Tissue homeostasis involves a complex balance of developmental signals and environmental cues that dictate stem cell function. We found that dietary lipids control enteroendocrine cell production from Drosophila posterior midgut stem cells. Dietary cholesterol influences new intestinal cell differentiation in an Hr96-dependent manner by altering the level and duration of Notch signaling. Exogenous lipids modulate Delta ligand and Notch extracellular domain stability and alter their trafficking in endosomal vesicles. Lipid-modulated Notch signaling occurs in other nutrient-dependent tissues, suggesting that Delta trafficking in many cells is sensitive to cellular sterol levels. These diet-mediated alterations in young animals contribute to a metabolic program that persists after the diet changes. A low-sterol diet also slows the proliferation of enteroendocrine tumors initiated by Notch pathway disruption. Thus, a specific dietary nutrient can modify a key intercellular signaling pathway to shift stem cell differentiation and cause lasting changes in tissue structure and physiology.

Disruptions in energy homeostasis severely affect reproduction in many organisms and are linked to several reproductive disorders inhumans. As a result, understanding the mechanisms that control nutrient accumulation in the oocyte will provide valuable insights into the links between metabolic disease and reproductive dysfunction. We show that the steroid hormone ecdysone functions in Drosophila to control lipid metabolism and support oocyte production. First, local EcR-mediated signaling induces a stage-specific accumulation of lipids in stage-10 oocytes. EcR induces lipid accumulation by promoting the activation of the lipogenic transcription factor SREBP and by controlling the expression of the low-density lipoprotein (LDL) receptor homolog, LpR2. Second, global signaling via the ecdysone receptor, EcR, establishes a female metabolic state and promotes whole-body triglyceride and glycogen storage at high levels. EcR acts in the CNS to mediate these effects, in part by promoting higher levels of feeding in females. Thus, ecdysone functions at two levels to support reproduction: first by inducing lipid accumulation in the late stages of oocyte development and second by providing a signal that coordinates lipid metabolism in the germline with whole-animal lipid homeostasis. Ecdysone regulation allows females to assess the demands of oogenesis and alter their behavior and metabolic state to support the biosynthetic requirements of oocyte production.

basecalling: CASAVA v1.8.2reads aligned to genome using Bowtie2 v 2.0.6identified reads hitting transcripts using TopHat v 2.0.7 with -G --no novel juncs and Refseq dm3-iGenomes.gtfcalculated transcript fpkm values and gene fpkm values using Cufflinks version 2.02 -G with dm3-iGenomes.gtfGenome_build: Refseq annotation file:dm3 and dm3-iGenomes.gtfSupplementary_files_format_and_content: Cufflinks output file: genes.fpkm_tracking:

basecalling: CASAVA v1.8.2reads aligned to genome using Bowtie2 v 2.0.6identified reads hitting transcripts using TopHat v 2.0.7 with -G --no novel juncs and Refseq dm3-iGenomes.gtfcalculated transcript fpkm values and gene fpkm values using Cufflinks version 2.02 -G with dm3-iGenomes.gtfGenome_build: Refseq annotation file:dm3 and dm3-iGenomes.gtfSupplementary_files_format_and_content: Cufflinks output file: genes.fpkm_tracking:

basecalling: CASAVA v1.8.2reads aligned to genome using Bowtie2 v 2.0.6identified reads hitting transcripts using TopHat v 2.0.7 with -G --no novel juncs and Refseq dm3-iGenomes.gtfcalculated transcript fpkm values and gene fpkm values using Cufflinks version 2.02 -G with dm3-iGenomes.gtfGenome_build: Refseq annotation file: dm3 (Release 5) and dm3-iGenomes.gtfSupplementary_files_format_and_content: Cufflinks output file (.xlsx)

basecalling: CASAVA v1.8.2reads aligned to genome using Bowtie2 v 2.0.6identified reads hitting transcripts using TopHat v 2.0.7 with -G --no novel juncs and Refseq dm3-iGenomes.gtfcalculated transcript fpkm values and gene fpkm values using Cufflinks version 2.02 -G with dm3-iGenomes.gtfGenome_build: Refseq annotation file:dm3 and dm3-iGenomes.gtfSupplementary_files_format_and_content: Cufflinks output file: genes.fpkm_tracking:

basecalling: CASAVA v1.8.2reads aligned to genome using Bowtie2 v 2.0.6identified reads hitting transcripts using TopHat v 2.0.7 with -G --no novel juncs and Refseq dm3-iGenomes.gtfcalculated transcript fpkm values and gene fpkm values using Cufflinks version 2.02 -G with dm3-iGenomes.gtfGenome_build: Refseq annotation file: dm3 (Release 5) and dm3-iGenomes.gtfSupplementary_files_format_and_content: Cufflinks output file (.xlsx)

basecalling: CASAVA v1.8.2reads aligned to genome using Bowtie2 v 2.0.6identified reads hitting transcripts using TopHat v 2.0.7 with -G --no novel juncs and Refseq dm3-iGenomes.gtfcalculated transcript fpkm values and gene fpkm values using Cufflinks version 2.02 -G with dm3-iGenomes.gtfGenome_build: Refseq annotation file:dm3 and dm3-iGenomes.gtfSupplementary_files_format_and_content: Cufflinks output file: genes.fpkm_tracking:

basecalling: CASAVA v1.8.2reads aligned to genome using Bowtie2 v 2.0.6identified reads hitting transcripts using TopHat v 2.0.7 with -G --no novel juncs and Refseq dm3-iGenomes.gtfcalculated transcript fpkm values and gene fpkm values using Cufflinks version 2.02 -G with dm3-iGenomes.gtfGenome_build: Refseq annotation file:dm3 and dm3-iGenomes.gtfSupplementary_files_format_and_content: Cufflinks output file: genes.fpkm_tracking:

basecalling: CASAVA v1.8.2reads aligned to genome using Bowtie2 v 2.0.6identified reads hitting transcripts using TopHat v 2.0.7 with -G --no novel juncs and Refseq dm3-iGenomes.gtfcalculated transcript fpkm values and gene fpkm values using Cufflinks version 2.02 -G with dm3-iGenomes.gtfGenome_build: Refseq annotation file:dm3 and dm3-iGenomes.gtfSupplementary_files_format_and_content: Cufflinks output file: genes.fpkm_tracking: