “the most common metabolic disease in the industrial world,” sharply raising the risk for diabetes, heart disease, and other health problems. Several newspaper articles have stated that an anti-fat producing drug, based on blocking the activity of PPAR-gamma, could provide an easier solution than disagreeable exercises and unappetizing diets.
“That’s inaccurate newspaper speculation,” Spiegelman insists. “Overweight and obesity are problems of energy balance not just fat storage.”
These cells are not just bags in which to store energy in the form of fat derived from food. They play a major role in the body’s energy balance. If there are not enough fat cells available for energy storage, the fat simply accumulates somewhere else. It can build up in the liver, blood vessels, or pancreas and damage these organs.
“Our lab made genetically engineered mice that lacked fat cells,” Spiegelman says. “They turn out to be very sick animals with fatty livers.”
Humans born without these cells also suffer from swollen, diseased livers.
It might be possible to mildly inhibit fat-cell production in a way that does not have such effects. PPAR-gamma does not work alone; it collaborates with other proteins, including C/EBP, to produce fat. “We’re trying to find out how all these factors interact,” Spiegelman notes. “But so far the jury is out on whether we can manipulate these interactions to help people lose weight, or keep them from gaining too much of it.”
Regulating the activity of PPAR-gamma may help treat diabetes, however. Recent research reveals that PPAR-gamma is the target of drugs currently given to more than a million diabetics. People with the disease do not produce enough insulin, a hormone needed for the proper balance of blood sugar in the body. That sugar balance, in turn, is necessary to provide energy to the brain and other vital organs. Determining the role of PPAR-gamma in a diabetic’s sensitivity or resistance to insulin could lead to better drugs for a disease that affects about 125 million people worldwide.
In the course of studying all these relationships, Spiegelman and his colleagues discovered the switch that regulates the liver’s production of sugar. When this switch sticks on the “on” position, as it does in diabetics, the sugar builds up to dangerous levels.
“It was a real eureka moment,” Spiegelman said of the discovery, made by people in his lab working with researchers in several other institutions, including the Joslin Diabetes Center in Boston. The team, which reported the finding in September, included J. Cliff Yoon of Harvard Medical School.
The hope is that new drugs can be found to reduce the excess blood sugar that is so difficult to control with current treatments.
PPAR-gamma, along with a number of its collaborators and relatives, turns up in several different reactions related to major maladies such as blood vessel disease and cancer. Just as switching it off stops fat cell production, switching it on seems to reduce tumor growth in a number of different malignancies including prostate cancer. An anti-diabetes drug called rosiglitazone is now being given to 100 prostate cancer patients at the Dana-Farber Cancer Institute.
“We want to know if the drug stabilizes or stops development of the disease,” Spiegelman explains. “Rosiglitazone treats diabetes without any side effects. Wouldn’t it be fantastic if we could use it on some patients to replace harsh treatments such as surgery, radiation, and hormone therapy?”
Physicians now detect early stages of prostate cancer by tracking rising levels of prostate specific antigen (PSA), a substance secreted by tumors in the prostate gland. “Some patients with early stages of the disease will eventually die from it if not treated,” Spiegelman says. “Others have tumors that grow so slow, they will die with prostate cancer rather than of it.”
At present, men in both situations often undergo surgery or radiation to rid themselves of the cancer, procedures that frequently result in impotence, incontinence, and other highly undesirable side effects. Spiegelman and Philip Kantoff, his colleague in the study, want to know if the disease can be controlled with a benign pill in those men who have high PSA but slow-growing tumors. They hope to have an answer by the end of this year.
“In previous experiments we have done, antidiabetic drugs have produced encouraging responses in patients whose prostate cancer is spreading,” Spiegelman notes. “This latest experiment is very cool. We are excited and hopeful that the results will be, too.”