[R01] Signaling mechanisms linking dietary nutrients to the control of stage-specific growth and metabolism by distinct insulin-receptor ligands in Drosophila
Ente: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Scadenza: 2031-06-30
Importo max: $560,381
Paese: US
Descrizione
PROJECT SUMMARY
Animals allocate dietary nutrients to the anabolic processes of growth and nutrient storage differently across
organs and across the stages of life. Across the animal kingdom, insulin-like hormones activate the conserved
intracellular PI3K/Akt signaling pathway to control the use of dietary sugar and protein to promote growth in
juveniles and to regulate metabolism across the lifespan. Production of insulin-like hormones is controlled by
nutrient sensing mechanisms operating cell-autonomously in endocrine tissues and cell-nonautonomously in
cell-types that mediate nutrient uptake from the environment. In mammals, hormones like insulin and the insulin-
like growth factors IGF1 and IGF2 control distinct processes, but how cells discriminate among hormones that
bind to the same receptor (such as insulin and IGF2 at the insulin receptor and IGF1 and IGF2 at the IGF1
receptor) is not well understood. The control of growth and metabolism by insulin signaling is conserved in the
genetic model organism Drosophila melanogaster. The Drosophila genome encodes seven insulin-like peptides
(Dilps) that are made by distinct cell types and that activate a single known insulin receptor (InR). A key question
in an endocrine system with many ligands is whether they respond uniformly to different environmental stimuli.
Our work shows that dietary nutrients exert opposite effects on circulating levels of Dilp2, an insulin homolog
produced by brain neurosecretory cells, and Dilp6, an IGF1 homolog produced by the fat body, an organ with
functional homology to the liver. In fruit fly larvae, Dilp2 is induced by dietary protein but not sugar, while Dilp6 is
suppressed by dietary protein but increased by sugar. The suppression of an insulin-like hormone by protein is
surprising, and the regulatory mechanisms connecting protein availability to Dilp6 production are unknown.
Although Dilp2 and Dilp6 circulate at different levels and are regulated differently by developmental timing and
dietary nutrients, whether they elicit distinct outcomes downstream of InR to regulate growth and metabolism is
unknown. We propose to use genetic, metabolomic and transcriptomic approaches to determine regulation and
action of Dilp2 and Dilp6 in fruit fly larvae, a stage characterized by substantial and insulin-dependent growth
and nutrient storage. In Specific Aim 1, we will determine how cell-autonomous and cell-nonautonomous nutrient
sensing mechanisms operating in fat body and gut regulate production of Dilps in response to dietary nutrients.
In Specific Aim 2, we will determine how Dilp2 and Dilp6 control the use of dietary nutrients for growth and
storage and determine whether Dilp identity or levels is the salient feature for activating InR to control growth
and metabolism in the larval stage. Finally, we will carry out a screen to identify additional proteins that mediate
cellular responses to Dilp6. Ultimately, the proposed studies will lead to new understanding of ho
Istituzione: UNIVERSITY OF VIRGINIA
PI: Michelle L Bland
Progetto: 1R01HD120548-01A1
Settori: Eunice Kennedy Shriver National Institute of Child Health and Human Development
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