Reviews & Analysis

Metabolites have emerged as important signalling molecules, and their biological effects are frequently investigated by treating animals and cells with solutions of commercially available metabolite salts. Such experiments require proper controls for osmolarity and the presence of counterions, as illustrated by dramatic confounding effects on energy balance in studies with sodium l-lactate.

A proteo-transcriptomic analysis of nonalcoholic fatty liver disease (NAFLD) uncovers biological pathways and potential biomarkers of high-risk disease. The work expands our understanding of the cellular origins of protein changes in NAFLD and translates them into an accurate diagnostic tool.

GAPDH is highly sensitive to oxidation by reactive oxygen species, but how exactly its oxidation alters carbon flux is not known. Talwar et al. demonstrate that oxidative inactivation of GAPDH is required for maximal pentose phosphate pathway flux to support NADPH generation during oxidative stress.

Diabetic kidney disease is influenced by a combination of genetic and environmental factors. A study identifies risk variants in the XOR promoter that elevate its own activity in response to hyperglycaemia, which has a causative role in the onset and progression of diabetic kidney disease.

Fatty acids generated through lipolysis are constantly re-esterified into triglycerides in what is known as the glyceride–fatty acid futile cycle. A recent quantification of the activity of this futile cycle in adipocytes suggests that it may have manifold implications for systemic energy homeostasis.

Although astrocytes are largely glycolytic, they catabolize a variety of substrates via oxidative phosphorylation in the mitochondria. In this issue, Mi et al. show that oxidative phosphorylation in astrocytes protects the brain from inflammation and degeneration by degrading excess fatty acids.

Matsumura, Wei and Sakai discuss epitranscriptomic modifications and their links to metabolic disease, how genetic and environmental factors influence epitranscriptomics, and how the epitranscriptome is linked to the epigenome.

PCYT2 is an enzyme involved in lipid biosynthesis, and its genetic deficiency in zebrafish, mice and humans causes progressive muscle weakness. Importantly, PCYT2 activity declines in ageing muscles of mice and humans, and PCYT2 gene therapy in aged mice improves muscle strength, suggesting new therapeutic avenues to explore for maintaining muscle health in ageing.

Animals need to be able to evaluate environmental pH. Mechanisms that mediate sour taste and acid sensing have been reported across species, but less is known about the detection of high pH. Mi et al. identify the gene alkaliphile, which encodes a high-pH-gated chloride channel in the gustatory system of flies.

Defective nicotinamide adenine dinucleotide (NAD⁺) metabolism is involved in various diseases. A study in Nature Metabolism identifies the cytosolic mitochondrial-RNA sensing system as a mediator that links NAD⁺ deficiency to kidney disease in humans and mice.

Both cell cycle arrest and secretions of senescent cells are subject to metabolic control. In this issue of Nature Metabolism, Roh et al. show that lysosomal partitioning of cholesterol potentiates inflammatory secretion during senescence.

By measuring protein abundance in blood using high-throughput antibody-based techniques, a genetic map of blood proteins in humans replicates findings from much larger studies, uncovers hundreds of new signals and bridges genetic variation to multiple diseases.

Identifying mechanistic pathways that link obesity with COVID-19 severity provides targets for interventions to reduce the high risk of severe outcomes owing to obesity. The authors of a recent study use genomics and proteomics to show that nephronectin could be involved in one of these pathways.

The rate of glycolysis increases markedly during the phagocytosis of apoptotic cells and upon macrophage activation by inflammatory stimuli. However, the motive for burning glucose differs in both conditions.

The alternative splicing landscape of pancreatic islets is dominated by an evolutionarily conserved program of microexons. These short exons encode only a few extra amino acids in genes related to hormone secretion. Microexons are important to islet function, affecting glycaemic control and the risk of type 2 diabetes.

Cell division is a highly regulated process and requires a concurrent supply of energy and nutrients. Shin et al. provide critical insights into the allosteric mechanisms by which UTP regulates CAD activity and pyrimidine synthesis during the cell cycle.

We show that the retinal pigment epithelium (RPE) — the outermost layer of the retina — is a local source of insulin that is modulated by starvation and phagocytosis, separate from pancreatic insulin. Further, this RPE-derived insulin has functional relevance in retinal physiology, retinal metabolic homeostasis and in limiting retinal disease.

Dai and colleagues show that activation of AMPK by glucose starvation leads to phosphorylation of GATOR2 and affects nutrient-dependent activation of mTORC1.

Lactate build up in the tumour microenvironments is thought to dampen anti-tumour immunity, but in vitro pre-conditioning T cells with lactate enhances anti-tumour activity in vivo in pre-clinical mouse models.

Some individuals with obesity have a healthy metabolic profile and are not at increased risk for diabetes or cardiovascular disease. The mechanisms behind this phenomenon are poorly understood, but recent work now characterizes the biological underpinnings of the metabolically healthy obese phenotype.