Fat chance

Throughout the leaner epochs of human history, when food supplies were unreliable, the species would not have survived without a way to hoard calories for later use. That is, without fat. Once a meal has supplied the body’s immediate energy needs, any unused fuel gets converted into long molecules called triglycerides, which are dispatched to fatty tissue where they wait for a signal that the body needs them.

But in an era of high-calorie smorgasbords and 24/7 convenience, unused energy can just pile on year after year, a major reason why one-third of the U.S. adult population is struggling with obesity. Laws of physics — the ones about conservation of matter and energy — dictate that schemes for burning off all that fat are pretty much limited to two options: Diet to lower the amount of energy consumed, or exercise to increase the amount of energy the body needs.

Most current antiobesity drugs work on the diet half of the equation, helping people limit calories by dampening appetite or by interfering with the digestion of food. Approaches that knock down cravings are based largely on research in the 1990s that worked out some of the biological underpinnings
of hunger.

More recently, though, experiments have deepened scientists’ understanding of the way fat locks up and releases surplus calories — providing hope that future therapies may offer a kind of virtual exercise. While there’s still no getting around the laws of thermodynamics, scientists are getting closer to finding ways to trick fat cells into releasing their stockpiled fuel.

One day — maybe not soon, but eventually — medical science might even offer pills that activate the body’s fat-burning machinery without a trip to the gym (in ways that today’s promoters of “fat-burning” products can only dream about).

“I see great opportunities,” says vascular biologist Yihai Cao of the Karolinska Institute in Stockholm. Cao studies how fat tissue remodels the circulatory system as it expands, with the idea of inhibiting blood vessel growth to arrest fat expansion. Recent findings have revealed other secrets about fat as well — among them, the discovery of molecules that help inform fat cells when a person is exercising, and insight into the mysterious role that calorie-burning brown fat plays in weight control. These and other findings could lead to new ways to dissipate fat long after it entrenches itself in
the body.

No approach is far enough along to predict how well it might work in people, or what the side effects might be. Despite the popular perception of fat — that it sits idly on the belly and thighs, doing nothing until it is used — fatty tissue is a dynamic, complex and necessary component of life. Any fat-fighting drug has to overcome daunting safety and logistical hurdles, especially since it would have the potential to be used, or misused, by millions. A therapy that attacks fat too broadly could get rid of one health problem only to create a new one.

A body needs fat “not only for energy storage, but also for the hormones it makes,” says Joel Elmquist of the Taskforce for Obesity Research at the University of Texas Southwestern Medical Center at Dallas. Fat cells play a role in metabolism and even in the ebb and flow of immune cells. “They are key in regulating almost every system in your body,” Elmquist says.

By weight, fat is also one of the most abundant types of tissue in the body. Scientists know that fat grows when existing cells enlarge and when new cells get created. And a bit of bad news here: The number of fat cells can go up, but not down. During weight loss, existing cells shrink. Scientists once thought that fat cells never went away, but a study published in Nature in 2008 demonstrated that a small percentage of them do eventually die. The problem is, the body quickly replenishes them with new ones.

Bring on the brown

Other recent findings have also challenged traditional thinking about fat. Perhaps most surprising has been the discovery that adults have a kind of fat that actually burns calories as well as storing them. Adipose tissue, which is mostly a conglomeration of fat cells, comes in two types — white and brown. White fat is the main energy-storage depot, and is the kind of adipose that makes your belt too tight. Overweight mammals — humans are not the only ones — have an abundance of white fat. Brown fat is found in infants (though they also have those adorable rolls of white fat) and has the ability to burn energy — primarily, researchers think, to generate body heat. “That’s why you have relatively more brown fat in small rodents and newborn babies,” says Stephan Herzig, head of molecular metabolic research at the German Cancer Research Center in Heidelberg. “Those little creatures use the brown fat to maintain temperature.”

