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

The study, led by Yinliang Zhang, Xiaochen Gai, Dong Zhao and Yongsheng Chang, with contributions from a team at Tianjin Medical University, Capital Medical University and Westlake University, began with a deceptively simple observation. When mice were exposed to cold, or when their fat cells were bathed in norepinephrine, the sympathetic neurotransmitter that surges during cold exposure, levels of ALKBH5 rose sharply in brown and subcutaneous fat. ALKBH5 belongs to a small family of enzymes that remove N6-methyladenosine, or m6A, the most abundant internal chemical modification on messenger RNA. By stripping these methyl marks, ALKBH5 can alter how long particular mRNA molecules survive before being degraded, and therefore how much protein the cell can manufacture from them.

Tracing the signal upstream, the investigators found that ALKBH5 expression is not a passive side effect of cold. Instead, norepinephrine binding to adrenergic receptors triggers the classic thermogenic signaling cascade: cyclic AMP accumulates, protein kinase A is activated, and the transcription factor CREB is phosphorylated and dispatched to the ALKBH5 gene, switching it on. Pharmacological tools confirmed the pathway’s logic. Forskolin and CW 008, which elevate cAMP signaling, boosted ALKBH5 expression in both mouse and human adipocytes, while the CREB inhibitor 666-15 and the PKA inhibitor H89 blunted that induction. In other words, the same sympathetic signal that commands fat cells to burn also instructs them to reprogram their RNA landscape.

The consequences of losing that reprogramming became clear when the team generated mice lacking ALKBH5 specifically in adipose tissue. Both male and female animals showed reduced thermogenic capacity, dropping their body temperature faster during acute cold exposure and dissipating less energy overall. When fed a high-fat diet, the knockout mice gained more weight, accumulated more fat mass and developed impaired glucose homeostasis compared with controls. Crucially, the metabolic defect appeared without changes in food intake or locomotor activity, pointing squarely at energy expenditure rather than appetite as the underlying problem. The findings applied across sexes, strengthening the physiological relevance of the pathway.

The mirror-image experiment proved equally striking. When the researchers delivered an ALKBH5 gene into brown and subcutaneous fat using adeno-associated virus, the treated animals became metabolic overachievers. They maintained higher core body temperatures in the cold, generated greater total energy expenditure, and resisted the weight gain and glucose intolerance induced by a high-fat diet. Human data added a correlative dimension: analysis of gene expression from public cohorts, including the Genotype-Tissue Expression project, showed that ALKBH5 levels in human subcutaneous fat inversely correlate with obesity, suggesting that the mouse findings may translate to human biology.

The deepest insight, however, came from the mechanistic work. Searching for the thermogenic machinery that ALKBH5 controls, the team landed on CKB, creatine kinase B, an enzyme central to the so-called futile creatine cycle. In this circuit, creatine kinase pumps phosphate onto creatine to build phosphocreatine, and a mitochondrial enzyme hydrolyzes it back again, forcing the cell to burn ATP in a loop that generates heat rather than useful work. Deleting ALKBH5 from fat lowered CKB expression and creatine kinase activity, while boosting ALKBH5 raised them. When the researchers depleted creatine with beta-guanidinopropionic acid, the thermogenic benefits of ALKBH5 overexpression largely evaporated, confirming that creatine metabolism is the load-bearing element of the pathway.

Molecularly, the connection between the demethylase and the creatine kinase is an elegant piece of RNA biology. ALKBH5 removes m6A marks from the CKB transcript itself. Those methyl tags, when present, are recognized by YTHDF2, a reader protein that escorts methylated mRNAs to degradation machinery. By demethylating CKB mRNA, ALKBH5 shields it from YTHDF2-mediated destruction, lengthening the transcript’s half-life and allowing more creatine kinase B protein to be produced. Experiments with mutated CKB constructs, methylated RNA immunoprecipitation, and YTHDF2 knockdown in both mouse brown and human beige adipocytes pieced this mechanism together site by site, and the m6A peaks identified on CKB mRNA matched the canonical DRACH sequence motifs predicted from genomic analysis.

Perhaps the most provocative result concerns UCP1, the long-reigning icon of thermogenesis. In mice genetically engineered to lack UCP1 entirely, ALKBH5 overexpression still raised energy expenditure and protected against cold exposure, demonstrating that the creatine-driven pathway operates in parallel with, and independently of, the classical uncoupling mechanism. This echoes recent single-cell studies suggesting that thermogenic fat contains distinct subpopulations of cells, some defined by UCP1 and others by futile cycling enzymes. The new work provides the first known regulatory link between an adrenergic signal and the creatine branch, effectively giving that parallel pathway its own commander.

The therapeutic implications are considerable. Obesity treatments based on increasing energy expenditure have long sought safe ways to activate thermogenic fat, but UCP1-centric strategies face hurdles, including uncertainty about how much functional brown fat adult humans carry and concerns about off-target adrenergic stimulation. A target that works through mRNA stabilization rather than receptor agonism, and that functions even without UCP1, opens a genuinely different door. The authors caution that ALKBH5 is a broad-acting demethylase implicated in diverse processes, from fertility to cancer metabolism to cardiac fibrosis, so any obesity therapy built on it would need careful tissue specificity. Still, the demonstration that a single RNA modification enzyme can rewire cellular fuel chemistry in response to cold reframes thermogenesis as an epitranscriptomic phenomenon, and it hands obesity researchers a new molecular lever precisely where they need it most: the fat that burns.

Subject of Research: The role of the m6A demethylase ALKBH5 in regulating creatine-driven non-shivering thermogenesis in adipose tissue

Article Title: ALKBH5 activates creatine-driven thermogenesis by stabilizing CKB mRNA in response to cold

Article References: Zhang, Y., Du, C., Qiao, W., Qiu, P., Xu, C., Yang, X., Hao, J., Zhao, D., Gai, X., & Chang, Y. (2026). ALKBH5 activates creatine-driven thermogenesis by stabilizing CKB mRNA in response to cold. Nature Metabolism. https://doi.org/10.1038/s42255-026-01592-y

Image Credits: AI Generated

DOI: 10.1038/s42255-026-01592-y

Keywords: ALKBH5, thermogenesis, brown fat, m6A methylation, CKB, creatine kinase, UCP1, obesity, YTHDF2, norepinephrine, CREB signaling, metabolism