Escaping overweight requires consuming fewer calories or burning more. Brown fat is one way to burn more because it consumes more energy than white fat, but people have little brown fat. However, researchers have found how exposure to cold can activate white fat and remodel it into brown-like fat by comprehensively analysing protein changes to discover what happens to the fat. The researchers hope that these mechanisms can eventually be artificially adjusted so you do not have to freeze to lose weight.
Most people know the feeling of showering in water that is slightly too cold or of jumping into even colder water. Our cells feel this shock in the same way, but instead of screaming, they initiate a series of metabolic processes. For fat cells, this increases the number of mitochondria, the cells’ tiny power plants, making them consume more energy. In practice, the fat changes colour from white to brown – a remodelling process called browning, and metabolism researchers are seeking to promote this process.
“We hope that we can learn to understand these processes so well that we can also learn how to tweak the metabolism in the cells. In our new study, we found that mice express a specific cold shock protein that seems to be crucial in determining whether the fat tissue changes from white to brown. We do not yet fully understand the molecular mechanisms, but we can see that this protein is rapidly induced by cold in brown fat and in the white fat depots that have the potential to acquire brown fat characteristics. Understanding the mechanisms by which this protein contributes to promoting healthy fat tissue may help to avoid obesity and type 2 diabetes,” explains Brice Emanuelli from the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen.
Up- and downregulation
The researchers investigated what happens in fat tissue in ordinary mice when the browning of white fat is promoted. The mice lived at 29°C until the researchers suddenly lowered the temperature to 5°C. They then monitored the fat tissue to determine how the mice reacted to the cold.
“We measured changes in protein abundance in the fat tissue across a 3-week time course in which cold remodelled the white fat into brown-like fat. Exposing the mice to cold dramatically altered the protein profile of the fat tissue, and we found that one of them, YBX1 (Y box binding protein 1), was induced early and especially caught our attention,” says Brice Emanuelli.
One reason why the researchers decided to focus on YBX1 was that its DNA code may be evolutionarily related to both bacteria and humans. When evolution preserves sequences and structures, this indicates that these are appropriate and essential functions. Another reason was YBX1’s very remarkable activation method.
“For decades, researchers have focused on the heat shock proteins that are activated if cells are exposed to intense heat, but YBX1 is one of the rarer cold shock proteins specifically activated by cold. We therefore decided to investigate what would happen if we up- or downregulated it,” explains Brice Emanuelli.
The researchers used small interfering RNAs, which can reduce or completely eliminate the expression of certain genes, and CRISPR-mediated induction of the same proteins to discover what happens if there is excess or no YBX1 protein.
“The evidence suggests that YBX1 plays a significant role in remodelling white fat into brown fat. The mice’s adipocytes (fat cells) failed to turn brown if we removed YBX1, whereas they were more brown and metabolically active when YBX1 protein was present in abundance,” says Brice Emanuelli.
Multifunctional protein
The new research is very exciting, since stimulating the browning of white fat is a promising way to improve metabolic health. Until now, the molecular mechanisms have been largely unknown, but with the new insight into how fat tissue responds to cold, researchers have obtained important knowledge about how to stimulate fat tissue to consume more energy – at least in mice.
“Among a core of 44 transcriptional regulators acutely regulated by cold, YBX1 is one of the key factors that we were seeking to discover, and we want to investigate how it is regulated, whether YBX1 plays a similar function in humans and especially whether YBX1, or some of the cellular processes it regulates, can be influenced in a sensible and safe way,” explains Brice Emanuelli.
YBX1 may not the obvious candidate to directly regulate, since it is involved in multiple biological processes such as the repression of protein translation, RNA stabilization and splicing, DNA repair, regulation of transcription and RNA composition of extracellular exosomes. YBX1 increases tumour growth in various types of cancer and is therefore a potential drug target in anticancer therapy. But it is also involved in cellular senescence and the determination of cell fate. The researchers therefore think that understanding the molecular mechanisms underlying its mode of action in fat cells is necessary to uncover promising alternative approaches to influencing fat metabolism.
“Activating white fat has enormous potential for combatting the obesity epidemic, and thus YBX1 is key to understanding the mechanisms behind the process. We will now continue trying to understand what YBX1 does and whether we can adjust other linked mechanisms to stimulate fat browning without compromising other key mechanisms in the cells,” says Brice Emanuelli.
