New data published in Cell report that testicular signals control carbohydrate metabolism in male Drosophila, which in turn controls food intake and spermatogenesis, suggesting the existence of a gut–gonad axis, whereby the testis alters metabolism to regulate its own function.
Researchers from the Gut Signalling and Metabolism team at the MRC London Institute of Medical Sciences demonstrated a male-biased pattern of gene expression in the Drosophila gut for genes encoding carbohydrate (sugar) metabolism. This sexually dimorphic expression was spatially restricted to the posterior R4 region of the midgut. Using RNA-sequencing analysis, they showed that these genes were upregulated in female flies that lacked tra, a gene that controls feminization in Drosophila. Generation of knock-in and knockout alleles for tra and its binding partner tra2 showed that the sex bias for sugar metabolism gene expression could be controlled: tra and/or tra2 mutation upregulated the expression of the sugar genes in (masculinized) female flies, whereas ectopic tra expression in (feminized) male flies reduced their expression to amounts comparable to that of a female. Interestingly, tra knockdown in specific cells of the intestinal epithelium did not identify a specific site for this effect, suggesting that the male bias in sugar genes is controlled outside the gut.
Thus, the team went on to consider the 3D arrangement of gene expression within the body as a starting point for investigating an origin for the male bias effect. The close proximity of the R4 gut region to the testicular apex led them to hypothesize that the testis itself might be controlling sugar gene expression. By disconnecting gonadal sex from somatic sex, they showed that masculization of the female gonad in female flies led to a male-like sugar gene expression pattern in the gut.
“Our study illustrates the overlooked influence of sex (through the action of the sex chromosomes or sex organs) in the biology of adult somatic cells,” commented first author Bruno Hudry.
To identify the pathway responsible, the group knocked down components of signal transduction pathways that had shown sexual dimorphism in earlier experiments; only disruption of the JAK–STAT pathway reduced the male bias in sugar gene expression. Furthermore, downregulation of JAK–STAT signalling in the R4 midgut of male flies reduced food intake, whereas exacerbation of JAK–STAT signalling in the same region increased food intake, an effect shown to be mediated by citrate. Thus, the team proposed a model in which male-biased activation of JAK–STAT signalling in the R4 region upregulates intestinal sugar gene expression to produce cytosolic citrate, which is exported into the circulation to promote food intake.
Hypothesizing that citrate might be affecting the testis itself, the team knocked down the citrate transporter Indy, which did not seem to affect testicular architecture; however, it did reduce spermatocyte numbers, suggesting that citrate is required for spermatogenesis.
“the testis itself might be controlling sugar gene expression”
In addition to its role in spermatogenesis, these data raise some interesting questions regarding the further roles of citrate in Drosophila and in humans — for example, in the prostate, where citrate levels are 1,000-fold higher than in plasma. The team are now working on a number of knockdown models to investigate the functions of citrate in the testis and to determine whether this role is observed only in Drosophila or if it is conserved across species.
Hudry, B. et al. Sex differences in intestinal carbohydrate metabolism promote food intake and sperm maturation. Cell 178, 901–918 (2019)
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Fenner, A. Gut–gonad communication masculinizes metabolism. Nat Rev Urol 16, 567 (2019). https://doi.org/10.1038/s41585-019-0231-1