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

The theoretical backdrop for the study is arousal-biased competition theory, developed by Mara Mather and Mary Sutherland and colleagues. According to this framework, arousal increases the competitive advantage of whatever information already dominates mental processing. If a person is focused narrowly on a specific location, arousal should further strengthen that narrow focus; if attention is broadly distributed, arousal should broaden it further. The theory draws on neuroscientific work suggesting that norepinephrine, released by the locus coeruleus during states of heightened arousal, ignites local hotspots of neuronal excitation that amplify the most active representations while suppressing weaker competitors. Earlier experiments had reported that arousal amplifies selectivity in perception and memory, and classic studies from the 1950s through the 1970s, including work by John Easterbrook on cue utilization and by Donald Cornsweet on peripheral cues under arousal, had suggested that stress and noise narrow the useful field of view.

Kolnes and Nieuwenhuis set out to test this amplification hypothesis directly for the spatial dimension of attention. Thirty-nine participants performed a visual search task specifically designed to measure the breadth of attention across the visual field. The critical manipulation involved tonic arousal, the relatively stable background level of physiological activation that fluctuates over minutes rather than seconds. In half of the experimental blocks, continuous auditory white noise was played to participants, a well-established method for raising tonic arousal without startling them or triggering phasic alerting responses. The researchers reasoned that if arousal genuinely amplifies the dominant attentional scope, then the difference in search performance between narrow-attention and broad-attention conditions should grow larger under noise than under quiet conditions.

Before each trial, the experimenters used a procedure intended to induce either a narrow or a broad breadth of attention. This manipulation of attentional scope is central to the design, because the amplification hypothesis makes a specific prediction: arousal should not change the baseline scope itself, but should exaggerate whatever scope is currently dominant. The team also drew on their own earlier findings, including a 2023 study showing that broadening attention dilates the pupil, suggesting a close relationship between attentional breadth and the autonomic arousal system. That relationship made the null result they ultimately obtained all the more theoretically pointed, since it indicates that the coupling between arousal physiology and attentional breadth does not translate into arousal-driven amplification of scope.

A crucial strength of the study lies in its manipulation checks. The researchers measured pupil size continuously, exploiting the well-documented link between pupil diameter and locus coeruleus-norepinephrine activity. Pupil measurements confirmed that the white-noise manipulation successfully raised tonic arousal, and task performance confirmed that the scope-induction procedure successfully shifted the breadth of attention between narrow and broad states. In other words, the experiment was not undermined by failed manipulations. Both arousal and attentional scope were demonstrably altered, yet the predicted interaction between them simply did not appear. The effect of attentional breadth on visual search remained statistically indistinguishable between high-arousal and low-arousal blocks.

The analysis relied on Bayesian statistical methods, which allow researchers to quantify evidence in favor of a null hypothesis rather than merely failing to reject it. The authors report strong Bayesian evidence against an amplifying effect of arousal on the dominant attentional scope. This distinction matters in the ongoing debate about replication and statistical practice in psychology, where nonsignificant p-values are often ambiguous. A Bayes factor indicating strong support for the null hypothesis means the data actively favor the absence of an amplification effect, not simply that the study lacked power. The researchers also used mixed-effects models with maximal random effects structures, following methodological recommendations for confirmatory hypothesis testing, and conducted simulation-based power analyses to ensure the design was sensitive enough to detect a plausible amplification effect if one existed.

The null result is not without precedent. Ásgeirsson and Nieuwenhuis had previously reported no arousal-biased competition in focused visuospatial attention in a 2017 study published in Cognition, and a 2019 follow-up examining attention and short-term memory produced similarly mixed support for the theory. The new findings extend this line of work by showing that even when both arousal and attentional scope are successfully manipulated and verified through physiological and behavioral measures, the amplification predicted by arousal-biased competition theory fails to materialize for spatial attention. This convergence across independent experiments and paradigms suggests that the earlier classic findings of arousal-induced narrowing, such as those from noise studies in the 1970s, may reflect mechanisms other than amplification of dominant attentional scope, such as changes in response bias, strategy, or the relative salience of stimuli.

The authors discuss the implications for arousal-biased competition theory in measured terms. The theory remains influential and has generated a large body of research on how emotion and arousal shape perception and memory, including findings that emotional arousal strengthens high-priority memory traces while weakening low-priority ones. However, the present results suggest that the amplification principle may not generalize to the spatial scaling of attention. Alternative accounts of arousal’s effects, including models emphasizing adaptive regulation of arousal and the inverted-U relationship described by the Yerkes-Dodson law, may better accommodate the full pattern of findings. Recent work on pharmacologically shifting the peak of the Yerkes-Dodson curve through catecholaminergic enhancement indicates that arousal’s effects on cognition are complex and state-dependent, defying simple amplification rules.

For everyday intuition, the study suggests that being stressed, caffeinated, or startled does not automatically zoom your mental spotlight further in or out. The spatial distribution of attention appears to be governed by its own control mechanisms, relatively insulated from the background hum of bodily arousal. This dissociation has practical implications for domains ranging from driving safety to sports performance and the design of warning systems, where it is often assumed that high arousal inevitably produces tunnel vision. The evidence here indicates that assumption is too simple. The study was not preregistered, a limitation the authors acknowledge, but subject-level data and analysis code are openly available in the Open Science Framework repository, allowing other researchers to scrutinize and extend the findings. Funded by the Estonian Research Council and the Dutch Research Council, the work exemplifies how careful manipulation checks, physiological validation, and Bayesian inference can turn an apparently negative result into a substantive theoretical contribution about how attention and arousal are, and are not, connected.

Subject of Research: Whether tonic arousal modulates the spatial scope of visual attention

Article Title: Arousal does not enhance the dominant spatial scope of attention

Article References: Kolnes, M., & Nieuwenhuis, S. (2026). Arousal does not enhance the dominant spatial scope of attention. Attention, Perception, & Psychophysics, 88(7), Article 184. https://doi.org/10.3758/s13414-026-03327-3

Image Credits: AI Generated

DOI: 10.3758/s13414-026-03327-3

Keywords: arousal, attentional scope, visual attention, arousal-biased competition, pupil size, norepinephrine, visual search, Bayesian inference, psychophysics, locus coeruleus, breadth of attention, tonic arousal