Abstract
BackgroundCaenorhabditis elegans provides a genetically tractable model organism to investigate the network of genes involved in fat metabolism and how regulation is perturbed to produce the complex phenotype of obesity. C. elegans possess the full range of desaturases, including the Δ9 desaturases expressed by fat-5, fat-6 and fat-7. They regulate the biosynthesis of monounsaturated fatty acids, used for the synthesis of lipids including phospholipids, triglycerides and cholesteryl esters.ResultsLiquid chromatography mass spectrometry (LC-MS), gas chromatography mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) spectroscopy were used to define the metabolome of all the possible knock-outs for the Δ9 desaturases, including for the first time intact lipids. Despite the genes having similar enzymatic roles, excellent discrimination was achievable for all single and viable double mutants highlighting the distinctive roles of fat-6 and fat-7, both expressing steroyl-CoA desaturases. The metabolomic changes extend to aqueous metabolites demonstrating the influence Δ9 desaturases have on regulating global metabolism and highlighting how comprehensive metabolomics is more discriminatory than classically used dyes for fat staining.ConclusionsThe propagation of metabolic changes across the network of metabolism demonstrates that modification of the Δ9 desaturases places C.elegans into a catabolic state compared with wildtype controls.
Highlights
Caenorhabditis elegans provides a genetically tractable model organism to investigate the network of genes involved in fat metabolism and how regulation is perturbed to produce the complex phenotype of obesity
Using a range of techniques, including gas chromatography mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) spectroscopy in addition to Liquid chromatography mass spectrometry (LC-MS), we aim to demonstrate that these deletions show marked changes in lipid composition and place C. elegans in a catabolic state not just in lipid metabolism and in terms of the impact on the TCA cycle and amino acid metabolism, demonstrating the influence the Δ9 desaturases have on regulating global metabolism
As already reported in previous publications [19,20] at 20°C the fat-6;fat-7 double mutant animals display a greatly reduced fertility and slow growth. These characteristics made the strain unsuitable for our studies, as it was neither possible to generate a sufficient number of animals in parallel with the other strains to be analysed, nor separate the metabolic changes associated with the genetic modifications per se and the restriction in growth/development
Summary
Caenorhabditis elegans provides a genetically tractable model organism to investigate the network of genes involved in fat metabolism and how regulation is perturbed to produce the complex phenotype of obesity. C. elegans possess the full range of desaturases, including the Δ9 desaturases expressed by fat-5, fat-6 and fat-7. They regulate the biosynthesis of monounsaturated fatty acids, used for the synthesis of lipids including phospholipids, triglycerides and cholesteryl esters. Because of the complexity of metabolic regulation, a genetically tractable system like C. elegans offers exceptional potential to unravel the connections across the genome that regulate fat metabolism and have led to the discovery of mammalian genes involved in energy balance [13,14]
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