Brown fat burns fuel to make heat, and this activity is controlled by the body clock: dropping during sleep and rising before waking. But a cold morning or a skipped meal makes demands the clock never planned for. How the body keeps to a fixed energetic timetable while still improvising has long been a puzzle.
Researchers at the University of Copenhagen's NNF Center for Basic Metabolic Research (CBMR) now show that SLC25A34, a little-studied protein in the mitochondria of fat cells, acts as a switch that connects the body clock, temperature and diet to how fat cells store and spend energy.
"We usually think of the body clock, the response to temperature, and the response to food as separate systems. A mitochondrial transporter that is tuned by the time of day, the temperature, and what we eat raises the possibility of therapies that shift when and how the body burns fuel. That would be a different kind of lever from today's obesity and diabetes treatments," says corresponding author Associate Professor Zach Gerhart-Hines of CBMR.
They started their study by searching large datasets for proteins in mouse brown fat that respond to both the clock and the cold. Only two passed every test: UCP1, the best-known heat-producing protein, and SLC25A34, a related transporter whose job was unknown. In mice kept comfortably warm, brown fat contains less SLC25A34 than almost any other organ. But after 24 hours in the cold its levels rose 90-fold, making brown fat the tissue with the most SLC25A34 in the body.
To work out how the Slc25a34 gene is controlled, the team studied mice engineered to lack particular regulatory proteins. They found three separate controls, each answering to a different signal. A clock protein, REV-ERBα, keeps it switched off during sleep and releases it before waking. Cold lifts this brake at any hour, overriding the schedule when extra heat is needed. And fat, from the tissue's own stores or the diet, switches the Slc25a34 gene on through another protein, PPARα.
Seemingly paradoxically, both fasting, which promotes using fat, and insulin, the hormone that promotes building fat, increase SLC25A34 levels. This means that signals for burning and storing fat run through the same transporter. However, this is explained by the fact that active brown fat actually builds new fat molecules to then burn, a cycle that generates heat and clears fat and sugar from the blood. SLC25A34 appears to keep the cycle turning by carrying a molecule called oxaloacetate back into the mitochondria. Without the transporter, brown fat cells burned less fuel, and in mice the tissue's fat-burning response was significantly weaker. The team has yet to show directly that the transporter carries oxaloacetate, or what losing it means for long-term health.
Silencing the transporter in brown fat cells from three of four human donors also reduced their fuel burning. Across 24 clinical studies, people with more SLC25A34 in the white fat beneath their skin tended to be leaner and metabolically healthier. This is an association and does not prove cause.
"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," says Iuliia Karavaeva of CBMR, first author of the study.
---
The study was led by the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen, in collaboration with researchers at the University of Southern Denmark, the University of Pennsylvania, Harvard Medical School, the Broad Institute of MIT and Harvard, Duke University, Temple University, the University of Kentucky, Wayne State University, The Rockefeller University, McGill University, the University of Cambridge (including the MRC Mitochondrial Biology Unit), Amsterdam UMC, the Medical University of Graz, the University of Debrecen and Helmholtz Munich, among others.
The research was supported by, among others, the Independent Research Fund Denmark through a Sapere Aude Starting Grant, the European Research Council through a Starting Grant (aCROBAT), and the Novo Nordisk Foundation, including a Bioscience PhD fellowship and a postdoctoral fellowship to Iuliia Karavaeva and support for the Center for Adipocyte Signaling (ADIPOSIGN).
Read the paper in Science: 'Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of adipocyte lipid cycling'. DOI: 10.1126/science.adz4797
