Articles in 2023

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.

Shin et al. gain structural insight into how pyrimidine synthesis is coupled to cell cycle regulation through the modulation of CAD activity, and identify allostery as a major means to regulate de novo pyrimidine biosynthesis during the mammalian 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.

Dai et al. show that in response to low glucose levels, AMP-activated protein kinase-mediated phosphorylation of WDR24, a component of the GATOR2 complex, leads to suppression of mTORC1 activation.

Retinal pigment epithelial cells are identified as a local source of insulin in the retina, which is stimulated by phagocytosis of photoreceptor outer segments and starvation and has the potential to influence retinal physiology and disease.

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.

Prolonged exposure to acid is shown to reprogram T cell intracellular methionine metabolism to preserve T cell stemness and increase anti-tumor efficacy.

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.

Investigation of multi-omic changes and their effects on regulation of metabolic pathways confirm anaplerotic deficiencies in methylmalonic acidaemia, strengthening the need for future therapies aimed at replenishing intermediates of the tricarboxylic acid cycle.

Coral et al. characterize genetically determined discordance between obesity and type 2 diabetes, identifying discordant genes that may convey protection against type 2 diabetes in obesity.

The authors combine multi-layered omics with clinical and biochemical features from individuals affected with methylmalonic aciduria, a rare inherited disease affecting succinyl-CoA synthesis, revealing that anaplerotic rewiring is a targetable feature.

Iron is a growth factor for many microbes, and its availability is critical for the course of infections. A new study uncovers a mechanism by which extracellular vesicles released by macrophages withdraw iron from the blood, thereby limiting iron access for bacteria and improving outcomes from sepsis.

Kuang, Dou et al. show that upon Salmonella Typhimurium infection in mice, macrophages release extracellular vesicles (EVs) that harbor iron-uptake receptors. By sequestering iron via a humoral mechanism, these EVs limit bacterial growth and thereby protect against infection.

In this study, Oaks and Patel et al. characterize the crosstalk between the pentose phosphate pathway and mitochondrial redox homeostasis in the context of aldose reductase and transaldolase deficiency and the contribution of pentose phosphate pathway mitochondria deregulation to the progression from cirrhosis to hepatocellular carcinoma.

Intracellular trafficking of cholesterol is essential for its uptake, storage and export. In this issue of Nature Metabolism, Xiao et al. provide powerful evidence for the importance of hepatic GRAMD1/Aster transporters in maintaining systemic cholesterol homeostasis.

Commensal bacteria in the gut and their metabolites modulate the tonus of cancer immunosurveillance. Mao, Huang et al. demonstrate that the anticancer effects of caloric restriction depend on the expansion of acetate-producing immunostimulatory Bifidobacterium bifidum.

Xiao and Kennelly et al. show that Aster-mediated nonvesicular cholesterol transport in the liver regulates hepatic and systemic lipid homeostasis during fasting, as well as reverse cholesterol transport.