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

The phenomenon at the centre of the study is known as browning. White adipose tissue is primarily a storage organ, packing energy into a single large lipid droplet per cell. Under certain conditions, however, white fat depots recruit or generate beige adipocytes, cells enriched with mitochondria and with uncoupling protein 1, or UCP1, a molecule that dissipates the mitochondrial proton gradient as heat rather than capturing the energy as ATP. Browning is normally driven by cold exposure or by beta-adrenergic signalling, the same sympathetic pathway that activates classical brown fat. When beige adipogenesis works well, the body burns more fuel and stores less fat. When it fails, visceral fat expands and metabolic disease tends to follow.

Using male mice, the researchers found that stimulating beta-adrenergic receptors with the drug CL316,243, or exposing animals to cold, unexpectedly triggered an influx of neutrophils into epididymal white adipose tissue, a visceral fat depot, but not into subcutaneous fat or brown fat. These infiltrating neutrophils carried activated neutrophil elastase and proteinase 3, enzymes stored in granules and released during inflammation. At the same time that the tissue was being instructed to brown, the arriving neutrophils were deploying proteases that shut the process down. The team showed that when neutrophil elastase was genetically deleted, or when the enzyme was blocked locally within the fat pad using sivelestat, an approved neutrophil elastase inhibitor, browning of visceral fat in response to adrenergic stimulation was substantially rescued, and UCP1 protein levels rose.

The mechanistic work went several layers deep. First, the proteases acted on beige adipocyte precursors, the progenitor cells from which new beige fat cells arise. Neutrophil elastase and proteinase 3 suppressed the proliferation of these precursors by downregulating CDK4 and cyclin D1, two core components of the cell cycle machinery that drive the G1 to S phase transition. With those drivers suppressed, precursor cells became arrested, reducing the pool of cells available for commitment to the beige lineage. This matters because de novo recruitment of beige adipocytes from progenitors, rather than mere activation of pre-existing cells, is a major route through which visceral fat gains thermogenic capacity during cold adaptation.

Second, the enzymes interfered with the differentiation programme itself. The researchers identified insulin-like growth factor binding protein 3, or IGFBP-3, as a critical substrate. IGFBP-3 supports beige adipocyte differentiation, and the neutrophil proteases cleaved it, degrading the factor and thereby weakening the differentiation signal. Prior literature had established that neutrophil elastase and proteinase 3 can function as IGFBP proteases in inflammatory settings, and the new work places that degradative activity squarely within fat tissue biology, linking it to impaired beige adipogenesis. When protease activity was inhibited, IGFBP-3 was preserved and differentiation proceeded more effectively.

Third, the study revealed an indirect route of inhibition. Neutrophil-derived proteases promoted the polarization of adipose tissue macrophages toward the M1, classically inflammatory phenotype. M1 macrophages secrete pro-inflammatory cytokines that are known to suppress thermogenic gene expression and to antagonize the type 2 immune signals, including eosinophil-derived interleukins and M2 macrophage activity, that normally support beige fat development. By tipping the macrophage balance toward inflammation, neutrophils created a tissue environment hostile to thermogenic adipocyte formation, compounding their direct effects on precursors and differentiation.

Importantly, the findings were not confined to mouse models. Analysis of publicly available single-cell RNA sequencing datasets from human adipose tissue revealed elevated expression of ELANE, the gene encoding neutrophil elastase, and PRTN3, the gene encoding proteinase 3, in visceral fat of individuals with obesity, particularly those with type 2 diabetes, compared with subcutaneous fat. Conversely, IGFBP3 expression in adipocytes showed correlations consistent with the proteolytic pathway identified in mice. In laboratory cultures, recombinant human neutrophil elastase and proteinase 3 suppressed the proliferation of human visceral preadipocytes, arrested their cell cycle, and impaired their differentiation into beige adipocytes, mirroring the murine results at the level of human cells.

The therapeutic implications emerged from experiments in mice fed a high-fat diet. Long-term feeding sustained neutrophil infiltration specifically in epididymal visceral fat over ten months. When diet-induced obese mice received sivelestat, the drug suppressed neutrophil activity, enhanced cold-induced browning of visceral fat, decreased visceral fat content, and increased energy expenditure. Sivelestat is already clinically validated for other indications, having been developed and used as a neutrophil elastase inhibitor for acute lung injury and acute respiratory distress syndrome, notably in Japan and in experimental protocols for COVID-19-related lung damage. The prospect of repurposing an existing, safety-characterized drug for obesity treatment is precisely the kind of translational shortcut that draws attention in metabolic medicine, although the authors and the field will recognize that mouse-to-human translation in adipose biology is notoriously fraught, and that sex differences in both browning and neutrophil behaviour, documented in this study and in prior work, complicate extrapolation.

What makes the study conceptually striking is the reversal of expectations. Earlier research had emphasized destructive roles of neutrophils in adipose tissue, including elastase-driven insulin resistance described by Talukdar and colleagues in 2012, and more recent work has even suggested neutrophils help preserve energy stores in activated fat. The new findings position neutrophils as active gatekeepers of adipose plasticity, dynamically throttling the tissue’s thermogenic capacity exactly when sympathetic signals demand it. Whether this represents an evolutionary trade-off, dampening energy expenditure during inflammatory stress, or a maladaptive modern interaction between chronic low-grade inflammation of obesity and an ancient immune programme, remains an open question. What is clear is that the protease activity provides a concrete, druggable point of intervention in a pathway previously managed only through diffuse targets such as sympathetic stimulation, which carries cardiovascular side effects in humans.

The work also refines the emerging picture of immune-metabolic crosstalk in fat. Eosinophils, M2 macrophages, and type 2 cytokines have been shown to promote beige fat; sympathetic neuron-associated macrophages can do the opposite by consuming norepinephrine. Neutrophils and their serine proteases now join this cast, with a mechanism that operates at three levels at once: cell cycle arrest of progenitors, proteolytic destruction of a differentiation factor, and inflammatory remodelling of the macrophage landscape. For the millions of people carrying metabolically harmful visceral fat, the study suggests that taming neutrophil elastase could, in principle, unlock the fat-burning potential already latent within their tissue, and it hands researchers a precise molecular target with which to test that proposition in the clinic.

Subject of Research: How neutrophil serine proteases inhibit thermogenic browning of visceral white adipose tissue

Article Title: Neutrophil serine proteases inhibit thermogenic capacity of visceral white adipose tissue

Article References: Yuan, L., Wu, X., Zong, J., Jiang, M., Gao, S., Zhang, Z., Huang, X., Zhu, M., Xiang, M., Wang, L., Ping, Z., Pan, Y., Ye, D., Xu, A., & Hoo, R. L. C. (2026). Neutrophil serine proteases inhibit thermogenic capacity of visceral white adipose tissue. Nature Metabolism. https://doi.org/10.1038/s42255-026-01598-6

Image Credits: AI Generated

DOI: 10.1038/s42255-026-01598-6

Keywords: neutrophils, neutrophil elastase, proteinase 3, visceral adipose tissue, fat browning, beige adipocytes, thermogenesis, UCP1, obesity, sivelestat, IGFBP-3, macrophage polarization