Sphingosine 1-Phosphate Mediates Adiponectin Receptor Signaling Essential For Lipid Homeostasis And Embryogenesis

Cells and organisms require proper membrane composition to function and develop. Phospholipids are the major component of membranes and are primarily acquired through the diet. Given great variability in diet composition, cells must be able to deploy mechanisms that correct deviations from optimal membrane composition and properties. Here, using unbiased lipidomics and proteomics, we found that the embryonic lethality in mice lacking the fluidity regulators Adiponectin Receptors 1 and 2 (AdipoR1/2) is associated with aberrant high saturation of the membrane phospholipids. Using mouse embryonic fibroblasts (MEFs) derived from AdipoR1/2-KO embryos, human cell lines and the model organism C. elegans we found that, mechanistically, AdipoR1/2-derived sphingosine 1-phosphate (S1P) signals in parallel through S1PR3-SREBP1 and PPAR{gamma} to sustain the expression of the fatty acid desaturase SCD and maintain membrane properties. Thus, our work identifies an evolutionary conserved pathway by which cells and organism maintain membrane homeostasis and adapt to a variable environment. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/456080v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@b6730aorg.highwire.dtl.DTLVardef@3a95e3org.highwire.dtl.DTLVardef@469027org.highwire.dtl.DTLVardef@a21790_HPS_FORMAT_FIGEXP M_FIG C_FIG In BriefCells and organisms require proper membrane composition to function and develop. Ruiz et al. identified AdipoR1/2-derived S1P as essential for membrane homeostasis in mammals and invertebrates. S1P signals through SREBP and PPAR{gamma} to sustain fatty acid desaturation. Targeting AdipoR1/2 pathway may be a therapeutic approach for disorders with dysfunctional membranes. Highlights- Excess membrane phospholipid saturation explains AdipoR1/2 DKO embryonic lethality - AdipoR1/2 DKO membrane defects are rescued by S1P - Parallel activation of S1PR3 and PPAR{gamma} by S1P mediates AdipoR2 membrane protection - Fatty acid desaturation is the final outputs of the AdipoR2-S1P signaling pathway