Tissue-specific metabolomic signatures for a doublesex model of reduced sexual dimorphism

Sex has a major effect on the metabolome. However, we do not yet understand the degree to which differences in metabolism are associated with anatomical dimorphism and modulated by sex-specific tissues. In the fruit fly, Drosophila melanogaster, knocking out doublesex (dsx) gives rise to adults with intermediate sex characteristics. Here, we sought to determine the degree to which this key node in sexual development leads to sex differences (SD) in the metabolome. We measured 91 metabolites across three tissues, comparing sex-dimorphic flies with those of reduced dimorphism: dsx null flies. The abundance of 51% of metabolites (46/91) differed between wildtype XX and XY flies in at least one tissue. However, in dsx flies, we only observed a sex difference in kynurenate, suggesting that dsx plays a major role in SD in fly metabolism. Kynurenate was consistently higher in XX flies in both dsx flies and controls. We also observed tissue-specific effects in dsx flies. Sex dimorphism manifests in part through dimorphic growth of organs, and we find that dimorphic metabolites across the fly enriched the growth-related branched-chain amino acid and mammalian target of rapamycin pathways. Our findings demonstrate that sex dimorphism is accompanied by substantial effects on the metabolome throughout the body.