Non-mammalian model organisms in metabolic research

Work in non-mammalian model organisms has shed light on many fundamental biological processes. At Nature Metabolism, we are interested in studies that make use of the unique advantages of these models to unravel new insights into metabolic biology.

Dutta et al. show that impaired mitochondrial fatty acid synthesis (mtFAS) leads to neurodegeneration, increased ceramide levels and disturbed iron metabolism in flies and in fibroblasts from individuals with a mutation in an mtFAS enzyme.

In this study, Rabah et al. investigate glucose usage in the brain, and show how glial cells transfer glycolysis-derived alanine to neurons in a fly model, thus supporting memory formation in cholinergic circuits.

The authors identify a high-pH-activated chloride channel as a taste receptor responsible for the avoidance of alkaline foods in fruit flies, laying the groundwork for future research on alkaline taste sensation in other animals.

Malita, Kubrak et al. show that the gut-derived hormone neuropeptide F suppresses sugar intake and increases the consumption of protein-rich food in Drosophila. This gives insight into the regulation of nutrient-specific appetite that ensures appropriate food choices to meet nutritional demands.

Amino acid-sensing is vital for adaptation to the nutritional environment. In this study, Kosakamoto et al. show that the non-essential amino acid tyrosine regulates the adaptive response to protein restriction via modulating ATF4 activity in Drosophila.

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.

Redox signal transduction from the mitochondrial matrix to the cytosol is shown to be mediated through interaction between MIC60 and Miro, the disruption of which ameliorates oxidative stress in Drosophila.

Hocaoglu et al. find a conserved shift in redox metabolites in fly oocytes and mammalian cells in response to mitochondrial respiratory quiescence that leads to reprogramming of progeny metabolism.

The Drosophila white mutant has been used extensively for genetics studies. Sasaki et al. show a metabolic role of white, which is found to regulate intestinal stem cell proliferation during ageing through folate metabolism.

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.

Carbohydrate metabolism in germ cells is shown to promote sugar appetite in female flies, thus demonstrating how metabolism in a subset of cells alters whole-animal behaviour.

Bevers and Litovchenko et al. sequence mitochondrial genomes from 169 different inbred Drosophila melanogaster strains to reveal mitochondrial population structure as well as links between mitochondrial haplotypes and metabolic variation in flies.

Proinflammatory activation of liver macrophages and their secretion of proinflammatory cytokines have been linked to obesity. Here Morgantini et al. report a mechanism through which liver macrophages can impair liver metabolism and promote insulin resistance in obesity in the absence of an overt proinflammatory phenotype, through secretion of non-inflammatory factors such as IGFBP7.

Ageing is associated with deteriorating immune function and metabolic diseases. Here, the authors show that plasma levels of the stress-response protein MANF decline with age in various organisms and that MANF has beneficial effects on immune and metabolic function, particularly in the liver, in old mice.

Wei et al. show that proteolytic cleavage of fatty acid synthase (FASN) upon stress contributes to stress resolution. This role in stress resolution of the resulting C-terminal fragment of FASN is independent of its canonical function in fatty acid synthesis.

A small-molecule aldolase inhibitor, aldolazin is reported and shown to selectively activate the lysosomal pool of AMPK, which has glucose-lowering effects in rodents.

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.

Tharyan et al. identify NFYB-1 as a regulator of mitochondrial function that represses lysosomal prosaposin. The NFYB-1–prosaposin signalling axis coordinates lysosomal-to-mitochondria signalling via cardiolipin to enhance cellular mitochondrial function and longevity in C. elegans.

Anoxia─lack of oxygen─commonly occurs during ischaemic heart disease. Using yeast, worms and mice, Hannich et al. show that anoxia-associated tissue injury and cell death are due to accumulation of a non-canonical sphingolipid, 1-deoxydihydroceramide, that damages the cytoskeleton.

Although germline removal normally extends Caenorhabditis elegans lifespan, Lee et al. show that low temperature does not extend lifespan in germline-lacking mutant worms. Cold temperatures (10 °C, 15 °C) delay germline stem cell exhaustion, releasing prostaglandin E2 hormone, which induces cbs-1 in the intestine to produce hydrogen sulfide and prolong lifespan.

Olfactory food perception is known to extend lifespan in C. elegans. Here the authors demonstrate food-odour-dependent brain-to-gut communication that extends lifespan in worms. Food odour downregulates tir-1 mRNA in AWC neurons, in a manner dependent on the miRNA miR-71, which triggers downstream effects in the gut, due to neuropeptide secretion, that promote proteostasis and longevity.

Endothelial cell metabolism is shown to regulate blood vessel maturation by controlling vascular matrix composition and the recruitment of vascular mural cells.

A high-throughput chemical screen identifies the salt-inducible kinase inhibitor HG-9-91-01 as a driver of β cell proliferation, acting through an ATF6-dependent unfolded protein response.

Bayraktar et al. construct a metabolic coessentiality network to cluster metabolic genes into networks from perturbation datasets derived from 558 cancer cell lines. They identify C12orf49 as an essential component of SREBP processing and cholesterol sensing in mammalian cells.

Pancreatic β-cells are highly connected, and this network is crucial for the pulsatile release of insulin. Here Salem and colleagues demonstrated the existence of leader β-cells that respond first to glucose and are more closely linked to the other β-cells. They also showed that glucose increases β-cell calcium dynamics and connectivity between the leader and non-leader β-cells.