The soft and squishy fat rolls on a baby serve a significant purpose. They are an important depot for brown adipocytes—fat cells that burn energy to release heat—that help keep the baby warm.1 As babies grow up, they lose a majority of these brown fat stores. Adults have a higher proportion of white adipose tissue (WAT), which stores fat as energy reserves for the body. However, some cells embedded within WAT can burn fat; these cells that show brown adipocyte-like properties are called beige adipocytes.
Now, researchers have found that suppressing a protein in subcutaneous WAT confers the fat-burning properties of beige adipocytes.2 The results, published in the Journal of Clinical Investigation, reveal that mature adipocytes exhibit plasticity, and identify a pathway that could inform the development of therapies for obesity and metabolic diseases.
Inducing fat burning by converting other cell types into those that expend energy is not a new concept; researchers have previously coaxed stem cells to become energy-burning beige adipocytes for therapeutic purposes.3 “But what's sort of been a stumbling block in the field is that [adult] stem cells are rare,” said Brian Feldman an academic pediatric endocrinologist at the University of California, San Francisco and coauthor of the study. In contrast, white adipocytes are easier to come by.
Feldman and his team previously found that the transcription factor Krüppel-like factor 15(KLF15) affects adipogenesis, the process by which stem cells create fat cells.4 To test whether KLF15 is involved in maintaining adipocytes, Feldman’s team measured its expression in fat isolated from various parts of the bodies of mice. They observed that WAT expressed higher levels of Klf15 compared to brown adipose tissue (BAT). Deleting Klf15 from white adipocytes isolated from mice induced the expression of genes associated with brown fat identity and function. These findings led the researchers to hypothesize that decreased Klf15 levels may be required for BAT to produce heat.
Cold exposure activates BAT, which results in heat production via a beta-adrenergic signaling pathway.5 When the researchers deleted Klf15 in white adipocytes from mice, they observed increased expression of the gene encoding beta-1 adrenergic receptor. Treating Klf15-deleted adipocytes with a beta-adrenergic stimulant enhanced the expression of brown fat-associated genes.
Next, the researchers used mice lacking Klf15 specifically in their adipocytes to investigate the effects of deleting the gene in vivo. The researchers observed that the subcutaneous WAT of mice lacking Klf15 appeared browner and expressed higher levels of brown fat-associated genes compared to the tissue in mice that expressed Klf15. In line with their in vitro findings, the researchers observed increases in beta-1 adrenergic receptor gene and protein expression in these mice.
When the researchers monitored the metabolic rates of the Klf15 knockout mice they observed that these mice burned more energy compared to controls.
“Rather than targeting the stem cells, targeting the mature fat provides a [therapeutic] avenue,” said Feldman.
To investigate whether these results translate to human fat cells, the researchers knocked down KLF15 in human adipocytes obtained from subcutaneous WAT biopsies. Consistent with results from animal experiments, KLF15 knockdown led to increased expression of brown adipocyte-associated genes. Using assays to estimate the metabolic rate of these human adipocytes, the researchers discovered that KLF15 knockdown induced increased oxygen consumption rate, indicating higher energy metabolism, a feature of BAT.
These results pinpoint the players in the fat-burning pathway in humans, said Feldman. “We think that some of the prior work has not translated well into therapeutics because it's been targeting particular proteins that aren't precisely the ones that we think are most relevant for humans,” he added.
“This is very important work,” said Shingo Kajimura, a molecular biologist at Harvard University, who was not involved in the study. However, he thinks that combining approaches to control both food intake and energy expenditure will yield more effective anti-obesity drugs than simply activating energy-burning brown fat.
“Having brown fat is beneficial when you think about metabolic health, which is beyond simply body weight regulation,” he noted. “In that sense, fundamentally understanding how brown and beige fat are regulated is very important. This paper contributes significantly to our basic understanding of biology.”
- Cannon B, Nedergaard J. Brown adipose tissue: Function and physiological significance. Physiol Rev. 2004;84(1):277-359.
- Li L, Feldman BJ. White adipocytes in subcutaneous fat depots require KLF15 for maintenance in preclinical models. J Clin Invest. 2024;134(13):e172360.
- Singh AM, et al. Human beige adipocytes for drug discovery and cell therapy in metabolic diseases. Nat Commun. 2020;11:2758.
- Aggarwal A, et al. The circadian clock regulates adipogenesis by a Per3 crosstalk pathway to Klf15. Cell Rep. 2017;21(9):2367-2375.
- Burl RB, et al. Deconstructing cold-induced brown adipocyte neogenesis in mice. eLife. 2022;11:e80167.
