News & Views in 2020

The restoration of the progressive decline in nicotinamide adenine dinucleotide (NAD⁺) levels mitigates certain age-associated dysfunctions. A fundamental question is how the NAD⁺-consuming enzyme CD38 decreases NAD⁺ levels during ageing. Two new studies by Chini et al. and Covarrubias et al. in this issue of Nature Metabolism show that CD38 expression in macrophages induced by senescence-associated inflammation accounts for the age-related decline in NAD⁺ levels.

A new global measure of cell-to-cell transcriptional variability from single-cell RNA-sequencing data has been developed by Levy et al., on the basis of the transcriptional interrelations between genes. The new variable, termed global coordination level, decreases with age in different organisms and cell types and correlates with high mutational load in cells.

The heart is an organ with high energy demands and metabolic flexibility, thus allowing for various energy substrates for ATP production under different physiological conditions. Zhang et al., Fernandez-Caggiano et al. and McCommis et al. converge on the mitochondrial pyruvate transporter as a key metabolic hub for the maintenance of cardiac metabolism and a critical determinant of cardiac metabolic plasticity during heart failure.

A recent study by Karunakaran et al. suggests that RIPK1 is important in obesity and related metabolic traits. With genetic variation associated with expression and the risk of obesity, and repression of activity leading to a favourable metabolic profile in an obesogenic model, is there evidence for a potential therapeutic role?

Aberrant upregulation of de novo lipogenesis is linked to non-alcoholic fatty liver disease and some cancers. A new study by Kelly et al. finds that inhibiting this pathway by blocking the activity of acetyl-CoA carboxylase has unexpected effects on the formation of platelets from megakaryocytes within the bone marrow of primates but not rodents, thus suggesting clinical implications for de novo lipogenesis inhibitors as a new class of therapeutics.

Islet of Langerhans transplantation as a cell therapy for type 1 diabetes faces obstacles that have prevented full and lasting engraftment in the liver, the currently preferred implantation site in clinical practice. Yu and colleagues circumvent these issues and achieve stable diabetes reversal by transplanting islets encapsulated in a simple collagen-based matrix into the more accessible subcutaneous space.

Cancer cells require exogenous cysteine for proliferation and survival. In this issue of Nature Metabolism, Zhang et al. demonstrate that deletion of 5-methylthioadenosine phosphorylase promotes the synthesis of polyamines from methionine, thereby conferring sensitivity to cysteine starvation.

The mechanistic target of rapamycin complex 1 (mTORC1) network integrates nutrient and energy signals that regulate metabolism and cell growth. Orozco et al. now show that the glycolytic intermediate dihydroxyacetone phosphate (DHAP) relays glycolytic activity to mTORC1 signalling.

GABA-expressing neurons in the arcuate nucleus of the hypothalamus regulate obesity in mice. A recent study indicates the importance of unexamined cell types.

AMPK is a crucial sensor of the cellular energetic state and is also activated during glucose starvation. A new study reports that AMP-activated protein kinase (AMPK) is activated by interaction with long-chain fatty acyl–CoA esters, which appear to be the long-sought endogenous AMPK ligands that bind the allosteric drug and metabolite (ADaM) site.

Diet and exercise are the two pillars of a healthful lifestyle for stemming the rising tide of metabolic disease. A new study in this issue reveals that the health benefits of diet and aerobic exercise are more interdependent than previously appreciated, thus reinforcing the importance of a holistic approach to maintaining a healthful lifestyle.

Caffa et al. report in Nature that hormone-receptor-positive breast cancer is sensitive to a form of ‘dietary augmentation therapy’ that implements periods of fasting, thus enhancing anti-cancer therapy.

In this issue of Nature Metabolism, Mi and colleagues provide evidence that super-enhancers play a critical role in autosomal-dominant polycystic kidney disease (ADPKD) and show that CDK7 targeting provides a novel therapeutic option.

A study published in this issue of Nature Metabolism adds to the emerging evidence that the small intestine is an initial site of dietary fructose metabolism, especially at low fructose doses, thus decreasing exposure of the liver and the colonic microbiome to intact fructose.

Pancreatic adenocarcinoma (PDAC) is often characterized by substantial amounts of fibrosis, and how these stromal components affect metabolite availability is not fully understood. Zhu et al. now show that cancer-associated fibroblasts consume branched-chain amino acids (BCAAs) at high levels but release corresponding branched-chain α-ketoacids that support PDAC cell growth.

The adipose tissue harbours multiple immune-cell types whose populations are known to be altered in disease conditions. A new study by Brigger et al. shows that restocking fat tissues of old mice with eosinophils prevents age-related declines in physical and immunological functions.

Selenium is a micronutrient essential for the generation of selenoproteins, which function predominantly by detoxifying cellular reactive oxygen species. In this issue, Carlisle et al. describe a novel mechanism whereby perturbing selenium utilization via inhibition of SEPHS2, a component of the selenocysteine-biosynthesis pathway, results in selenide poisoning and cancer cell death.

Maternal exercise during pregnancy results in metabolic benefits for offspring, but how mothers transfer these benefits to newborns has been a mystery. A new study now shows that a breast-milk component transmits the metabolic effects of exercise to offspring

Genetic-interaction mapping and co-essentiality analyses in human cells reveal the orphan gene C12orf49 (also known as SPRING1) as a novel regulator of lipid-metabolism homeostasis.

Whereas textbooks depict metabolism in perfect homeostasis, disturbances occur in real life. One particularly relevant disturbance, caused by excess food and alcohol consumption and exacerbated by genetics, is reductive stress. New work by Goodman et al. identifies a biomarker of reductive stress and uses a gene therapy solution in mice. This work suggests how exercise and an accessible nutritional technology can synergistically increase catabolism and relieve reductive stress.