Research Briefing in 2024

Despite their abundance and despite being the most numerous biological entities on Earth, viruses remain one of the least understood components of the human microbiome. In our study, we show how Microviridae bacteriophages in the gut microbiome are associated with food addiction through changes in tryptophan, serotonin and dopamine metabolism.

A common feature of neurodegenerative diseases is that select neuronal types are particularly sensitive to disease pathology at early stages. Altered TrkB signalling in the neuronal type most affected by Huntington’s disease increased expression of the enzyme GSTO2, leading to dopaminergic dysfunction, impaired energy metabolism, progressive degeneration and hyperkinetic symptoms.

Farnesyl pyrophosphate (FPP), an intermediate of cholesterol biosynthesis in the mevalonate pathway, prolongs the survival of migratory dendritic cells (mig-DCs) by remodelling mitochondrial structure and metabolism. Treating a mouse model of systemic lupus erythematosus with simvastatin (an inhibitor of this pathway) led to recovery from dysregulation in mig-DCs and ameliorated systemic autoimmune pathogenesis.

Brown adipose tissue (BAT) facilitates thermogenesis through fatty acid oxidation (FAO). Paradoxically, BAT simultaneously increases anabolic fatty acid synthesis (FAS), the reason for which is unclear. We provide evidence that thermogenic mitochondria within brown adipocytes export TCA cycle intermediates that fuel de novo lipid synthesis, in part to protect against metabolic stress.

The metabolic sensor enzyme OGT dynamically O-GlcNAcylates hexokinase 1 (HK1). This modification enhances the localization of HK1 to mitochondria in response to glucose flux and facilitates the formation of a glycolytic metabolon on the mitochondrial outer membrane, leading to increased rates of both glycolytic and mitochondrial ATP production.

Adults with overweight or obesity who have been exercising regularly for at least a few years have distinct structural and biological characteristics in their abdominal subcutaneous adipose tissue. These changes could underlie improved cardiometabolic health outcomes in this population, when compared with well-matched sedentary adults with overweight or obesity.

Pancreatic β-cells do not appear to require interactions with neighbouring non-β-cells (α-cells, δ-cells and γ-cells) to regulate insulin secretion. These results are clinically relevant and support the development of treatments for diabetes that involve the generation of β-like cells alone, whether from pluripotent cells or by in situ conversion of non-β-cells.

In mouse gut microbiome studies, the significance of the results for control and experimental groups varies at different time points during the day. As inconsistent results across studies might stem from variation in sample collection times, standardization is crucial for reliable comparisons.

Agmatine produced by gut microbiota — specifically, Bacteroides vulgatus — activates the farnesoid X receptor (FXR) in intestinal epithelial L cells in a bile-acid-independent manner, which inhibits host glucagon peptide 1 (GLP-1) secretion and leads to polycystic ovary syndrome (PCOS) in mice. Supplementing mice with the GLP-1 receptor (GLP-1R) agonist liraglutide or inhibiting the production of agmatine reverses the PCOS phenotype.

A systematic deep-mutational-scanning analysis of the mitochondrial complex I assembly factor NDUFAF6 reveals its molecular function and aids in the identification of pathogenic variants in mitochondrial disease.

A new engineering strategy for improving the biosynthesis of secondary metabolites in Streptomyces has been developed through the analysis of genes co-evolved with biosynthetic gene clusters. This strategy has been verified in 11 Streptomyces strains to enhance production of 16,385 metabolites, showing potential applications in drug discovery and industrial production.

A new sensor that detects optoacoustic signals generated by mid-infrared light enables measurement of glucose concentration from intracutaneous tissue rich in blood. This technology does not rely on glucose measurements in interstitial fluid or blood sampling and might yield the next generation of non-invasive glucose-sensing devices for improved diabetes management.

AMPK directly phosphorylates the mitochondrial protein SYNJ2BP to facilitate its interaction with the RNA-binding protein SYNJ2a, which transports Pink1 mRNA into neurites. AMPK inhibition downstream of insulin signalling untethers Pink1 mRNA from neuronal mitochondria and favours PINK1-dependent mitophagy in neurons. ApoE4-induced insulin receptor internalization reverses the process by stabilizing Pink1 mRNA binding to neuronal mitochondria.

Individuals with osteoporosis have increased risk of Alzheimer’s disease or cognitive impairment during ageing. We elucidated a partial explanation for bone dysmetabolism’s association with such cognitive decline, by demonstrating how elevated sclerostin secretion from osteocytes in bone impaired cognitive function in aged mice and in an Alzheimer’s disease mouse model.

Glycerol-3-Phosphate (G3P) and phosphoethanolamine (pEtN) biosynthetic pathways are modulated during senescence establishment to sustain lipid droplet accumulation and senescence-associated secretome. These findings reveal new targets for an immunomodulatory approach against senescent cells.

Here, we reveal functional heterogeneity among β cells and discover that readily releasable β cells (RRβs) are a subpopulation that disproportionally contributes to biphasic glucose-stimulated insulin secretion. We further show that the dysfunction of RRβs has a crucial role in the progression of diabetes.

Murine blastocysts and embryonic stem cells mimicking the pre-implantation epiblast import extracellular protein through macropinocytosis and engage a robust lysosomal digestive programme to meet their nutrient demands. We found that as development proceeds, post-implantation epiblast-like cells downregulate protein digestion, increase expression of amino acid transporters and become dependent on soluble amino acids.

Calcium sensing receptor (CaSR) and peptide transporter 1 (PepT1) have been implicated in protein sensing in the gut, although the mechanisms are poorly understood. We find that, in the small intestine, CasR and PepT1 are necessary for protein sensing to regulate gut peptide release, feeding and glucose tolerance in rats in vivo.