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Telomere shortening in adipocyte progenitors, promoted by genetic Tert inactivation, is shown to compromise adipose tissue health and systemic metabolism, providing a possible mechanistic link between obesity, ageing and metabolic disease.
Martin-Perez et al. show that the beneficial effects of rapamycin in a mouse model of Leigh syndrome are associated with downregulation of protein kinase C.
Hibernation is a state of extreme metabolic and physiological plasticity occurring in conjunction with physical inactivity and prolonged fasting. Using in vivo tracing, Rice et al. reveal that nitrogen recycling staves off ammonia toxicity during hibernation in ground squirrels.
A particularly aggressive subtype of lung cancer with mutations in KRAS and LKB1 is shown to depend on increased hexosamine biosynthesis mediated by the enzyme GFPT2.
By using single-cell transcriptomics, Weng et al. reveal complex temporal gene control during pancreatic beta-cell differentiation from human embryonic stem cells, allowing for the construction of a unique lineage tree and optimization of differentiation protocols.
Wei et al. identify the HDL receptor SR-B1 as a host factor that enhances infection of cultured cells with SARS-CoV-2 in the presence of ACE2, thus providing a possible molecular connection between lipoprotein metabolism and COVID-19.
Oncogenic transformation can render cancer cells dependent on aberrant expression of glycolytic enzyme isoforms. Lin et al. describe a novel enolase inhibitor, POMHEX, that can selectively kill ENO1-deleted glioblastomas.
Chini et al. demonstrate that CD38+ expression in immune cells increases during aging, owing to the senescence-associated secretory phenotype of senescent cells, and the ecto-enzymatic activity of CD38+ affects intracellular NAD+ levels in vivo by hydrolyzing the NAD+ intermediate nicotinamide mononucleotide extracellularly.
Senescent cells in fat and liver are shown to attract M1-like macrophages with increased expression of the NAD-consuming enzyme CD38, leading to their local accumulation and providing a mechanism for the age-associated decline in tissue NAD+ levels.
The PI3K–PTEN signalling pathway is a central regulator of metabolic homeostasis. Brunner et al. find that cell-intrinsic PI3K signalling allows adipose tissue macrophages to buffer obesity-induced lipotoxicity by promoting lipid uptake and catabolism.
The nuclear factor kappa B subunit c-Rel acts as a master regulator of metabolism and signalling in epithelial cells and macrophages that drives inflammation and fibrogenesis in various models of fibrosis.
PDGFRβ+ perivascular mesenchymal cells are shown to regulate chronic adipose-tissue inflammation in obesity through downregulation of ZFP423, a transcriptional corepressor of NF-κB.
Levy et al. report a method to measure transcriptional coordination between cells in single-cell RNA sequencing data and demonstrate that transcriptional dysregulation between cells is a general phenomenon in ageing and is associated with genetic damage.
Metformin holds the potential to extend healthy lifespan in aged, insulin-resistant individuals. Using C. elegans, Espada et al. uncover a deleterious metabolic response to metformin treatment in aged worms with unaltered insulin signalling.
Impaired myocardial metabolic flexibility is associated with cardiac dysfunction in diabetes and heart failure. McCommis et al. reveal a critical role for mitochondrial pyruvate use in cardiac function, and use dietary interventions to enhance cardiac fat metabolism in dilated cardiomyopathy.
Metabolic substrate partitioning underlies myocardial homeostatic capacity and adaptation to stress. Zhang et al. show that decreasing mitochondrial pyruvate carrier expression redirects glycolytic intermediates and leads to heart failure, which is prevented or reversed with a high-fat or ketogenic diet.
Folkersen et al. report the first results from the SCALLOP consortium, a collaborative framework for pQTL mapping and biomarker analysis of proteins on the Olink platform. A total of 315 primary and 136 secondary pQTLs for 85 circulating cardiovascular proteins from over 30,000 individuals were identified and replicated to yield new insights for translational studies and drug development.
Using data from 74,629 individuals from 4 independent surveys, Bonnefond et al. report a much stronger burden of pathogenic genetic variants of MODY genes among people diagnosed with type 2 diabetes than has previously been reported.
Developmental checkpoints are crucial for regulating metabolite utilization to ensure future survival. Yamada et al. use mathematical modelling to uncover a central role for ecdysteroids in regulating Drosophila larval metabolism.
Li et al. describe a new form of ATP sensing pathway that induces mitochondrial anchoring at presynaptic terminals during sustained synaptic activity. This mechanism involves AMPK–PAK energy signalling that recruits mitochondria from axons to presynaptic filamentous actin via myosin VI phosphorylation and interaction with the mitochondrial anchoring protein syntaphilin.