SummaryThe control of systemic metabolic homeostasis involves complex inter-tissue programs that coordinate energy production, storage, and consumption, to maintain organismal fitness upon environmental challenges. The mechanisms driving such programs are largely unknown. Here, we show that enteroendocrine cells in the adult Drosophila intestine respond to nutrients by secreting the hormone Bursicon α, which signals via its neuronal receptor DLgr2. Bursicon α/DLgr2 regulate energy metabolism through a neuronal relay leading to the restriction of glucagon-like, adipokinetic hormone (AKH) production by the corpora cardiaca and subsequent modulation of AKH receptor signaling within the adipose tissue. Impaired Bursicon α/DLgr2 signaling leads to exacerbated glucose oxidation and depletion of energy stores with consequent reduced organismal resistance to nutrient restrictive conditions. Altogether, our work reveals an intestinal/neuronal/adipose tissue inter-organ communication network that is essential to restrict the use of energy and that may provide insights into the physiopathology of endocrine-regulated metabolic homeostasis.

Cancer cells have high demands for non-essential amino acids (NEAA), which are precursors for anabolic and anti-oxidant pathways supporting cell survival and proliferation. It is well established that cancer cells consume the NEAA cysteine, and that cysteine deprivation can induce cell death, however, the specific factors governing acute sensitivity to cysteine starvation are poorly characterised. Here we show that that neither expression of enzymes for cysteine synthesis nor availability of the primary precursor methionine correlated with acute sensitivity to cysteine starvation. We observed a strong correlation between efflux of the methionine-derived metabolite methylthioadenosine (MTA), and cysteine starvation sensitivity. MTA efflux results from genetic deletion of methylthioadenosine phosphorylase (MTAP), which is frequently deleted in cancers. We show that MTAP loss up-regulates polyamine metabolism which, concurrent with cysteine withdrawal, promotes elevated ROS and prevents cell survival. Our results reveal an unexplored metabolic weakness at the intersection of polyamine and cysteine metabolism.

Bursicon is the main regulator of post molting and post eclosion processes during arthropod development. The active Bursicon hormone is a heterodimer of Burs-α and Burs-β. However, adult midguts express Burs-α to regulate the intestinal stem cell niche. Here, we examined the potential expression and function of its heterodimeric partner, Burs-β in the adult midgut. Unexpectedly, our evidence suggests that Burs-β is not significantly expressed in the adult midgut. burs-β mutants displayed the characteristic developmental defects but showed wild type-like adult midguts, thus uncoupling the developmental and adult phenotypes seen in burs-α mutants. Gain of function data and ex vivo experiments using a cAMP biosensor, demonstrated that Burs-α is sufficient to drive stem cell quiescence and to activate dLGR2 in the adult midgut.Our evidence suggests that the post developmental transactivation of dLGR2 in the adult midgut is mediated by Burs-α and that the β subunit of Bursicon is dispensable for these activities.

SUMMARY1. Intracellular pH (pHi) and phosphorus metabolites were measured in isolated ferret hearts with 31P nuclear magnetic resonance (NMR).2. The application of cyanide (to mimic hypoxia) produced a fall of the concentration of phosphocreatine ([PCr]) and a rise of those of inorganic phosphate ([Pi]) and sugar phosphates. These were accompanied by an intracellular acidosis.3. If glycolysis was partly inhibited by prior exposure to a glucose-free solution then the application of cyanide also produced a fall of [ATP]. The acidosis was similar to that observed in the presence of glucose.4. If glycolysis was completely inhibited by iodoacetate then the acidosis produced by subsequent addition of cyanide developed more quickly.5. The results are reproduced by a model which incorporates lactic acid production as well as the effects of protons released and absorbed by the changes in metabolite concentrations. The results suggest that the acidosis produced by cyanide (without inhibition of glycolysis) is largely due to lactic acid production. When glycolysis is partly inhibited (glucose-free solution) the acidosis produced by cyanide is partly due to protons released by ATP breakdown. Finally, when glycolysis is entirely inhibited the acidosis is completely due to ATP breakdown. There is no need to postulate a contribution on this time scale from inhibition of pH regulating mechanisms.

p120ctn is a ubiquitously expressed core component of cadherin junctions and essential for vertebrate development. Surprisingly, Drosophila p120ctn (dp120ctn) is dispensable for adherens junctions and development, which has discouraged Drosophila researchers from further pursuing the biological role of dp120ctn. Here we demonstrate that dp120ctn loss results in increased heat shock sensitivity and reduced animal lifespan, which are completely rescued by ectopic expression of a dp120ctn-GFP transgene. Transcriptomic analysis revealed multiple relish/NF-κB target genes differentially expressed upon loss of dp120ctn. Importantly, this aberrant gene expression was rescued by overexpression of dp120ctn-GFP or heterozygosity for relish. Our results uncover a novel role for dp120ctn in the regulation of animal stress response and immune signalling. This may represent an ancient role of p120ctn and can influence further studies in Drosophila and mammals.

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