Metabolic communication across biological scales

Diehl et al. show that imbalance among nucleotide species is not sensed by canonical metabolic regulatory pathways, causing excessive cell growth despite a DNA replication block. ATR is needed to increase nucleotide availability in normal S phase.

Nuclear receptors are transcription factors that transduce hormonal, nutrient, metabolite and redox signals into regulation of metabolic genes, in particular the transcriptional control of energy metabolism. Accordingly, nuclear receptors have central roles in adapting gene expression to changing energetic demands, thereby maintaining cellular energy homeostasis

Walpole et al. show that the Salmonella effector SopB generates phosphatidylinositol 3,4-bisphosphate de novo via a phosphotransferase mechanism, independently of phosphoinositide 3-kinases and ATP.

Zhou, Duan, Wang et al. show that d-2-hydroxyglutarate affects mitochondrial health by inhibiting the 3-hydroxypropionate (3-HP) dehydrogenase HPHD-1, leading to a build-up of 3-HP and interference with IMMT-1 (also knowns as MIC60) function in mitochondria structure.

The metabolism of somatic stem cells must be regulated to meet their specific needs, to enable long-term maintenance as well as their activation, proliferation and subsequent differentiation. Better understanding of metabolic regulation in stem cells will open new opportunities to manipulate stem cell function, with potential applications in tissue regeneration and cancer prevention.

Reactive oxygen species (ROS) comprise a wide variety of oxidant molecules with vastly different properties and biological functions in physiology and in disease. Approaches to characterize oxidants in the in vivo context and identify their specific cellular targets will be required to understand and control the pathophysiological activities of ROS.

Mitochondrial respiration relies on five enzymatic complexes that couple electron transport with proton pumping, leading to ATP synthesis. Recent studies have shed new light on the organization, assembly and mechanisms of the respiratory complexes, including the formation of their larger assemblies — respiratory supercomplexes — and their roles in physiology.

Cereghetti et al. report that the glycolytic metabolite fructose-1,6-bisphosphate initiates the disassembly of amyloids formed by the yeast pyruvate kinase Cdc19 to resume ATP production during stress recovery.

The transcriptional response to hypoxia and the role of hypoxia inducible factors have been extensively studied. Yet, hypoxic cells also adapt to hypoxia by modulating protein synthesis, metabolism and nutrient uptake. Understanding these processes could shed light on pathologies associated with hypoxia, including cardiovascular diseases and cancer, and disease mechanisms, such as inflammation and wound repair.

Gomes, Ilter, Low et al. show that alterations in propionate metabolism contribute to cancer aggressiveness through the accumulation of the by-product methylmalonic acid.

Endothelial cells in white adipose tissue are shown to produce polyamines, which regulate adipocyte lipolysis, thus demonstrating how local angiocrine signals contribute to healthy adipose tissue homeostasis.

In the Drosophila starved brain, memory formation undergoes adaptive plasticity. Silva et al. show that neurons in the olfactory memory centre of the starved fly are fuelled by glial-derived ketone bodies in order to sustain memory formation.

Döhla et al. show that selectively and asymmetrically inherited mitochondria impose a metabolic bias on progeny in mammary stem-like cells that alters the balance between stem cell self-renewal and differentiation.

Maqdasy, Lecoutre et al. show that increased an phosphocreatine/creatine ratio in white adipocytes drives changes in AMP-activated protein kinase activity and promotes white adipocyte inflammation during obesity.

Ding et al. report a mechanism that allows cells to sense cellular fatty acid levels and adjust lipolysis as needed, which involves peroxisomal degradation of fatty acids, production of reactive oxygen species and post-translational regulation of adipose triglyceride lipase.

Brown and beige adipocytes are mammalian thermogenic fat cells that regulate whole-body energy metabolism. Notably, brown/beige adipocytes are heterogeneous and their functions extend beyond thermogenesis, encompassing roles as metabolite sinks, as secretory cells and as regulators of adipose tissue homeostasis. Thus, induction of brown/beige fat activity correlates with improved metabolic health.

Shi et al. show that following adrenergic signalling, PKA phosphorylates AIDA, which in turn interacts with and promotes oxidation of UCP1 to regulate UCP1-dependent adaptive thermogenesis.

Insulin secretion from pancreatic β-cells is potently activated by an increase in glucose after feeding but other dietary components — amino acids, fatty acids, metabolites, α-cell-produced peptides and gastrointestinal tract hormones — further control this response. Deciphering this complex regulation is important to increase our understanding of pancreatic dysfunction in diabetes.

Savini et al. report that lysosomal lipolysis in peripheral adipose depots produces polyunsaturated fatty acids (PUFAs). PUFAs and the lipid chaperone LBP-3 induce a nuclear hormone receptor, neuropeptide-mediated cascade in neurons to extend lifespan.

While glucose homeostasis in the circulation is tightly controlled by insulin and other hormones, dedicated hormonal regulators do not exist for most other circulating metabolites. Using perturbative metabolite infusions with isotope labelling in mice, Li et al. show that homeostasis of many circulating metabolites is considerably regulated through mass action-driven oxidation.

Using a model of time-restricted feeding in mice, Levine et al. show that the hepatic NADH cycle links nutrient state to whole-body energetics through the rhythmic regulation of SIRT1.

Dietary restriction in rodents and non-human primates affects key nutrient-sensing signalling pathways to increase healthspan and lifespan. This Review discusses these geroprotective mechanisms and recent insights suggesting that dietary restriction results in similar molecular and metabolic changes in humans, contributing to the prevention of ageing-associated diseases.

Ji and Luo et al. show that miR-3075 in hepatocyte-derived exosomes from mice at early stages of obesity improves insulin sensitivity in chronically obese mice, while hepatocyte exosomes from chronically obese mice induce insulin resistance.

Insulin resistance is one of the earliest manifestations of several human diseases, including type 2 diabetes and cardiovascular disease. This Review discusses the causes of insulin resistance and recent insights into the underlying mechanisms, providing directions for the development of novel therapeutic strategies

NADPH exists in separate cellular pools within the cytosol and mitochondria. Tran et al. find that mitochondrial NADPH is essential to enable proline biosynthesis during cell growth.

MicroRNAs widely regulate systemic metabolism, prominently that of glucose and lipids. Consequently, microRNA misexpression can lead to metabolic diseases such as diabetes and atherosclerosis. MicroRNAs are therefore emerging as potential therapeutic targets to control metabolism and, owing to their secretion in extracellular vesicles, as metabolic biomarkers.

Elevated hepatic alanine catabolism is shown to promote hyperglycaemia and reduce skeletal muscle protein synthesis, thereby linking sarcopenia with hyperglycaemia in the context of type 2 diabetes.

Flippo and Potthoff provide a concise overview of the major physiological and pharmacological effects of FGF21 in nutrient and energy homeostasis.

Nicotinamide adenine dinucleotide (NAD⁺) is a central redox factor and enzymatic cofactor that functions in a plethora of cellular processes, including metabolic pathways and DNA metabolism, and affects cell fate and function. NAD⁺ levels gradually decline with age, and therapeutic elevation of NAD⁺ levels is being trialled for extending human healthspan and lifespan.

Cellular metabolic demand skyrockets during intense exercise, thus rendering the communication of metabolic state essential for organismal homeostasis. Murphy, Watt and Febbraio discuss the physiological processes governing intertissue communication during exercise and the molecules mediating such cross-talk.