Reviews & Analysis

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.

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.

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.

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.

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.

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.

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.

Sepsis takes a severe toll in the heart and can in some instances induce irreversible dysfunction. Zhang et al. discover a subset of macrophages that protects the septic heart by removing inflammogenic material released by cardiomyocytes.

Multiomic analyses in an individual with severe, early-onset obesity, followed by targeted screening in additional patients identifies a tandem duplication at the ASIP gene (encoding agouti-signalling protein) as a novel cause of monogenic obesity, with implications for genetic diagnosis of obesity.

mTORC1 integrates environmental signals to promote anabolism and repress catabolism. In this issue of Nature Metabolism, Hosios et al. identify a role for mTORC1 in controlling endosomal trafficking and degradation of membrane phospholipids in the lysosome, revealing a novel process used by cells to adapt to poor growth conditions.

The physiological role of aerobic glycolysis (also known as the Warburg effect), which is observed in many tumours, is still not fully understood. The finding that lactate dehydrogenase A (LDHA) activates RAC1 in breast cancer sheds new light on this persistently enigmatic aspect of cancer metabolism.

Sustained weight loss and weight maintenance are key challenges for the treatment of obesity. Here, the authors show that a high-protein diet following weight loss can protect against weight regain, through a process dependent on the gut microbiome.