Research Briefing

Plasma metabolic variation reflects dietary exposures. We show that biomarker panels are objective and reproducible in assessing dietary intake and quality, and can accurately predict clinical phenotypes such as diabetes and hypertension.

Metabolism is dynamic during early development in animals. To study this process, we developed a single-embryo metabolomics and transcriptomics method that captures rapid, small-scale changes in metabolism and how they coordinate with gene expression. Our work showcasing this method in Drosophila embryos provides a valuable resource for understanding developmental systems biology.

Dual incretin agonists, such as tirzepatide (a GLP1R–GIPR agonist), show excellent efficacy for type 2 diabetes and obesity therapy. Research identifies the cells and neurons in the pancreas and brain that are targeted by dual agonists, providing further details on their modes of action.

We present a cost-effective normalization strategy for spatial metabolomics using uniformly ¹³C-labelled yeast extract, which addresses limitations of conventional methods and the physico-chemical complexity of water-soluble metabolites. Our approach outperforms standard normalization strategies and reveals hitherto unrecognized metabolic remodelling in the cortex after stroke, demonstrating its applicability.

During cell division, a subset of intestinal stem cells (ISCs) inherits old mitochondria that increase intracellular α-ketoglutarate levels. α-Ketoglutarate facilitates remodelling of DNA methylation and boosts the ability of ISCs to regenerate the stem cell niche. Metabolite intervention with α-ketoglutarate during ageing can replace defective niche cells and enhance regeneration.

Salicylic acid nitroalkene (SANA) is a derivative of the aspirin precursor, salicylate. We discovered that SANA effectively reduces body weight in a mouse model of diet-induced obesity by stimulating creatine-dependent thermogenesis. In preliminary human trials, SANA was found to be safe, well-tolerated and demonstrated promising results in promoting weight loss.

Glucagon-like peptide 1 (GLP-1) receptor-expressing neurons in the paraventricular nucleus of the hypothalamus send descending excitatory projections to the dorsal vagal complex of the brainstem. GLP-1 signalling regulates synaptic transmission in this circuit in an energy state-dependent manner to control feeding and energy homeostasis.

Activated brown adipose tissue takes up large amounts of branched-chain amino acids (BCAAs), but their fate remains unclear. We provide evidence of a metabolic link between BCAA catabolism and haem biosynthesis, which supports mitochondrial function and regulates gene expression by influencing the epigenetic landscape of brown adipocytes.

We observed that an MRI surrogate of myelin content, myelin water fraction, is reduced in white matter regions after marathon running but recovers later. These findings suggest that brain myelin content is reversibly reduced after prolonged exercise, consistent with evidence in rodents that myelin lipids provide energy under extreme metabolic conditions.

Glutamatergic medial vestibular nuclei parvocellular part (MVePC^Glu) neurons have a dominant role in motion-induced hypothermia — a physiological correlate of motion sickness — via their downstream targets in the lateral parabrachial nucleus, and inhibition of this neural circuit alleviated motion-induced hypothermia in mice. Chronic inhibition of MVePC^Glu neurons also prevented diet-induced obesity by increasing energy expenditure.

Pro-inflammatory macrophages produce mitochondria-derived reactive oxygen species (mtROS) such as superoxide, but it is not understood how it is produced or how it affects macrophage effector functions. We show that mitochondrial superoxide is produced by reverse electron transport at complex I of the respiratory chain and regulates pro-inflammatory cytokine production.

Genetic deletion of Kdm2a or pharmacological blockade of KDM2A, a histone 3 demethylase, in skeletal muscle shifts fuel preference from glucose to lipids under cold challenge in mice fed a high-fat diet. KDM2A loss increases the proportion of mitochondria-rich, slow-twitch myofibres, conferring flexible protection against metabolic stress.

Body-to-brain communication profoundly affects physiology and behaviour. Sensory neurons that express oxytocin receptors relay mechanical stretch of the gut and heart to the brain. Surprisingly, simultaneous firing of these neurons reliably elicits a hypometabolic state that resembles torpor. These observations could have implications ranging from cardiometabolic therapeutics to space travel.

Ageing is associated with proteomic changes in the blood. However, most research on the ageing blood proteome is cross-sectional in nature. Using a longitudinal analysis, we identified 86 ageing-related blood proteins and further revealed a subset of 22 protein biomarkers that, in combination, predict healthy ageing status and age-related cardiometabolic disease risk.

Despite their abundance and despite being the most numerous biological entities on Earth, viruses remain one of the least understood components of the human microbiome. In our study, we show how Microviridae bacteriophages in the gut microbiome are associated with food addiction through changes in tryptophan, serotonin and dopamine metabolism.

A common feature of neurodegenerative diseases is that select neuronal types are particularly sensitive to disease pathology at early stages. Altered TrkB signalling in the neuronal type most affected by Huntington’s disease increased expression of the enzyme GSTO2, leading to dopaminergic dysfunction, impaired energy metabolism, progressive degeneration and hyperkinetic symptoms.

Farnesyl pyrophosphate (FPP), an intermediate of cholesterol biosynthesis in the mevalonate pathway, prolongs the survival of migratory dendritic cells (mig-DCs) by remodelling mitochondrial structure and metabolism. Treating a mouse model of systemic lupus erythematosus with simvastatin (an inhibitor of this pathway) led to recovery from dysregulation in mig-DCs and ameliorated systemic autoimmune pathogenesis.

Brown adipose tissue (BAT) facilitates thermogenesis through fatty acid oxidation (FAO). Paradoxically, BAT simultaneously increases anabolic fatty acid synthesis (FAS), the reason for which is unclear. We provide evidence that thermogenic mitochondria within brown adipocytes export TCA cycle intermediates that fuel de novo lipid synthesis, in part to protect against metabolic stress.

The metabolic sensor enzyme OGT dynamically O-GlcNAcylates hexokinase 1 (HK1). This modification enhances the localization of HK1 to mitochondria in response to glucose flux and facilitates the formation of a glycolytic metabolon on the mitochondrial outer membrane, leading to increased rates of both glycolytic and mitochondrial ATP production.

Adults with overweight or obesity who have been exercising regularly for at least a few years have distinct structural and biological characteristics in their abdominal subcutaneous adipose tissue. These changes could underlie improved cardiometabolic health outcomes in this population, when compared with well-matched sedentary adults with overweight or obesity.