Brown fat gradually erodes with age. Scientists once thought that adults had only rudimentary, inactive deposits between their shoulder blades, if any at all. But in April 2009, three research papers in the New England Journal of Medicine (followed by a fourth in July in the journal Diabetes) confirmed that adults can indeed possess metabolically active brown fat (SN: 5/9/09, p. 10). Taken together, the reports make the case that brown fat helps control body weight, raising the tantalizing possibility of fighting fat with fat. 

Though the true role of brown fat in adults is still a subject of investigation, its presence might help explain why some people gain weight more easily than others, or why a propensity for obesity tends to increase as people age. In general, the older you are, the less brown fat you have. “If we were able to increase either the mass or the activity of brown fat in adults, in particular in obese adults, that might be a safe and effective way of using the fat stores in the white fat deposits,” Herzig says.

One of the New England Journal papers described a way to do this — with cold. Dutch researchers studied 24 healthy men, 14 of whom were overweight or obese, and exposed each to two hours of mild chill (about 16º Celsius). Using PET scans to measure the activity of brown fat in the men’s bodies, the scientists found energy radiating from the fat, presumably to help hold body temperature.

What’s more, the brown fat in lean volunteers used more energy in the cold than did the brown fat in obese men. “Brown adipose tissue may be metabolically important in men, and the fact that it is reduced yet present in most overweight or obese subjects may make it a target for the treatment of obesity,” the researchers wrote.

Other than joining a polar bear club, there’s no obvious way to boost your brown fat activity. In May, in the journal Science, Herzig and his colleagues reported that the enzyme COX-2, which is involved in many body processes, plays a role in turning white fat brown. He and his colleagues described experiments in which they rebooted white fat in mice, turning it brown, after increasing the animals’ exposure to COX-2 and mimicking the physiological changes caused by cold. Even more important, mice with new deposits of brown fat lost weight.

These and other experiments have generated intense interest in the creation of brown fat. Still, “It’s naïve and wrong to say we’re going to make your white fat disappear,” says cell biologist Bruce Spiegelman of the Dana-Farber Cancer Institute in Boston.
Spiegelman’s laboratory has revealed much about the biology of brown fat (SN: 8/29/09, p. 9), including the discovery that it shares a cellular origin with muscle cells, a finding that helps explain brown fat’s energy-burning qualities (muscle being an energy-hungry tissue). He and others are now homing in on the exact genetic switches that prompt the body to make brown fat, with the hope that drugs might one day trigger those genes.

One of the genes of interest is called PRDM16. In 2008, Spiegelman and his colleagues reported in Nature that activating the gene in myoblasts — immature
cells that have not yet committed to becoming muscle or fat — spurred the cells to turn into brown fat. Similar results have been found in other precursor cells for fat. “Certainly natural or synthetic compounds that can induce PRDM16 in white fat precursors or in myoblastic cells could have great value in human metabolic disease,” the researchers wrote in Nature in 2009.

Treadmill pills

Brown fat is not the only potential scheme for improved thermodynamics. In one instance, scientists at the Salk Institute in La Jolla, Calif., startled even themselves with experiments in 2008 on an enzyme, called AMP kinase, that is triggered during exercise. To the researchers’ surprise, their studies suggested a way to make lazy cells burn energy as if they were exercising.

One of AMP kinase’s main jobs is to send out a signal to adipose tissue to release its cargo for muscles to use. A few years ago, Salk molecular biologist Ron Evans and his collaborators began to ask themselves if they could mimic the action of AMP kinase without exercise, in the hopes of tricking fat cells into thinking the body needed energy.

Turns out, there are at least two ways. Experimental drugs known as AICAR and GW1516 can reprogram inactive muscle cells to behave as if they were exercising. Chemically, AICAR looks a lot like AMP kinase. It is similar enough that after mice are given AICAR, they are able to run on a treadmill an average of 44 percent farther than untreated mice, just as if their bodies had undergone the conditioning of repeated exercise. “The fact that a drug could do that was pretty remarkable,” says Evans, who reported his results in 2008 in the journal Cell. “I was pretty stunned.”

