The body's ability to produce heat is closely linked to its internal clock, with brown fat becoming more active at certain times of the day. But factors such as cold temperatures and changes in food intake can disrupt that routine, raising questions about how the body adjusts its energy use while maintaining its daily rhythm.
A new study led by researchers at the University of Copenhagen's Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR) has identified a mitochondrial protein that may help coordinate these competing signals. The researchers found that SLC25A34 appears to connect the body's circadian clock with temperature and nutritional signals, influencing how fat cells store and use energy.
Protein responds to the clock and cold
The researchers initially examined large datasets to identify proteins in mouse brown fat that respond to both circadian signals and cold exposure. Two proteins emerged from the analysis: UCP1, which is already well known for its role in heat production, and SLC25A34, a mitochondrial transporter whose function in brown fat has been less understood.
Under warm conditions, SLC25A34 was present at relatively low levels in brown fat compared with most other tissues. The picture changed dramatically when the mice were exposed to cold. After 24 hours, levels of the protein increased by about 90 times, making brown fat the tissue with the highest amount of SLC25A34 in the animals.
Three signals control the protein
Further experiments showed that the Slc25a34 gene is influenced by three different regulatory mechanisms.
One involves REV-ERBĪ±, a protein associated with the body's internal clock. It suppresses the gene during sleep and allows its activity to increase before waking. Cold exposure can override this timing mechanism, activating the gene when the body needs additional heat regardless of the time of day.
Food-related signals provide another layer of control. PPARĪ±, a protein involved in regulating fat metabolism, can activate Slc25a34 in response to fat available from the body's stores or diet.
The researchers found that both fasting and insulin increased SLC25A34 levels, despite having different effects on metabolism. Fasting generally encourages the body to use stored fat, while insulin promotes processes associated with storing energy.
Brown fat both makes and burns fat
The apparently conflicting responses may be explained by the way brown fat generates heat. Rather than simply breaking down stored fat, active brown fat can first produce new fat molecules and then burn them. This process helps generate heat while also using circulating fat and sugar.
The study suggests that SLC25A34 may help sustain this metabolic cycle by transporting oxaloacetate, a molecule involved in cellular energy metabolism, back into mitochondria.
When researchers removed or reduced the transporter in brown fat cells, the cells used less fuel. Mice lacking the protein also showed a weaker fat-burning response.
However, the researchers have not yet directly demonstrated that SLC25A34 transports oxaloacetate. The long-term effects of losing the transporter also remain unclear.
Findings seen in human cells and clinical data
The researchers also tested brown fat cells from four human donors. Reducing SLC25A34 activity lowered fuel consumption in cells from three of the donors.
In addition, the team examined data from 24 clinical studies and found that people with higher levels of SLC25A34 in subcutaneous white fat tended to have lower body weight and better metabolic health.
The researchers stressed that this was an association and does not establish that higher levels of the protein directly cause better metabolic health.
Could it lead to new metabolic treatments?
The findings could eventually provide researchers with another way to investigate conditions involving energy metabolism, including obesity and diabetes.
Associate Professor Zach Gerhart-Hines of CBMR, the study's corresponding author, said the findings raise the possibility of targeting the timing and activity of fuel burning rather than simply altering energy intake or expenditure.
“Many of these mitochondrial transporters still have no known function. This one turned out to be needed both for building fat and for burning it. And we are only scratching the surface: SLC25A34 is also highly expressed in the heart and is implicated in brain and liver metabolism, but what it does in those organs remains a mystery,” said Iuliia Karavaeva of CBMR, the study's first author.
The researchers noted that SLC25A34 is also found at high levels in organs including the heart, while previous evidence has linked it to metabolism in the brain and liver. Its precise role in those tissues remains to be established.
Published: 03 Oct 2026, 05:04 pm IST
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