Hypoxia couples growth and developmental timing by decoupling steroid synthesis and secretion

In almost all animals, low physiological levels of oxygen (hypoxia) reduce
growth rate and adult body size. Despite the near ubiquity of this
response, the systemic mechanisms that coordinate growth and development
under hypoxia remain poorly understood. In Drosophila, hypoxia increases
circulating levels of the steroid hormone ecdysone to inhibit insulin/IGF
signaling and slow growth. At the same time, ecdysone biosynthesis is
reduced to delay pupation and extend development. Traditionally, the
secretion of lipid-soluble steroids is thought to be regulated at the
level of biosynthesis. This therefore presents a paradox: how can a single
environmental factor both increase ecdysone levels yet decrease ecdysone
synthesis? Our data show that this paradox is resolved by the dual
regulation of ecdysone at the levels of secretion and biosynthesis. We
show that, in the short term, hypoxia increases basal levels of ecdysone
through the Atet-dependent exocytosis of ecdysone-containing vesicles. In
the long term, hypoxia decreases the expression of ecdysone synthesis
genes to delay the peak in ecdysone that triggers pupation. We also
present evidence that both ecdysone synthesis and secretion are regulated,
in part, by NO-signaling. Collectively, our findings reveal regulated
steroid secretion as a critical and environmentally-responsive component
of endocrine control, expanding our understanding of how animals integrate
growth and developmental timing in response to acute and chronic
environmental change.