Sphingosine 1-phosphate mediates adiponectin receptor signaling essential for lipid homeostasis and embryogenesis

Abstract

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 lipidomics and unbiased 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 PPARγ 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 organisms achieve membrane homeostasis and adapt to a variable environment.

Raman Imaging Reveals Insights into Membrane Phase Biophysics in Cells

“…Since then, more studies have supported the physiological importance of solid-like membranes. ,− For example, from a panel of patient-derived melanoma cancer cells, Du et al recently identified fatty acid stearoyl-CoA desaturase (Δ-9-desaturase) to be a druggable target in an aggressive mesenchymal form of melanoma cells with known resistance to the targeted BRAF inhibition (Du et al., 2020). Using drug CAY10566 (CAY) to block this monodesaturase, which catalyzes the rate-limiting step from SFAs to the formation of monounsaturated fatty acids (mainly the de novo conversion of the stearic acid (C18:0) to the oleic acid (C18:1)) in the de novo fatty acid synthesis pathway, SRS imaging in the label-free CH 2 channel could readily capture the formation of a phase-separated membrane (Figure a).…”

Polyunsaturated Lipids in the Light-Exposed and Prooxidant Retinal Environment

“…Therefore, Nrl appears to reduce Elovl2 expression while promoting Adipor1 expression, which increases Elovl2 expression. The Nrl may fine-tune Elovl2 expression acting via two separate, unknown pathways, although recent evidence points to sphingosine 1-phosphate involvement in signalling via Adiponectin receptors [ 118 ]. Adiponectin receptors may not sense adiponectin [ 119 ] and instead operate as sensors of membrane fluidity (discussed in [ 120 ]), underscoring the importance of controlling membrane fluidity in photoreceptors (see Section 3 and Figure 3 above).…”

Striking membrane defects in AdipoR-deficient cells

“…Membrane homeostasis defects likely underly numerous conditions. AdipoR1 and AdipoR2 sense excesses of saturated fatty acids in phospholipids and correct such imbalance by generating sphingosine 1-phospate that promotes fatty acid desaturation via sterol regulatory-element binding protein and peroxisome proliferator– activated receptor gamma ( 1 , 2 , 3 ).…”

“…Mouse embryonic fibroblasts lacking AdipoR1 and AdipoR2 (AdipoR1/2 double KO) and treated with palmitic acid form abnormal endoplasmic reticulum structures: long straight lines visualized by confocal microscopy (white arrows), whereas electron micrographs reveal distinctive spirals of packed membranes (red arrows) that are likely cross-sections of the lines seen with Laurdan staining ( 1 ). These endoplasmic reticulum structures are not present in basal conditions ( 1 ).…”

“…EQUIPMENT AND REAGENTS: LSM880 confocal microscope with Airyscan (Zeiss), Laurdan dye, palmitic acid, Wohlwend Compact 3 high pressure freezer, Leica AFS, Tecnai T12 transmission electron microscope, Ceta CMOS 16M camera ( 1 ).…”