Reviews & Analysis

Macrophages that clear apoptotic cells (efferocytosis) proliferate to enhance tissue repair and resolution. Here, we find that a previously elucidated nucleotide ‘cargo’ proliferation pathway that increases Myc mRNA is complemented by efferocytosis-induced lactate, which stabilizes Myc protein through SIRT1-mediated Myc protein deacetylation.

We demonstrated increased phospholipid peroxidation due to the formation of monolysocardiolipin–cytochrome c complexes in tafazzin-deficient models of Barth syndrome. We found that a specific anti-peroxidase agent inhibited this complex and improved mitochondrial respiration. Thus, targeting the deleterious peroxidase activity offers a potential therapeutic approach to treat Barth syndrome.

Analysis of cells shed from the mouse gut, using bulk and single-cell transcriptomics, as well as single-molecule FISH and intravital imaging, revealed that shed cells are diverse, remain viable for a few hours and upregulate anti-microbial gene expression programs.

The molecular underpinnings of the extensive cellular, morphological and functional plasticity of skeletal muscle in exercise training are poorly understood. We have now begun to unravel the complex epigenetic, transcriptional and proteomic networks that determine the muscle response to exercise in a manner depending on the training state.

Glucagon-like peptide 1 (GLP-1) controls insulin secretion and body weight through activation of its receptor, GLP1R. Large-scale functional analysis of 60 GLP1R genetic variants revealed that loss-of-function (LoF) phenotypes, in particular of cell surface expression, are associated with impaired glucose control and increased adiposity.

A mouse pancreatic islet atlas comprising over 300,000 single-cell transcriptomes was integrated from nine biologically diverse datasets to unify existing knowledge in the islet biology community. This interactively accessible resource reveals new insights into the molecular identity and plasticity of islet and β-cells across sex, life span and diabetes progression.

Sensory association learning is impaired in people with insulin resistance but can be restored following a one-time intervention with liraglutide. These findings provide ample evidence for metabolic signals as modulators of adaptive behaviour and suggest a potential role for GLP-1 receptor agonists in obesity management.

By using a combination of transcriptomics, primary adipocyte culture and experimental medicine approaches, we identified the sodium-dependent serotonin transporter SERT as a novel regulator of human brown adipose tissue function.

This study shows that a 10% weight loss induced by calorie restriction and multimodal exercise training results in a much greater increase in whole-body insulin sensitivity than matched weight loss induced by calorie restriction alone. This result underscores the importance of adding regular exercise to a weight loss programme, as it improves metabolic health.

This study reveals that oxidative aneuploid cancer cells exhibit an upsurge of NADPH levels during mitosis, which neutralizes excessive reactive oxygen species and protects against chromosome mis-segregation.

Comparative metabolomic analyses of the guts of healthy colonized versus germ-free mice helped map microbial metabolites across the various intestinal niches. The microbial origin and biochemical processes underlying several metabolites could be inferred, even in areas difficult to access, such as the small intestine.

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.

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.

PCYT2 is an enzyme involved in lipid biosynthesis, and its genetic deficiency in zebrafish, mice and humans causes progressive muscle weakness. Importantly, PCYT2 activity declines in ageing muscles of mice and humans, and PCYT2 gene therapy in aged mice improves muscle strength, suggesting new therapeutic avenues to explore for maintaining muscle health in ageing.

The alternative splicing landscape of pancreatic islets is dominated by an evolutionarily conserved program of microexons. These short exons encode only a few extra amino acids in genes related to hormone secretion. Microexons are important to islet function, affecting glycaemic control and the risk of type 2 diabetes.

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.

Human pluripotent stem cell-derived pancreatic islets (PSC-islets) hold promise in type I diabetes treatment, although their delivery is a challenge. We describe a new abdominal infusion transplantation protocol that enables the survival, maturation and maintenance of functional PSC-islets in diabetic monkeys.