Image
© Laura Austgen and R. BowenThis micrograph image of brown fat showing the extraordinary number of mitochondria involved in heat generation
In the war on our waistlines, fat is the enemy. It is fat, or adipose tissue, that gives us our beer bellies and our love handles, our man boobs and our muffin tops. And when plastic surgeons sculpt people into slenderness, it is fat tissue they suck up and throw out with the clinical waste.

It seems odd, then, that a type of fat tissue could also be the key to weight control. Not ordinary white adipose tissue, but a special kind called brown fat.

In some mammals, brown fat turns the energy obtained from food into heat, burning up calories without the animal expending any effort. It used to be thought that adult humans had no brown fat, but a raft of new evidence indicates that this is wrong, and it is in fact present and functional in at least some individuals. Differences in the amount of brown fat each person has may help to explain why some of us are slim while others are overweight, and why many of us pile on the pounds as we age.

Researchers are experimenting with various ways to increase the amount or activity of our brown fat, either pharmaceutically or even surgically, by extracting ordinary white fat through liposuction, transforming it into brown fat and re-implanting it. A mere 50 grams of brown fat - well within the range of what some of us already have - could dissipate around 500 calories a day. "I exercise on an elliptical trainer and it's pretty hard for me to burn up 500 calories," says Ronald Kahn, head of obesity research at Harvard Medical School's Joslin Diabetes Center. "If I could do it without working and do it every day, it would be pretty great."

Image
© W. Van Marken LichtenbeltIn this PET-CT scan Brown fat (black) shows up after exposure to cold (right) but is not apparent in a scan at room temperature (left).
Brown fat's role in heat generation, also known as thermogenesis, has been extensively studied by animal physiologists. It turns out that brown fat cells have unusual mitochondria, the tiny structures found in almost all cells that release energy from food. In the vast majority of cells this energy is either stored or used to power cellular processes. The mitochondria in brown fat, however, contain a protein called thermogenin (or uncoupling protein 1), which causes energy to dissipate as heat. "This is a tissue whose sole purpose is burning energy," says Francesco Celi, a researcher at the US National Institutes of Health.

As you might expect, this form of heat generation is important when it is cold, and as such might have been an important step in the evolution of mammals (see "Central heating for mammals"). In humans, it comes in useful for babies, who are prone to heat loss because their small size gives them a high surface-to-volume ratio and their temperature regulation systems are immature - they can't even shiver. Under the skin, babies have clearly visible deposits of brown fat, principally around the back, shoulders and neck.

By adulthood, however, things look very different. Autopsies of adults reveal, either no brown fat at all, or apparently insignificant traces within white fat. This led to the assumption that other tissues take over the role of heat generation when necessary. Muscles, for example, can generate heat through shivering and also non-shivering thermogenesis.

Then in 2002, a new way of looking inside the human body, called PET-CT scanning, threw up some odd results. The technique involves X-raying people after they have been injected with a radioactive tracer that picks up metabolic hotspots - a telltale sign of tumours. But the images were occasionally spoiled by constellations of bright spots around the collarbone, shoulders and back. Clad only in hospital gowns, patients tended to get chilly during their scans. When the rooms were warmer the trouble spots disappeared. Radiologists came to suspect that they were seeing brown fat firing up in response to the cold.

Interest in brown fat picked up, and several groups began looking for the tissue more systematically in volunteers. A clutch of studies published in the past few months have shown that some people have small but distinct islands of brown fat, each with a dense blood supply and nerve network. Analysis of tissue samples from the hotspots shows they contain thermogenin, the molecular hallmark of brown fat.

Image
© New Scientist
"Everyone would now unequivocally say that adult humans have brown fat, and that the brown fat can be active under normal circumstances," says Ronald Kahn, who authored one of the papers (The New England Journal of Medicine, vol 360, p 1509). But not everyone has it. While only small numbers of people have been tested so far, researchers are starting to draw some tentative conclusions about who has the most.

Age is one factor. In a recent study, metabolically active brown fat was found in about half of subjects aged 23 to 35, but was present in only two out of 24 people aged 38 to 65 (Diabetes, vol 58, p 803). That team also found that people with less brown fat tended to be fatter.

Can we conclude, then, that brown fat protects against weight gain? "We cannot say anything about cause and effect," says Jan Nedergaard of Stockholm University in Sweden, a veteran of brown fat research. It is possible, he points out, that being obese somehow leads to a decline in brown fat.

Research in animals, however, supports the idea that a lack of brown fat may be a cause rather than a consequence of obesity. For example, mice that are genetically modified to lack thermogenin are more likely to become obese (Cell Metabolism, vol 9, p 203). "We believe it's probably the case that leanness is secondary to having greater amounts of active brown fat," says Kahn.

