Scientists from the University of Copenhagen have discovered a protein that links the body's internal clock to temperature and nutrition, helping brown fat cells regulate energy expenditure. The findings, led by researchers at the Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), were published in the journal Science.
Brown fat differs from conventional white adipose tissue because its primary function is burning energy to generate heat. Its metabolic activity fluctuates throughout the day: dipping during sleep and rising prior to waking. However, exposure to cold or hunger can prompt the body to boost energy expenditure regardless of the time of day.
Investigating brown fat proteins in mice, researchers identified two substances whose levels shifted in response to both circadian rhythms and cold exposure. One was the well-studied uncoupling protein 1 (UCP1), which drives thermogenesis. The second was an obscure protein, SLC25A34, whose function had remained unknown until now.
At thermoneutral temperatures, brown fat expressed relatively low levels of SLC25A34. Following 24 hours of cold exposure, its abundance increased nearly 90-fold—a surge far exceeding that observed in any other tissue.
Subsequent experiments demonstrated that the activity of the Slc25a34 gene is governed by multiple concurrent signals. REV-ERBα, a core circadian clock protein, suppresses gene expression during sleep and lifts this inhibition before waking. Cold exposure can override this daily mechanism when the body requires supplemental heat generation. Additionally, another regulator, PPARα, activates the gene in response to lipid intake and shifts in energy metabolism.
Notably, SLC25A34 appears to participate in both lipid storage and utilization. This aligns with the unique physiology of brown adipose tissue: active cells can synthesize new fat molecules only to rapidly consume them as fuel. This futile cycling generates heat while simultaneously clearing triglycerides and glucose from the bloodstream.
In mouse models lacking SLC25A34, brown fat cells burned less fuel, and the tissue's capacity to respond to cold conditions deteriorated. The researchers hypothesize that the protein helps transport oxaloacetate back into the mitochondria, a step crucial for sustaining this metabolic cycle. However, direct experimental verification that SLC25A34 specifically transports oxaloacetate has yet to be confirmed.
Findings from human cell models yielded similar results: knocking down SLC25A34 in brown fat cells derived from three out of four human donors reduced energy expenditure. Furthermore, an analysis of data across 24 clinical studies revealed that individuals with higher SLC25A34 expression in subcutaneous white adipose tissue exhibited lower average body weight and improved metabolic profiles.
Follow NEWS.am Medicine on Facebook and Twitter