How the Body Clock and Cold Team Up to Burn Fat

Scientists discover mitochondrial transporter SLC25A34 connects the body clock, cold, and diet to control brown fat burning.

Silencing the transporter blunted thermogenesis in brown fat, while human clinical data linked higher levels of the protein to lower body fat and improved metabolic health. Key Facts: The Triple-Input Master Switch: SLC25A34 is controlled by three distinct physiological levers: the circadian repressor REV-ERBα keeps it silenced during sleep; cold exposure overrides this schedule to induce a 90-fold surge; and dietary or stored fatty acids activate it via PPARα. The “Build-to-Burn” Paradox: Both fasting and insulin stimulate SLC25A34 expression because active brown adipose tissue builds new lipid molecules specifically to burn them for thermogenesis, a substrate cycle fueled by SLC25A34 shuttling oxaloacetate into mitochondria.

Human Metabolic Relevance: Silencing SLC25A34 in human brown fat cells

Human Metabolic Relevance: Silencing SLC25A34 in human brown fat cells significantly reduced fuel consumption, and an analysis of 24 clinical cohorts revealed that individuals with higher expression of the protein in subcutaneous fat were leaner and metabolically healthier. Source: University of Copenhagen / NNF Center for Basic Metabolic Research Brown adipose tissue (BAT) functions as an internal furnace, consuming glucose and lipids to generate heat through non-shivering thermogenesis. Under typical conditions, this energetic output adheres strictly to a circadian timetable, dipping during sleep when energy conservation is prioritized and ramping up prior to waking to prepare the body for daily activity.

Yet the biological environment is rarely predictable. A sudden drop in ambient temperature or a skipped meal introduces urgent thermal and energetic demands that run counter to the pre-programmed clock. How brown adipocytes balance an inflexible 24-hour schedule with the immediate need to improvise has remained an enduring biological puzzle.

Now, an international team led by researchers at the Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR) at the University of Copenhagen has unmasked the molecular junction linking these disparate systems. The study reveals that SLC25A34, a previously uncharacterized transporter embedded in the inner mitochondrial membrane of brown fat cells, serves as a central switch that synchronizes internal circadian rhythms, external thermal cues, and nutritional intake. We usually think of the body clock, the response to temperature, and the response to food as separate systems.

Key details

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,” said corresponding author Zach Gerhart-Hines, Ph.D., Associate Professor at CBMR. Uncovering an Overlooked Thermogenic Engine The investigators initiated their search by mining large-scale functional datasets to identify mouse brown fat proteins that respond simultaneously to circadian pacing and acute cold stress.

Out of thousands of candidates, only two met every screening benchmark: uncoupling protein 1 (UCP1), the canonical engine of non-shivering thermogenesis, and SLC25A34, a member of the mitochondrial solute carrier family whose physiological function had never been resolved. In mice housed at warm, thermoneutral temperatures, SLC25A34 was barely detectable in brown fat compared to virtually every other organ. However, following 24 hours of cold exposure, the transporter experienced an astonishing 90-fold increase, elevating brown fat to the tissue with the highest concentration of SLC25A34 in the entire body.

Investigating the genetic architecture of the Slc25a34 locus in knockout models revealed a tripartite regulatory mechanism: Circadian Control: The clock repressor protein REV-ERBα represses Slc25a34 transcription during sleep, lifting the block just ahead of awakening. Thermal Override: Cold temperatures rapidly lift the REV-ERBα brake regardless of the hour, overriding the circadian clock whenever emergency heat generation is required. Nutritional Activation: Lipids mobilized from intracellular lipid droplets or absorbed from the diet bind to the nuclear receptor PPARα, driving direct transcription of the Slc25a34 gene.

Out of thousands of candidates, only two met every screening

Resolving the “Build-to-Burn” Lipid Cycling Enigma The researchers noticed an apparent biochemical contradiction: both fasting (which drives lipid catabolism) and insulin signaling (which promotes lipid storage) provoked marked increases in SLC25A34 levels. Rather than working at cross-purposes, this dual regulation reflects a fundamental property of brown fat biology. To generate sustained heat while clearing circulating glucose and lipids from the bloodstream, active brown adipocytes simultaneously synthesize new fatty acid chains only to funnel them directly into mitochondrial oxidation.

SLC25A34 acts as a metabolic linchpin in this futile cycle by transporting oxaloacetate across the mitochondrial membrane. When the researchers depleted SLC25A34, brown fat cells exhibited blunted fuel consumption, and knockout mice suffered a marked deficit in their capacity to burn lipids for heat. 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 first author Iuliia Karavaeva, Ph.D., of CBMR. Clinical Potential for Obesity and Metabolic Disorders To assess human relevance, the researchers silenced SLC25A34 in human brown adipocytes harvested from donor tissue, which resulted in an immediate reduction in cellular fuel consumption in three out of four donor lines.

Furthermore, across 24 human clinical cohorts, higher expression of SLC25A34 in subcutaneous white adipose tissue consistently correlated with lower body mass index (BMI), reduced adiposity, and enhanced systemic metabolic fitness. While the authors emphasize that this clinical correlation does not establish direct causality, the convergence of molecular, animal, and clinical findings establishes SLC25A34 as an attractive candidate for metabolic pharmacology. Developing targeted agonists capable of activating this mitochondrial transporter could offer a novel avenue for treating obesity and type 2 diabetes by retraining fat cells to burn fuel on demand.