Abstract
PDGF/VEGF ligands regulate a plethora of biological processes in multicellular organisms via autocrine, paracrine, and endocrine mechanisms. We investigated organ-specific metabolic roles of Drosophila PDGF/VEGF-like factors (Pvfs). We combine genetic approaches and single-nuclei sequencing to demonstrate that muscle-derived Pvf1 signals to the Drosophila hepatocyte-like cells/oenocytes to suppress lipid synthesis by activating the Pi3K/Akt1/TOR signaling cascade in the oenocytes. Functionally, this signaling axis regulates expansion of adipose tissue lipid stores in newly eclosed flies. Flies emerge after pupation with limited adipose tissue lipid stores and lipid level is progressively accumulated via lipid synthesis. We find that adult muscle-specific expression of pvf1 increases rapidly during this stage and that muscle-to-oenocyte Pvf1 signaling inhibits expansion of adipose tissue lipid stores as the process reaches completion. Our findings provide the first evidence in a metazoan of a PDGF/VEGF ligand acting as a myokine that regulates systemic lipid homeostasis by activating TOR in hepatocyte-like cells.
Highlights
Specialized organ systems compartmentalize core metabolic responses such as nutrient uptake, nutrient storage, feeding behavior, and locomotion in multicellular organisms
To investigate tissue-specific roles of PDGF/VEGF-like factors (Pvfs) in regulating lipid homeostasis, we knocked down pvf1, pvf2, and pvf3 in various metabolically active tissues in the adult male fly using temperature-inducible drivers and looked for effects on the adiposity of the fly
Our results demonstrate that in adult flies the PDGF/VEGF like factor, Pvf1, is a muscle-derived signaling molecule that suppresses systemic lipid synthesis by signaling to the Drosophila hepatocyte-like cells/oenocytes
Summary
Specialized organ systems compartmentalize core metabolic responses such as nutrient uptake, nutrient storage, feeding behavior, and locomotion in multicellular organisms. Mechanisms by which these molecules regulate lipid metabolism are complex and multiple context dependent and confounding models of their action have been proposed (Elias et al, 2012; Hagberg et al, 2012; Lu et al, 2012; Robciuc et al, 2016; Sun et al, 2012; Sung et al, 2013; Wu et al, 2014) In all these studies the effect of VEGFs on obesity and insulin resistance have been attributed to their roles in modulating tissue micro-vascularization and endothelial cell biology. To facilitate visualization of this rich resource of gene expression profiles, we have created a searchable webtool where users can mine and explore the data (https://www.flyrnai.org/scRNA/abdomen/)
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