Mouse and human beige adipocytes use futile sodium-potassium cycling for energy expenditure

Researchers report that mouse and human beige adipocytes can increase energy expenditure through a futile sodium and potassium transport cycle that operates independently of uncoupling protein 1 (UCP1). The study found that this ion-transport system was preferentially amplified in beige adipocytes and identified the Na+/K+-ATPase subunit ATP1A2 as a critical contributor to the process. Acute inhibition of Na+/K+-ATPase reduced energy expenditure in both mouse and human beige adipocytes, while overexpressing Atp1a2 in murine adipocytes increased energy expenditure independently of UCP1.

Cold exposure produced a coordinated response in mice. The experiments showed that cold activated a sympathetic-nerve and thyroid-hormone signaling axis that induced ATP1A2 together with sodium and potassium channels. These components increased bidirectional ion flux across the plasma membrane while maintaining ionic balance, creating a cycle of sodium and potassium transport that consumed ATP.

After cold exposure, researchers detected Atp1a2-positive and Kcnk3-positive adipocytes in mouse inguinal white adipose tissue, showing that the transport machinery was enriched in a subset of adipocytes within this fat depot. The inhibitor and overexpression experiments provide functional evidence that Na+/K+-ATPase contributes causally to energy expenditure in beige adipocytes. Suppressing the pump acutely lowered energy expenditure in mouse and human cells, whereas raising ATP1A2 expression in mouse adipocytes potentiated energy expenditure without requiring UCP1.

The findings therefore identify futile ion transport as an ATP-consuming thermogenic mechanism that adds to the repertoire by which beige adipocytes can expend energy. The reported experiments do not test whether the mechanism can be manipulated safely or effectively to produce weight loss or other clinical benefits in people. Genetic experiments in living mice connected the transport cycle with thermogenesis and obesity.

Adipocyte-specific deletion of Atp1a2 impaired thermogenic capacity and aggravated diet-induced obesity in mice. These results extend the cell-based observations to a whole-animal phenotype, although the metabolic consequences were demonstrated in mice rather than humans. The experiments also included human beige adipocytes, where acute Na+/K+-ATPase inhibition reduced energy expenditure, but no human intervention was conducted to assess weight change, disease prevention or treatment.

The researchers also examined a human ATP1A2 missense variant. Expressing the variant in mouse adipocytes reduced ATP1A2-dependent respiration, indicating that the variant impaired the respiratory function attributed to the protein. The article associates ATP1A2 with metabolic diseases, but the supplied findings do not establish that people carrying the variant have a defined risk of obesity or that targeting the sodium-potassium pump would be an effective therapy for human metabolic disease.

Subject of Research: Futile sodium-potassium transport as an ATP-consuming thermogenic mechanism in beige adipocytes

Article Title: A futile Na+ K+ transport cycle augments energy expenditure in beige adipocytes

Article References: Liu, Q., Cheng, Y., Yan, D., Wu, W., Lei, Z., Long, Q., Zhao, Z., Gao, Y., Wang, B., Feng, T., Shin, J., Zhao, J., Zhao, S., Chen, K., Cheng, K., Yao, X., Gu, P., Gao, X., Cheung, C.-L., … Hui, H. X. (2026). A futile Na+ K+ transport cycle augments energy expenditure in beige adipocytes. Nature Metabolism. https://doi.org/10.1038/s42255-026-01630-9

Image Credits: AI Generated

DOI: 10.1038/s42255-026-01630-9

Keywords: beige adipocytes, ATP1A2, sodium-potassium ATPase, ion transport, UCP1, energy expenditure, cold exposure, thermogenesis, obesity, mouse models, human adipocytes, metabolic disease