CAN BROWN FAT DEFEAT OBESITY?

Why turning down the thermostat could help win the battle of the bulge.

For most people, “fat,” particularly the kind that bulges under the skin, is a four-letter word. It makes our thighs jiggle; it lingers despite our torturous attempts to eliminate it. Too much of it increases our risk for heart disease and type 2 diabetes (the most common form of the condition). For decades researchers have looked for ways to reduce our collective stores of fat because they seemed to do more harm than good.

But biology is rarely that simple. In the late 2000s several research groups independently discovered something that shattered the consensus about the absolute dangers of body fat. Scientists had long known that humans produce at least two types of fat tissue—white and brown. Each white fat cell stores energy in the form of a single large, oily droplet but is otherwise relatively inert. In contrast, brown fat cells contain many smaller droplets, as well as chestnut-colored molecular machines known as mitochondria. These organelles in turn burn up the droplets to generate heat. Babies, who have not yet developed the ability to shiver to maintain their body temperature, rely on thermogenic deposits of brown fat in the neck and around the shoulders to stay warm. Yet investigators assumed that all brown fat disappears during childhood. The new findings revealed otherwise. Adults have brown fat, too.

Suddenly, people started throwing around terms like holy grail to describe the promise of brown fat to combat obesity. The idea was appealingly simple: if researchers could figure out how to incite the body to produce extra brown fat or somehow rev up existing brown fat, a larger number of calories would be converted into heat, reducing deposits of white fat in the process.

Brown fat proved difficult to study, however, in part because it was so hard to find in adults. In addition, some experts doubted that enough brown fat could remain in the grown-up body to make much of a difference for the obese. Finally, the easiest way to get brown fat warmed up and going is to expose people to low temperatures, which somewhat diminishes brown fat’s appeal as a weight-loss tool. The more researchers learned about brown fat, the more complications and questions arose.

Now, however, the understanding of brown fat is turning a corner. Scientists have learned new ways to pinpoint its location underneath the skin. The latest evidence suggests that it can indeed reduce excess stores of fat even in the obese. Researchers have also identified compounds that can activate brown fat without the need for unpleasantly chilling temperatures. As bizarre as it sounds, fat may become an important ally in the fight against obesity.

BIG FAT COMPLEXITIES

In 2009 three different groups independently published papers in the New England Journal of Medicine confirming their discovery of active brown fat cells in healthy adults. Investigators spent the next five years figuring out how to study brown fat more easily and in greater detail.

The most popular method of mapping where brown fat is located under the skin has been to scan the body using combined positron-emission tomography and computed tomography (PETCT). This technique produces highly detailed images of the body’s interior but requires a costly and invasive procedure, says Paul Lee, a research officer at the Garvan Institute of Medical Research in Sydney. To perform such scans, doctors first inject patients with solutions of radioactive but benign sugar molecules. Once the mitochondria inside brown fat cells start working, they consume the radioactive sugar, which emits gamma rays that the PET part of the scan can detect. The CT scan outlines the various different types of tissue, and the combination of the two technologies identifies brown fat cells that happen to be active while overlooking all the dormant deposits.

Lee says several new methodologies are on the horizon that could make investigating brown fat in people easier and far more accurate. Scientists have, for example, devised ways of measuring brown fat with magnetic resonance imaging (MRI), a technology that uses giant magnets to harmlessly align water molecules in the body in such a way that detailed images of its different tissues are created and that is much less invasive than PET-CT scans because no injections are necessary. Another relatively inexpensive and noninvasive option is thermal imaging, which identifies hotspots of brown fat under the skin by monitoring the temperature of the overlying skin.

As tools for studying brown fat have improved, experimenters have challenged previous pessimism about its ability to help people lose weight. In a 2012 study, six men remained inactive for three hours while wearing a cold suit that circulated water with a temperature of 64.4 degrees Fahrenheit over their skin—cold enough to lower their body temperature without causing too much shivering. That way the researchers could be sure that most of the extra calories burned during those three hours were expended by brown fat cells rather than quivering muscles.

