Volume 5 Issue 4, April 2023

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.

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.

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.

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.

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.

Obesity is caused by a mismatch between energy intake and expenditure. How much reduced expenditure (which is assumed to result from reduced activity) or elevated food intake contribute to obesity is debated. We show that total energy expenditure has been falling owing to a reduction in basal metabolic rate and not in activity expenditure.

The authors of this Perspective argue that the commonly used terms ‘mitochondrial function’ and ‘mitochondrial dysfunction’ do not do justice to the diverse mitochondrial features, activities, functions and behaviours within cells, and thus call for the field to adopt more specific terminology in the context of mitochondrial biology.

The authors provide an overview of the current and emerging wearable and digital devices that can inform about specific metabolic outcomes in people, discussing how they could be used to create more tailored preventive and therapeutic strategies against cardiometabolic disease.

Govaere et al. integrate circulating protein data from more than 300 patients with non-alcoholic fatty liver disease (NAFLD) with transcriptomics and develop a non-invasive diagnostics tool to identify patients with at-risk NAFLD based on body mass index, type 2 diabetes status and four circulating proteins.

Using a database of doubly labelled water energy expenditure measurements spanning more than 30 years, Speakman and colleagues show that total energy expenditure in humans has declined over time, while adjusted physical activity energy expenditure has increased over time.

Elevated plasma branched-chain amino acid (BCAA) levels have been associated with insulin resistance and type 2 diabetes. Blair et al. show that altering BCAA oxidation in skeletal muscle or liver does not influence insulin sensitivity in male mice, despite the effects on BCAA plasma levels.

Wang et al. identify a promoter variant in xanthine oxidoreductase associated with diabetic kidney disease through increased podocyte depletion and glomerular injury.

In this study, Hu et al. identify a new mechanism through which sirtuin-4 fine-tunes urea cycle flux through decarbamylation of ornithine transcarbamylase to ensure proper ammonia detoxification upon increased amino acid catabolism.

In this study, Green, Marttila, Kiweler et al. characterize one-carbon metabolism rewiring in response to a dual MTHFD1 and MTHFD2 inhibitor. This work provides insight into one-carbon fluxes, and reveals a previously uncharacterized vulnerability in cancer cells created by folate trapping.

Human and mouse cells expressing a redox-insensitive GAPDH mutant that otherwise retains its catalytic activity are shown to be unable to upregulate the oxidative pentose phosphate pathway in response to oxidative stress.

Studies of the physiological effects of metabolites often rely on injections of metabolite salts. In this study, Lund et al. show that the hypertonicity of the injected solutions can drive the metabolic effects attributed to pharmacological administration of lactate. This work highlights the importance of taking treatment osmolarity and counterions into account in the experimental design.

Wunderling et al. develop a fatty acid tracing technology based on alkyne-labelled fatty acids and directly demonstrate triglyceride cycling in 3T3-L1 adipocytes, which allows maintenance and modification of stored fatty acid pools.