Volume 2 Issue 10, October 2020

Cancer cells require exogenous cysteine for proliferation and survival. In this issue of Nature Metabolism, Zhang et al. demonstrate that deletion of 5-methylthioadenosine phosphorylase promotes the synthesis of polyamines from methionine, thereby conferring sensitivity to cysteine starvation.

A recent study by Karunakaran et al. suggests that RIPK1 is important in obesity and related metabolic traits. With genetic variation associated with expression and the risk of obesity, and repression of activity leading to a favourable metabolic profile in an obesogenic model, is there evidence for a potential therapeutic role?

Aberrant upregulation of de novo lipogenesis is linked to non-alcoholic fatty liver disease and some cancers. A new study by Kelly et al. finds that inhibiting this pathway by blocking the activity of acetyl-CoA carboxylase has unexpected effects on the formation of platelets from megakaryocytes within the bone marrow of primates but not rodents, thus suggesting clinical implications for de novo lipogenesis inhibitors as a new class of therapeutics.

Franco et al, review how metabolic insufficiency and prolonged stress responses impact signaling cascades and epigenetic reprogramming to lock T cells into an exhausted state.

Yu et al. report a preparation that enables transplantation of pancreatic islets underneath the skin and achieves long-term euglycaemia in several preclinical models of type 1 diabetes, thus providing a simple method that might enable a more widespread adoption of islet transplantation in the clinic.

The authors report the case of a young patient who displayed insulin-dependent diabetes after SARS-CoV-2 infection in the absence of autoantibodies indicative of autoimmune type 1 diabetes.

A single intracerebroventricular injection of FGF1 leads to a remarkable remission of diabetes in various rodent models. Here, Alonge et al. show that FGF1-induced diabetes remission in rats requires remodelling of perineuronal nets that enmesh glucoregulatory neurons in the arcuate nucleus.

Fructose consumption has greatly increased in recent years and has been linked to the development of hepatic steatosis. Here, the authors show that fructose promotes gut-barrier deterioration and subsequent endotoxaemia that in turn induces hepatic lipogenesis by activation TLR signalling in liver macrophages.

After activation, conventional T cells undergo metabolic reprogramming. de Kivit et al. show that in human thymic regulatory T cells, TNFR2 stimulation promotes a glycolytic switch with a preferential glucose-derived carbon flux into the TCA cycle to support suppressive functions.

Cancer cells have heightened demands for non-essential amino acids to support proliferation and redox homeostasis. Here, Zhang et al. propose the intersection of cysteine metabolism and polyamine synthesis as an unexplored metabolic vulnerability of cancer cells.

Li et al. describe a new form of ATP sensing pathway that induces mitochondrial anchoring at presynaptic terminals during sustained synaptic activity. This mechanism involves AMPK–PAK energy signalling that recruits mitochondria from axons to presynaptic filamentous actin via myosin VI phosphorylation and interaction with the mitochondrial anchoring protein syntaphilin.

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.

Using holistic and reductionist approaches, Karunakaran et al. identify a causal association between higher expression of RIPK1 (a central regulator of inflammatory cell function) and the risk of obesity. RIPK1 induces activation of proinflammatory signalling in adipose tissue, promoting the accumulation of macrophages that drive metabolic inflammation and obesity simultaneously.

Using data from 74,629 individuals from 4 independent surveys, Bonnefond et al. report a much stronger burden of pathogenic genetic variants of MODY genes among people diagnosed with type 2 diabetes than has previously been reported.

Folkersen et al. report the first results from the SCALLOP consortium, a collaborative framework for pQTL mapping and biomarker analysis of proteins on the Olink platform. A total of 315 primary and 136 secondary pQTLs for 85 circulating cardiovascular proteins from over 30,000 individuals were identified and replicated to yield new insights for translational studies and drug development.

Linke et al. use unbiased and quantitative techniques to directly link both known and unknown liver and plasma lipid moieties to specific genomic loci, as compiled in a public web resource, LipidGenie. LipidGenie aided in the identification of a new group of sex-specific phosphatidylcholines.

Pharmacological targeting of de novo lipogenesis is an attractive clinical target for a wide range of diseases. Kelly et al. report that de novo lipogenesis is essential for platelet production in primates, but not in dogs and rats.