Fig. 8

HIF-1a/Sima is required in the fat body for hypoxia-induced growth suppression. a–c Fat-body-specific loss of sima via tissue-specific CRISPR/Cas9-mediated gene disruption reduces hypoxia-induced IPC DILP2 retention (a) and suppression of Dilp3 expression (b) and rescues hypoxia-induced growth restriction (c). Statistics: Student’s t-test for pairwise comparisons and one-way ANOVA with Dunnett’s for multiple-comparisons test. *P < 0.05, ***P < 0.001, compared with controls (ppl > Cas9/+ and UAS-sima^KO/+ ). Error bars indicate SEM. Underlying data are provided in the Source Data file. a: n = 9. b: n = 6. c: n = 18–33. d Proposed model for integration of hypoxia and amino-acid sensing via the fat body and insulin regulation. Tracheation of the fat body is regulated by the FGF ligand Branchless secreted from this tissue in response to local tissue hypoxia, triggering tracheal outgrowth via the FGF receptor Breathless. When the tracheal system is unable to deliver sufficient oxygen because of environmental oxygen levels or body growth, Hph is unable to trigger the degradation of Sima/HIF-1a, which induces the expression or release of one or more humoral factors from the fat tissue that act on the insulin-producing cells (IPCs) to downregulate Dilp transcription and to block DILP release. Through a separate pathway, Hph inhibition also blocks Tor activity in the fat body, which alters lipid distribution. Hypoxia thereby reduces circulating insulin through activation of a central oxygen sensor in the fat tissue, which slows the growth of the whole organism. During these low-oxygen conditions, secretion of Branchless from the fat tissue promotes insulin-independent growth of the tracheal airways to increase oxygen supply. This system allows the organism to adapt its metabolism and growth to limited-oxygen conditions by reducing overall body growth through downregulation of insulin signaling, while at the same time promoting development of the tracheal system to maintain oxygen homeostasis