Summary:
Researchers at the University of Copenhagen and collaborators have identified SLC25A34, a previously little-known mitochondrial transporter, as a central energetic switch in brown adipose tissue (BAT). This inner mitochondrial membrane protein integrates signals from the circadian clock, cold exposure, and dietary fat availability to coordinate lipid synthesis and oxidation for heat production. Suppressing SLC25A34 reduced thermogenic fuel use in brown fat cells, and human cohort data show higher expression in subcutaneous fat associates with lower body fat and better metabolic health.
Key Facts:
- Triple-input regulator: SLC25A34 responds to three independent signals: the circadian repressor REV-ERBα keeps it off during sleep, acute cold exposure overrides this repression to trigger a dramatic induction, and dietary or stored fatty acids activate it via PPARα.
- “Build-to-burn” lipid cycling: Both fasting and insulin signaling increase SLC25A34, reflecting brown fat’s need to synthesize fatty acids and immediately oxidize them for thermogenesis. SLC25A34 supports this substrate cycle by transporting oxaloacetate into mitochondria.
- Human metabolic relevance: Knocking down SLC25A34 in human brown adipocytes lowered cellular fuel use, and analysis across multiple clinical cohorts found that higher SLC25A34 expression in subcutaneous adipose tissue correlates with leanness and improved metabolic markers.
Source: University of Copenhagen / NNF Center for Basic Metabolic Research
Brown adipose tissue acts as an internal furnace: it burns glucose and lipids in mitochondria to produce heat through non-shivering thermogenesis. This heat production normally follows a circadian rhythm—lower during sleep to save energy and higher before waking to prepare the body for activity.
Yet environmental and nutritional challenges—sudden cold or skipped meals—require immediate adjustments that can conflict with the circadian program. How brown adipocytes reconcile a fixed daily schedule with fast, adaptive responses has been unclear.
An international team led by the Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR) at the University of Copenhagen identified the molecular junction that integrates clock, temperature, and diet signals in thermogenic fat.
They found that SLC25A34, an orphan mitochondrial solute carrier in brown adipocytes, functions as a central metabolic switch. Its regulation allows brown fat to preserve a daily rhythm while remaining able to respond rapidly to acute demands.
“We often treat the circadian clock, temperature sensing, and nutrient sensing as separate systems. A mitochondrial transporter regulated by time of day, cold exposure, and dietary lipids suggests new ways to control when and how the body burns fuel—different from current obesity and diabetes therapies,” said corresponding author Zach Gerhart-Hines, Ph.D., Associate Professor at CBMR.
Uncovering an Overlooked Thermogenic Engine
Using large-scale datasets, the team screened for proteins in mouse brown fat that respond to both circadian cues and acute cold. Only two proteins passed all filters: the well-known uncoupling protein 1 (UCP1) and the previously uncharacterized SLC25A34.
Under thermoneutral conditions SLC25A34 levels in BAT are low, but 24 hours of cold exposure increased its expression roughly 90-fold, making cold-stimulated brown fat the organ with the highest SLC25A34 concentration in the body.
Genetic and regulatory studies showed a three-part control mechanism:
- Circadian repression: REV-ERBα suppresses Slc25a34 transcription during the sleep phase.
- Thermal override: Cold exposure rapidly removes REV-ERBα–mediated repression, allowing induction of the transporter regardless of time.
- Nutritional activation: Mobilized or dietary fatty acids activate PPARα, which directly drives Slc25a34 expression.
Resolving the “Build-to-Burn” Lipid Cycling Enigma
The team addressed an apparent contradiction: fasting (which promotes lipid breakdown) and insulin (which promotes lipid synthesis) both elevate SLC25A34. Rather than opposing each other, these signals enable a coordinated lipid cycle: brown adipocytes synthesize fatty acids and then immediately oxidize them to sustain thermogenesis while clearing circulating nutrients.
SLC25A34 facilitates this futile but thermogenically productive cycle by transporting oxaloacetate into mitochondria. Oxaloacetate balance is essential because cytosolic pathways that produce acetyl–CoA for fatty acid synthesis also generate oxaloacetate, which must be returned to mitochondria to maintain TCA cycle flux. When SLC25A34 is depleted, brown adipocytes consume less fuel and mice show diminished capacity to burn lipids for heat.
