Research Briefing

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.

Mitochondria of young adipocytes release RNA molecules that serve as signals to stimulate the transcription of nuclear-encoded genes for mitobiogenesis and thermogenesis. Mitochondrial RNA (mtRNA) efflux thus establishes retrograde mitochondria–nucleus signalling and triggers heat production from fat. Stimulating this signalling protects against obesity in mice.

A maternal high-fat diet (mHFD) alters behavior in offspring in a sex-specific manner. We demonstrate that mHFD increases endotoxin levels in fetal tissues and decreases long-term serotonin bioavailability in male offspring owing to removal of serotonin neurons by microglia in the embryonic brain.

The immune-modulatory metabolite itaconate is secreted by myeloid-derived suppressor cells and taken up by CD8⁺ T cells to suppress their proliferation and function. In mice, blocking itaconate production enhances the efficacy of immune checkpoint blockade.