By suppressing just one protein, stores of white fat can switch to becoming calorie-burning beige fat, in a feat that so far has eluded scientists working on this long-studied area of obesity treatment.
University of California San Francisco researchers found that by suppressing the protein KLF-15 – which they'd earlier identified as playing a role in cell metabolism, and one that is far more abundant in calorie-burning beige and brown fat – the cells themselves switched their function.
And without the protein present, the default setting for fat cells appeared to be beige, not the predominant white.
“A lot of people thought this wasn’t feasible,” said Brian Feldman, MD Distinguished Professor in Pediatric Endocrinology and senior author of the study. “We showed not only that this approach works to turn these white fat cells into beige ones, but also that the bar to doing so isn’t as high as we’d thought.”
Previously, scientists had focused on turning stem cells into calorie-burning brown or beige fat, which is essentially used by our bodies as fuel for temperature regulation. As such, these cells burn through fat stores, whereas white adipose tissue are the stores we find so hard to shift in weight loss.
And until now, it was thought that stem cells were needed from the outset, so by suppressing KLF-15, it might be much simpler to speed up effective, long-term weight loss than previously thought. And why there have been so many roadblocks with earlier stem-cell research.
As many of us would already know, thanks to the huge amount of research in the area, mammals have a mix of brown and white fat, with the most recently discovered beige adipose tissue sitting somewhere in between. White fat cells are the spare energy stocks, which can release fatty acids when energy is needed – yet most of us have a too abundant supply to be able to use these for easy calorie burning and in turn weight loss.
Beige fat cells burn energy efficiently, like brown adipose tissue, yet they are found spread throughout white fat tissue. Switching off the KLF-15 protein, as the scientists demonstrated in mice, saw the beige fat cells grow in size, sacrificing white fat cell space and essentially resulting in significantly less fat stores.
“For most of us, white fat cells are not rare and we’re happy to part with some of them,” Feldman said. “We’re certainly not at the finish line, but we’re close enough that you can clearly see how these discoveries could have a big impact on treating obesity."
Here, the scientists cultured human fat cells to see how KLF-15 was able to change stores to calorie-burning powerhouses. What they found was that the protein was directly controlling a receptor known as Adrb1. It's a far cry from targeting the previously known Adrb3 receptor, which had great results in mice but failed once research was applied to humans.
As such, a drug that could target the Adrb1 receptor is more likely to have the same effects as in mice, and it may be an even better weight-loss option than the GLP-1 treatments that can come with wide-ranging side-effects, from stomach complications to nausea and other brain-gut related concerns.
The researchers believe their discovery could lead to treatment that would limit fat deposits without affecting the brain, and provide long-lasting effects due to the lifespan of fat cells.
The new study was published in the Journal of Clinical Investigation.
