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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 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 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 organism maintain membrane homeostasis and adapt to a variable environment.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Embryonic Fibroblast

SUBMITTER: Proteomics Core Facility

LAB HEAD: Marc Pilon

PROVIDER: PXD029163 | Pride | 2022-12-13

REPOSITORIES: Pride

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Project description:The prevalence of the metabolic syndrome (MS) is rapidly increasing all over the world. Consequently, there is an urgent need for more effective intervention strategies. Both animal and human studies indicate that lipid oversupply to skeletal muscle can result in insulin resistance which is one of the charecteristices of the MS. C57BL/6J mice were fed a low fat (10 kcal%) palm oil diet or a high fat (45 kcal%; HF) palm oil diet for 3 or 28 days. By combining transcriptomics with protein and lipid analyses we aimed to better understand the molecular events underlying the early onset of the MS. Short-term HF-feeding led to altered expression levels of genes involved in a variety of biological processes including morphogenesis, energy metabolism, lipogenesis and immune function. Protein analysis showed increased levels of the myosin heavy chain, slow fiber type protein and the complexes II, III, IV and V of the oxidative phosphorylation. Furthermore, we observed that the main mitochondrial membrane phospholipids, phosphatidylcholine and phosphatidylethanolamine, contained more saturated fatty acids. Altogether, these results point to a morphological as well as a metabolic adaptation by promoting a more oxidative fiber type. We hypothesize that after this early adaptation, a continued transcriptional down-regulation of genes involved in oxidative phosphorylation will result in decreased oxidative capacity at a later stage. Together with increased saturation of phospholipids of the mitochondrial membrane this can result in decreased mitochondrial function which is a hallmark observed in insulin resistance and type 2 diabetes. Keywords: diet intervention and time course In the present study we investigated the short versus the long term effects of a high fat diet on the mouse muscle transcriptome by performing a genome-wide analysis of high fat diet-responsive genes. C57BL/6J mice were fed a low fat (LF) diet (10 kcal% palm oil) or a high fat (HF) diet (45 kcal% palm oil) for 3 or 28 days. Total RNA samples (n = 6 per diet per time point) were individually hybridised tot the Affymatrix mouse genome 430 2.0 array.

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SPHINGOSINE 1-PHOSPHATE MEDIATES ADIPONECTIN RECEPTOR SIGNALING ESSENTIAL FOR LIPID HOMEOSTASIS AND EMBRYOGENESIS

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