The volunteers burned an extra 250 calories compared with what they would have used up during three hours of inactivity at more typical indoor temperatures. Although that may not sound like a lot, an extra 250 calories a day for two weeks would consume enough energy to allow a dieter to lose a pound of fat. “Even very modest increases in metabolism over a long period can lead to significant weight reduction,” says Barbara Cannon, a physiologist at the Wenner-Gren Institute for Experimental Biology in Stockholm, who was not involved in the study.

Recent experiments have also revealed that brown fat’s benefits go far beyond burning calories. A 2011 study using mice found that brown fat can fuel itself with triglycerides taken from the bloodstream—exactly the kind of fatty molecules known to increase the chances of developing metabolic syndrome, a cluster of conditions that raises the risk for heart disease, stroke and diabetes. Brown fat cells also draw sugar molecules from the blood, which could help lower the risk for type 2 diabetes; chronically high levels of blood glucose wreak havoc on the body’s ability to manage those levels in the first place, which in turn sets the stage for diabetes.

BEIGE POWER

Given these findings, an increasing number of scientists and biotech companies are trying to develop ways to multiply the number of brown fat cells in the body or somehow boost their activity. In addition, they are exploring the possibility of transforming white fat cells into tissue that behaves a lot like brown fat—what they call “beige” or “brite” (brown in white) fat.

Figuring out whether cool temperatures trigger the production of beige fat, in addition to revving up brown fat, seemed like a good starting point. Last year Japanese researchers asked 12 young men with lower than average amounts of active brown fat to sit in a 63 degree F room for two hours a day for six weeks. At first, the study participants burned an average of 108 extra calories in the cold compared with more normal indoor temperatures. After six weeks, however, their bodies were burning an extra 289 calories in the cold, and PET-CT scans indicated that their beige fat activity had indeed increased. A group of similarly aged and healthy men who were not repeatedly exposed to the cold showed no change in their metabolism. The researchers think that over the six weeks low temperatures increased the activity of a gene named UCP1, which seems to guide the conversion of white fat into beige fat.

Don’t fancy low temperatures? Investigators have identified several molecules that may be able to stimulate such “browning” of white fat without the need for cold. Two 2012 studies showed that a hormone called irisin, which is released from muscle cells after exercise, coaxes white fat to behave like brown fat. In one of these studies, researchers injected mice with a gene that tripled the levels of the hormone in the blood of mice that were obese and had dangerously high amounts of sugar in their bloodstream. The mice lost weight and regained control of their glucose levels in just 10 days.

Exercise has also been shown to increase UCP1 activity in brown fat, making it more active. Other naturally derived browning stimulators currently under investigation include brain-derived neurotrophic factor—a molecule that usually promotes growth of neurons—and SIRT1, a protein whose purpose remains mysterious but that may help the body manage stress.

Whereas converting existing white fat into beige fat is a promising approach, some researchers, including Cannon, think it may prove more helpful to increase amounts of brown fat itself. In 2013 she and her colleagues reported that brown fat can burn at least five times more stored energy than beige fat. Ideally, Cannon says, scientists will learn how to keep stores of brown fat as large and active throughout adulthood as they are in infancy: “The goal should be to maintain brown fat forever rather than having to re-create it.”

Many researchers are confident that they will eventually hit on specific brown fat–based treatments, although most admit that such interventions most likely are 10 years away at least. In the meantime, though, self-motivated individuals can start applying some of the insights about brown fat to their own lives. “There is no doubt that an unhealthy diet and sedentary lifestyle are the two chief drivers of the obesity epidemic,” Lee says, but “lack of exposure to temperature variation could be a subtle contributor.”

In other words, central heating has its drawbacks, in part because it may dampen brown fat’s activity. No one is quite ready to suggest turning down the thermostat in winter as a way of losing weight, however—although it undoubtedly saves money on your heating bill. Whether it might also help keep you trim and ward off chronic diseases remains to be seen.

By Melinda Wenner Moyer in "Scientific American",USA, August 2014, volume 311, number 2, excerpts p.30-32. Digitized, adapted and illustrated to be posted by Leopoldo Costa.

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