“Many mitochondrial carriers remain functionally unassigned. SLC25A34 is required both for lipid synthesis and mitochondrial oxidation in thermogenic fat. It is also highly expressed in heart and implicated in brain and liver metabolism, highlighting broader physiological roles that need investigation,” said first author Iuliia Karavaeva, Ph.D., of CBMR.
Clinical Potential for Obesity and Metabolic Disorders
To test relevance for humans, researchers silenced SLC25A34 in brown adipocytes derived from human donors, reducing cellular fuel use in most donor lines tested. Analysis across 24 clinical cohorts revealed that higher SLC25A34 expression in subcutaneous white adipose tissue associates with lower BMI, reduced adiposity, and better systemic metabolic health.
Although correlation does not prove causation, the molecular, animal, and human data converge to nominate SLC25A34 as a promising pharmacological target. Drugs that selectively activate this mitochondrial carrier could help retrain fat cells to burn fuel on demand and offer new strategies for treating obesity and type 2 diabetes.
Funding: Supported by the Independent Research Fund Denmark (Sapere Aude grant), the European Research Council (Starting Grant aCROBAT), and the Novo Nordisk Foundation, including fellowships and support for the ADIPOSIGN center.
Questions & Answers
A: White adipose tissue primarily stores energy as triglycerides. Brown adipose tissue contains many mitochondria and burns glucose and lipids to generate heat through non-shivering thermogenesis, contributing to energy expenditure and metabolic regulation.
A: SLC25A34 is a mitochondrial inner membrane transporter in brown adipocytes that appears to shuttle oxaloacetate into mitochondria, supporting TCA cycle activity and the lipid synthesis–oxidation cycle required for thermogenesis.
A: Brown fat activity follows a 24-hour rhythm, decreasing during sleep and increasing before waking. REV-ERBα enforces this rhythm by repressing Slc25a34 during sleep, but cold exposure or nutrient signals can override this repression to increase heat production at any time.
A: Active brown fat engages in lipid cycling—synthesizing fatty acids while simultaneously oxidizing them. This “build-to-burn” process helps clear circulating nutrients and sustain thermogenesis; SLC25A34 supports the metabolic flows that enable this cycle.
Editorial Notes:
- Article edited by a Neuroscience News editor.
- Journal paper was reviewed in full before reporting.
- Additional context was added by editorial staff.
About this neuroscience Research:
- Media Contact: Peter Andrew Stanners
- Source: University of Copenhagen
- Image Credit: Image credited to Neuroscience News
- Original Research (Open Access): Science (Oct 1, 2026). Title: “Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of adipocyte lipid cycling.” Authors: Iuliia Karavaeva et al.
- DOI: 10.1126/science.adz4797
Abstract
Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of adipocyte lipid cycling
INTRODUCTION
Brown and beige thermogenic adipocytes have high capacity for energy expenditure, which defends temperature in small mammals and supports cardiometabolic health in humans. Thermogenic activity follows a circadian rhythm—rising after waking and falling during sleep—but can also be rapidly induced by cold exposure or a high-fat meal. How thermogenic adipocytes balance rhythmic control with acute responsiveness is a central question in energy homeostasis.
RATIONALE
To identify molecular mechanisms integrating clock, temperature, and dietary cues, the team used unbiased analyses of DNA-binding, gene expression, and protein abundance in thermogenic fat under varying circadian, environmental, and dietary conditions. These efforts highlighted the orphan mitochondrial transporter SLC25A34 as the point of convergence.
RESULTS
Slc25a34 expression cycles daily under control of REV-ERBα/β transcriptional repressors. During wakefulness, PPARα and PPARγ promote Slc25a34 expression, but cold or lipid signals quickly override REV-ERB repression and activate PPARs to raise SLC25A34 levels. Biochemical and metabolic studies indicate SLC25A34 transports oxaloacetate into mitochondria, sustaining TCA cycle flux needed for thermogenesis and supporting lipid cycling where fatty acids are both synthesized and oxidized.
CONCLUSION
SLC25A34 functions as a molecular node that integrates circadian, thermal, and dietary signals to coordinate lipid cycling and thermogenic fuel use in adipocytes. This mechanism explains how thermogenic fat can preserve daily rhythmicity while remaining acutely responsive to energy demands and suggests a potential target for therapies aimed at increasing energy expenditure in metabolic diseases.
