When brown fat — calorie-burning adipose tissue once thought to exist only in infants — was discovered in adults 15 years ago, obesity medicine researchers started searching for ways to help people make more of it.
A biologic pathway responsible for regulating and maintaining white fat cells, newly identified by researchers at the University of California, San Francisco (UCSF), could be key to making progress in that quest.
The pathway could be a potential target for weight loss drugs, said lead researcher Brian Feldman, MD, PhD, a professor of pediatrics at UCSF. Developing such drugs would probably take several years, ”but we’re very optimistic that one of these approaches that involves this specific pathway is likely to be relevant.”
Unlike white fat, which stores energy, brown fataround the neck and organs burns energy to generate heat. Then there’s beige fat — which forms within pockets of white fat and behaves like brown fat.
Experts have long thought that to create brown or beige fat, you must start with their distinct stem cells and stimulate growth, either physiologically ( through cold exposure or exercise) or pharmacologically (drugs) — a difficult proposition because stem cells are rare.
But Feldman’s study, published last week in The Journal of Clinical Investigation, shows a way to turn mature white fat cells, which tend to be plentiful in adults, into thermogenic beige fat cells — no stem cells needed.
https://www.jci.org/articles/view/172360
Revealing a Pathway for ’Browning’ Fat
In previous studies of adipocyte stem cells, Feldman and his team observed that the transcription factor KLF15 affects the generation and storage of fat cells. Looking to better understand the protein, they knocked out KLF15 in mice — and found the rodents’ white subcutaneous fat cells shifted to beige.
”What our studies suggest is that KLF15 is necessary to keep bad fat cells bad,” said Feldman.
The reason: KLF15 binds to the beta-adrenergic receptor ADRB1 and switches it off. In experiments with white adipocytes from mice and humans, removing KLF15 led to increased ADRB1 expression and a boost in sensitivity to adrenergic stimulation.
”Our studies indicate that if you have more of this receptor, ADRB1, then your fat cells become more sensitive to the signals that are telling it to burn energy,” said Feldman.
Any approach that increases ADRB1 expression, whether shutting down KLF15, targeting ADRB1 directly, or pursuing other paths that feed into this mechanism, could be a therapeutic opportunity in obesity, he said.
Lee Roberts, PhD, who researches brown fat and the mechanisms of metabolic disease, agreed. ”Although any translation of this research to the clinical setting is unlikely to be in the immediate future,” said Roberts, a professor at the University of Leeds’s School of Medicine, Leeds, England, who was not involved in the study.
Moving From Lab to Clinic
Feldman’s team is already exploring potential therapeutics that build on this discovery. Their work involves identifying small molecules that could be taken as oral medication (either by repurposing existing compounds and/or developing novel ones) and investigating biologics that target this pathway.
”It is possible that there will be a clear ’winner’ that will be translated in a single therapy or, alternatively, a family of therapies,” Feldman said, ”with small molecules often being [easier] to rapidly get to patients and biologics following with potential improvements, for example, in efficacy.”
Small molecule drugs or next-generation biologics, in particular, could offer advantages over invasive methods proposed in prior literature, such as transplants of brown fat cells or stem cells, Feldman said.
Once developed, such drugs could likely be used alongside existing therapies, such as glucagon-like peptide 1 agonists, he said, because their target pathways do not overlap.
What’s Next
Feldman’s research group is not the first to consider the role of beta-adrenergic receptors in activating brown or beige fat. However, prior preclinical studies in mice involved the ADRB3 receptor instead of ADRB1, and results in humanswere underwhelming.
”It turns out that this adrenergic receptor that mice use is not exactly the same one that is most likely relevant in humans — at least, that’s what our data is suggesting,” Feldman said.
He hopes this realignment accelerates discovery. ”We think that we’ve identified one of the reasons why prior thinking about this, along the same lines, has not been successful in translating to therapeutics,” said Feldman.
These findings could also facilitate scientific efforts to understand the metabolic consequences of obesity. The study showed browning specifically in subcutaneous fat, the kind that nestles under the skin, not the visceral fat that surrounds organs.
This ”adds nuance to our understanding of the distinct metabolic differences in these fat tissue types,” said Roberts. ”It may also help scientists to better understand why visceral adipose tissue is more closely associated with metabolic diseases over subcutaneous adipose tissue.”
From www.medscape.com
Nyhetsinfo
White adipocytes in subcutaneous fat depots require KLF15 for maintenance in preclinical models
Liang Li1and Brian J. Feldman1,2
ABSTRACT
Healthy adipose tissue is essential for normal physiology. There are 2 broad types of adipose tissue depots: brown adipose tissue (BAT), which contains adipocytes poised to burn energy through thermogenesis, and white adipose tissue (WAT), which contains adipocytes that store lipids. However, within those types of adipose, adipocytes possess depot and cell-specific properties that have important implications. For example, the subcutaneous and visceral WAT confers divergent risk for metabolic disease. Further, within a depot, different adipocytes can have distinct properties; subcutaneous WAT can contain adipocytes with either white or brown-like (beige) adipocyte properties. However, the pathways that regulate and maintain this cell and depot-specificity are incompletely understood. Here, we found that the transcription factor KLF15 is required for maintaining white adipocyte properties selectively within the subcutaneous WAT. We revealed that deletion of Klf15is sufficient to induce beige adipocyte properties and that KLF15’s direct regulation of Adrb1is a critical molecular mechanism for this process. We uncovered that this activity is cell autonomous but has systemic implications in mouse models and is conserved in primary human adipose cells. 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.
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