Amourda_2026_Dev.Cell__

Organs exhibit distinct transcriptional and metabolic territories; how and why such organ zonation differs between the sexes is unclear. Using adult Drosophila intestines, we combine whole-organ 3D cellular mapping with metabolic profiling to uncover regional differences in gene expression and metabolism that vary by sex and genotype. Zonation emerges from opposing, region-specific, and sex-biased actions of the sex determinant doublesex (Dsx) and the transcription factor Myc. In enterocytes, male-specific Dsx represses Myc, resulting in female-biased Myc expression. Myc acts in specific gut regions to increase enterocyte ploidy in females. Myc also sustains a female-specific lipid profile, marked by sex-biased expression of a cluster of lipases and selective triacylglycerol storage in the anterior midgut. Myc activity in female enterocytes sustains peripheral lipid reserves and fecundity. These findings identify relevant roles for Myc in sex differentiation and the intestine as a key, previously overlooked contributor to sex differences in lipid metabolism.