Researchers from the University of California, San Francisco, have discovered that ordinary white fat cells, which store calories, can be converted into beige fat cells that burn calories to maintain body temperature.

The discovery in mice could pave the way for developing a new class of weight-loss drugs and explain why clinical trials of similar therapies have been unsuccessful.

Until now, researchers believed that creating beige fat might require starting from stem cells. New research published on July 1 in the Journal of Clinical Investigation has shown that ordinary white fat cells can be converted into beige fat cells simply by restricting the production of a certain protein.

"Many thought this was not feasible," said Brian Feldman, MD, PhD, Walter L. Miller, MD, and distinguished professor of pediatric endocrinology, and the study's senior author. "We have shown not only that this approach works in converting white fat cells to beige, but also that the barrier to achieving this is not as high as we thought."

Microscopic image of ordinary white fat, which is transparent.
Ordinary white fat, which is common and stores calories to maintain the body's energy reserves. Image by Liang Li.

Microscopic image of ordinary white fat, which is transparent, and pockets of beige fat cells, which are beige.
White fat without KLF-15 protein, containing small spots of beige fat cells that burn calories (shown above in beige areas within the black circle). Image by Liang Li.

Fat transformation
Many mammals have three "shades" of fat cells: white, brown, and beige. White fat serves as the body's energy reserves, while brown fat cells burn energy to release heat, helping to maintain body temperature.

Beige fat cells combine these characteristics. They burn energy, and unlike brown fat cells, which grow in clusters, beige fat cells are embedded within white fat deposits.

Humans and many other mammals are born with brown fat deposits that help maintain body temperature after birth. However, while brown fat in human babies disappears within the first year of life, beige fat remains.

Humans can naturally convert white fat cells into beige in response to diet or a cold environment. Scientists have tried to mimic this process by encouraging stem cells to become mature beige fat cells.

But stem cells are rare, and Feldman wanted to find a switch that could be turned on to directly convert white fat cells into beige.

"For most of us, white fat is not rare, and we would be happy to part with some of it," Feldman said.

Mice and humans
Feldman knew from his earlier experiments that a protein called KLF-15 plays a role in the metabolism and function of fat cells.

With postdoctoral researcher Liang Li, PhD, Feldman decided to investigate how the protein works in mice, which retain brown fat throughout their lives. They found that KLF-15 is much less prevalent in white fat cells than in brown or beige fat cells.

When they then bred mice with white fat cells that lacked KLF-15, the mice converted them from white to beige. Not only could fat cells switch from one form to another, but without the protein, the default state appeared to be beige.

Researchers then looked at how KLF-15 exerts this influence. They grew human fat cells and found that the protein controls the amount of a receptor called Adrb1, which helps maintain energy balance.

Scientists knew that stimulating a related receptor, Adrb3, causes weight loss in mice. However, human trials of drugs that act on this receptor have had disappointing results.

Another drug targeting the Adrb1 receptor in humans is more likely to work, according to Feldman, and could have significant advantages over new injectable weight-loss drugs that target appetite and blood sugar.

It could avoid side effects like nausea because its activity would be limited to fat deposits rather than affecting the brain. And the effects would be long-lasting, as fat cells live relatively long.

"We're not there yet, but we're close enough to see how these discoveries could have a major impact on obesity treatment," he said.

Source: University of California