Articles in 2023

Spatial metabolomics has matured and is driving innovation in mass spectrometry, metabolomics and spatial omics. With exciting discoveries, complementary capabilities and increasing accessibility, it has secured its place in the spatial biology toolbox, showing promise in biology, medicine and pharmacology.

TMEM164 is an early-response intrinsic factor that inhibits the induction of neurotoxic reactive astrocytes, and whose astrocyte-specific overexpression alleviates the symptoms of neurodegenerative diseases in mice.

In this study, Wang et al. show that the glycolytic metabolite phosphoenolpyruvate, produced by enolase 2, contributes to colorectal cancer malignancy and resistance to antiangiogenic therapy by inhibiting endogenous histone deacetylase 1 and favouring β-catenin signalling.

Sa et al. identified a distinct neuronal subpopulation that controls brown adipose tissue thermogenesis. In mice fed a high-fat diet, hypothalamic GABRA5 neurons are deactivated by GABA released by surrounding astrocytes and inhibition of GABA synthesis ameliorates diet-induced obesity.

Dutta et al. show that impaired mitochondrial fatty acid synthesis (mtFAS) leads to neurodegeneration, increased ceramide levels and disturbed iron metabolism in flies and in fibroblasts from individuals with a mutation in an mtFAS enzyme.

Here Mukherjee et al. characterize the bidirectional communication between adipose tissue and ovarian cancer cells and show that adipocytes instruct cancer cells to divert glycolytic glycerol-3-phosphate towards lipid synthesis, thus promoting metastasis.

The authors identify a role for GABRA5 neurons in the lateral hypothalamus for energy balance regulation. Inhibiting these neurons increases weight gain and lipid accumulation through a process dependent on astrocytic GABA release.

Okreglak et al. explore the molecular mechanisms that link organellar pH dynamics with the cell cycle, and find that vacuolar pH oscillates during cell cycle phases to ensure an adequate supply of amino acids during cell division. This study offers metabolic insight into the fundamental mechanisms that couple amino acid availability to the cell cycle through pH fluctuations.

Perszyk et al. identify the neural basis for odour-imagery ability and show that it indirectly predicts weight-gain susceptibility through a mechanism that is dependent on food-cue reactivity.

In this study, Okreglak et al. identify dynamic regulation of pH in the lysosome-like vacuole of growing S. cerevisiae cells and link pH dynamics in this subcellular compartment to amino acid release into the cytoplasm to meet metabolic demands during cell cycle progression.

In this Review, TeSlaa, Ralser, Fan and Rabinowitz comprehensively review the fundamental biochemical aspects of the pentose phosphate pathway and discuss its biological relevance in the context of physiology and pathology.

Rosenbaum and Foster discuss the metabolic underpinnings of weight loss and weight loss maintenance, as well as the implications of considering them as distinct metabolic states for the treatment of obesity.

In this issue of Nature Metabolism, a study shows that glutarate increases memory T cells as well as T cell cytotoxicity and reduces tumour growth. During T cell activation, glutarate levels and glutarylation increase. Glutarate inhibits α-ketoglutarate-dependent dioxygenases, and glutarylation reduces pyruvate dehydrogenase complex activity and enhances glycolysis.

Minogue et al. show that glutarate, a metabolite derived from tryptophan catabolism, has the ability to shape anti-tumour T cell responses by modulating pyruvate handling and alpha-ketoglutarate-dependent dioxygenases.

Sensory association learning is impaired in people with insulin resistance but can be restored following a one-time intervention with liraglutide. These findings provide ample evidence for metabolic signals as modulators of adaptive behaviour and suggest a potential role for GLP-1 receptor agonists in obesity management.

The relationship between stress and gastrointestinal function is poorly understood and of major clinical importance as a potential contributor to irritable bowel syndrome, functional dyspepsia and numerous other disorders of gut–brain interaction. A recent study investigates a descending neural circuit that regulates gastric motility and is inversely modulated by chronic versus acute stress.

Hanssen et al. demonstrate that associative learning is reduced when metabolic sensing is impaired in obesity and can be restored by liraglutide.

The authors uncover a brain-to-stomach signalling axis that communicates gastric dysfunction associated with stress.

By combining multimodal metabolomics technologies to investigate colorectal tissues and tumours in situ, Vande Voorde et al. found tumour genotype-specific metabolic profiles and revealed the methionine-cycle enzyme AHCY to be a potential therapeutic target in colorectal cancer.