Weight-Loss Drugs Could Exploit Fat Cells’ White-to-Beige' Mechanism

Researchers at UC San Francisco have figured out how to turn ordinary white fat cells, which store calories, into beige fat cells that burn calories to maintain body temperature.

Until now researchers have largely believed that creating beige fat might require starting from stem cells. The new study, primarily in engineered mice, and with confirmatory investigation in human cells, showed that ordinary white fat cells can be converted into beige fat simply by limiting production of a protein called KLF15. The team identified the gene on which KLF-15 acts, and validated the pathway as conserved in human adipose tissue.

They suggest that their discoveries could lead to development of a new class of weight-loss drug and may explain why clinical trials of related therapies have not been successful.  “A lot of people thought this wasn’t feasible,” said Brian Feldman, MD, PhD, the Walter L. Miller, MD Distinguished Professor in Pediatric Endocrinology. “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.”

Senior author Feldman, and colleague Liang Li, PhD, also in the Feldman lab, reported on their work in Journal of Clinical Investigation in a paper titled “White adipocytes in subcutaneous fat depots require KLF15 for maintenance in preclinical models.” In their report the team stated, “Our results elucidate a pathway for depot-specific maintenance of white adipocyte properties that could enable the development of therapies for obesity and associated diseases.”

Healthy fat, or adipose tissue, is essential for normal physiology, the authors wrote. Many mammals have three “shades” of fat cells: white, brown and beige. White fat (white adipose tissue; WAT) contains adipocytes that store lipids, and so serves as the body’s energy reserve. Brown fat cells (brown adipose tissue; BAT) burn energy to release heat, which helps maintain body temperature.

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

They are also known as ‘brite’ (brown within white) adipocytes. “The precise origin of these cells remains incompletely understood, leaving it an open question whether they are derived from a distinct progenitor population, share a common progenitor with white adipocytes, or are converted from white adipocytes,” the authors noted.

Humans and many other mammals are born with brown fat deposits that help them maintain body temperature after birth. But, while a human baby’s brown fat disappears in the first year of life, beige fat persists. Humans can naturally turn white fat cells into beige ones in response to diet or a cold environment. Scientists tried to mimic this by coaxing stem cells into becoming mature beige fat cells.

But stem cells are rare, and Feldman wanted to find a switch he could flip to turn white fat cells directly into beige ones.  “For most of us, white fat cells are not rare and we’re happy to part with some of them,” he said.

Feldman knew from his earlier work that a protein called KLF-15 plays a role in metabolism and the function of fat cells. This protein is one of a family of 17 Kruppel-like factors (KLFs), which are zinc finger motifs containing transcription factors that regulate development and systemic metabolism, the team explained. “We, and others have found that the Klf family member Kllf15 affects adipose tissue, including regulating adipogenesis, lipid storage and BAT.

With postdoctoral scholar Li, Feldman decided to investigate how the protein functioned in mice, which retain brown fat throughout their lives. They first found that found that KLF-15 was much less abundant in white fat cells than in brown or beige fat cells. “Strikingly, we found that the expression level of Klf15 is approximately 75% lower in brown adipose tissue (BAT) than in white (WAT),” they wrote. “These results suggest physiological implications for these differences, including raising the possibility of a requirement to downregulate Klf15 levels for proper brown fat function.”

When they then bred mice with white fat cells that lacked KLF-15, the mice converted them from white to beige. Not only could the fat cells switch from one form into another, but without the protein, the default setting in mature adipocytes appeared to be beige. The researchers then looked at how KLF-15 exerts this influence. They cultured human fat cells and found that the protein controls the abundance of a receptor called Adrb1, which helps maintain energy balance “We revealed that deletion of Klf15 is sufficient to induce beige adipocyte properties and that KLF15’s direct regulation of Adrb1 is a critical molecular mechanism for this process,” they stated. “We uncovered that this activity is cell autonomous but has systemic implications in mouse models and is conserved in primary human adipose cells.”

Scientists knew that stimulating a related receptor, Adrb3, caused mice to lose weight. But human trials of drugs that act on this receptor have had disappointing results. “Intriguingly, while ADRB3 appears to play a prominent role in rodent brown fat activation, ADRB1 is the predominant adrenergic receptor in human BAT,” they pointed out. “Further, expression of ADRB3 is not detectable in human WAT. These observations likely, at least partially, explain why attempts to develop ADRB3 agonist as therapeutics for obesity in humans have not been successful.”

A different drug targeting the ADRB1 receptor in humans is more likely to work, according to Feldman, and it could have significant advantages over the new, injectable weight-loss drugs that are aimed at suppressing appetite and blood sugar.

Feldman’s approach might 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, because fat cells are relatively long-lived. “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,” he said.

In conclusion, the authors commented, “These discoveries not only expand our understanding of adipose biology, including the plasticity of mature white adipocytes, but they also elucidate and define previously unrecognized pathways with plausible prospects for being more relevant, and therefore potentially more effective, therapeutic targets for humans than other approaches.”