The second drug, GW1516, activates a genetic switch in a cell’s nucleus that’s also triggered during exercise. When that drug was given to mice that exercised regularly — and therefore also had their AMP kinase on board — endurance rose 68 percent. It appears the activation of AMP kinase by AICAR fooled the body into believing it had exercised or, in the case of GW1516, exercised more than it actually had.

Drugs that could activate the fat-burning machinery triggered by exercise might have few harmful side effects, Evans says. Exercise already has a global effect on many body systems, almost always for the better. “Most drugs are designed to inhibit something, to block something in a cell from occurring,” he says. Drugs that throw up cellular roadblocks to a biological reaction cause side effects when that same process has a day job in some other tissue. But, he says, a drug that promotes the effects of exercise would flip on chemical pathways that the body already uses regularly. “There’s a benefit to activating a natural pathway,” he says.

Starving fat

There may also be a benefit to inhibiting the mechanisms that adipose tissue uses to expand itself. For example, some scientists have become interested in the idea of arresting angiogenesis, the growth of new blood vessels into developing tissue. The idea of slowing angiogenesis has gotten attention in cancer research with the introduction of drugs that impair the ability of tumors to develop a new blood supply, in the hopes of simply starving the malignancy to death. And now it has become clear that adipose tissue, like cancer, feeds itself oxygen with new blood vessels.

In 2002, cardiovascular researcher Maria Rupnick of Brigham and Women’s Hospital in Boston — who had done some of her graduate training in cancer angiogenesis — began to explore whether fat growth would be a good way to study angiogenesis in healthy tissue. “Fat is a normal organ that expands or shrinks depending on the body’s needs,” she says. She began to test the effects of cancer drugs that inhibit angiogenesis on obese mice. “Anything we had on the shelf, we tested,” she says. “All the animals lost weight.”

Fat tissue, like cancer, has a voracious need for oxygen. “It can’t expand without expanding its blood vessels, just like a city can’t expand without expanding its roads,” Rupnick says.

Research in the years since has led to experimentation with almost a dozen antiangiogenesis drugs, many of which are already approved for cancer treatment. In the February issue of Nature Reviews Drug Discovery, Cao reports that all but one have led to weight loss or slowed weight gain in mice. However, he concedes that research is still preliminary, and the relationship between adipose tissue and blood vessel growth is highly complex. For example, while angiogenesis may assist the growth of white fat, it promotes energy expenditure in brown fat — so interfering with angiogenesis in brown fat might impair weight loss. “We are learning,” he says.

To market

Encouraged by recent findings — and the scent of a huge market — drug companies are already beginning to test potential fat-fighting drugs in people. The experiments highlight just how much remains to be understood about fat. Zafgen, a biotech firm based in Cambridge, Mass., sought to develop an antiangiogenesis obesity drug, only to discover that its candidate drug might work in an entirely different way. At high doses, the drug, called ZGN-433, indeed inhibits angiogenesis. But the company now says it is testing the compound at a fraction of the amount needed to inhibit angiogenesis, and at those levels rodents appear to lose weight and eat less even though the blood supply in the adipose tissue looks unaffected.

Zafgen is investigating how the drug might work — it appears to affect metabolic machinery in the liver — and is sponsoring a test in people. One day, says CEO Tom Hughes, such a drug could be distributed through the kind of centers that specialize in surgical weight loss, or bariatrics. “If this drug works the way it does in animals, we see it as being a pharmacological alternative to bariatric surgery,” he says. He expects to have the first data from human studies by the end of this year.

Researchers know well that antiobesity drugs have had a long and often disappointing history. Many a drug has launched with fanfare only to later shipwreck on its own safety concerns. In January, for example, European regulators said doctors should stop prescribing the drug Meridia, which helps control appetite, because of evidence that it raises risk of heart attacks and strokes in people with cardiovascular disease. Then in May, federal officials changed labels on the antiobesity drugs Xenical and Alli to warn consumers about a rare risk of severe liver injury.

Setbacks in the war against obesity should not be too surprising. For at least a couple hundred thousand years, human biology has been perfecting a means to hold onto fat. It will not easily let go.