It may be our genes that give some of us lucky tickets in this metabolic lottery and consign others to a lifetime of battling their weight. "We know that in some animals there seems to be a genetic difference in the amount of activatable brown fat the animals have," says Kahn. "So I would think that the same is possibly true in humans."

That raises the all important question: can we harness the power of brown fat to help overweight people trim their waistlines? This could, in theory, be done either by boosting the amount of our brown fat, or boosting its activity at normal, everyday temperatures - or preferably both.
Hormone replacement

Nedergaard believes the focus should be on preventing the decline in brown fat as people get older. "Most obesity appears in middle age and onwards, and this is when it seems brown fat activity starts to disappear," he says. It might be possible to identify the cause of this decline and then reverse it, perhaps by replacing a lost hormone. What this hormone might be, though, remains a mystery.

Some existing diabetes drugs of the class known as glitazones, or thiazolidinediones, have been shown to increase the quantity of brown fat in rats and to stimulate the formation of human brown fat cells in the lab. However, when used to treat diabetes they do not seem to activate brown fat, nor cause weight loss.

Another approach is to look at the mechanism that causes brown fat to be activated when an animal is exposed to cold. In animals and adult humans too, activation is triggered through the release of the hormone noradrenalin, which interacts with a receptor on the surface of the cells called the beta-3 adrenergic receptor. Rodents and dogs lose weight when given drugs that stimulate these receptors, but attempts to do the same for humans have shown a much smaller effect. Perhaps this is because most people have little active brown fat left.

If our natural stores of brown fat have dwindled, perhaps a more radical approach is needed. Although the work is still at an early stage, at least two groups are investigating ways of creating brown fat cells in the lab with the goal of surgically implanting them.

Kahn's team is focusing on a compound called bone morphogenetic protein 7, or BMP-7, also known as osteogenic protein 1. It is best known for promoting the formation of bone and cartilage, and a genetically engineered version is used in bone surgery. Last year, the group showed that if cells derived from mouse embryonic stem cells are treated with BMP-7 they turn into brown fat cells. When transplanted into a special breed of mouse that accepts tissue from unrelated individuals, they formed discrete islands of brown fat (Nature, vol 454, p 1000).

To test this approach in people, the team now plans to take white fat cells obtained through liposuction and treat them with BMP-7. The resulting brown fat cells could then be reimplanted into the original donor. "It's got a lot of potential," says Kahn.

Liposuction might not be the only source for brown fat cells though. In a paper that Science listed as one of the top 10 scientific breakthroughs of 2008, a team at Harvard Medical School showed that during embryonic development, brown fat cells arise not from fat, but from muscle precursor cells (Nature, vol 454, p 961). The team also identified the command gene, called PRDM16, that switches these cells onto the brown fat development pathway. This is "the master regulator of brown fat", says Bruce Spiegelman, who led the research.

Last month, his team described taking skin cells from mice, switching on PRDM16 and another gene, and transplanting the altered cells back into the same mice. On subsequent PET-CT scans, the mice had tiny hotspots where the tissue transplants had turned into islands of brown fat (Nature, DOI: link). The researchers are now investigating whether a similar approach could be repeated in people, as well as screening potential drug candidates for their ability to switch on PRDM16. "It's clear that these pathways exist in humans," says Spiegelman.

Manipulating brown fat, whether by drugs or surgery, may not be risk-free, however. By increasing energy expenditure you generate a high-flux metabolic state, points out Celi. This could increase our exposure to potentially harmful free radicals generated by the metabolism, which could conceivably cause cancer or even hasten ageing.

So instead of trying to artificially boost brown fat, with the attendant risk of side effects, why not just activate it by going out in the cold more, or turning down the heating? At first glance, the latter offers the tantalising possibility of helping to save both our waistlines and the planet.

We do not yet know, however, just how uncomfortably low indoor temperatures would have to dip to make a meaningful difference. Another unknown is whether cold-inducing stimulation of brown fat would cause any compensatory mechanisms to kick in. As Nedergaard points out, our natural response to being cold is to eat more - or put on a jumper.

Many other questions remain, but the old dogma that brown fat is either absent or has no physiological role in adult humans has been overturned. This is likely to open up a whole new set of potential options for weight control. Could drugs that enhance brown fat one day be licensed for the treatment of obesity? If they are proved safe and effective will they eventually become available to those of normal weight in pursuit of the perfect figure?

The global rise of obesity is a hugely complex issue, involving not just biological factors but also social, economic and psychological ones. No one is suggesting that these could be cured by means of magic pills, but perhaps it's a case of "every little helps". As Spiegelman says: "We have the potential to develop a whole new approach to obesity."