title: The CDP-Ethanolamine Pathway Regulates Skeletal Muscle Diacylglycerol Content and Mitochondrial Biogenesis without Altering Insulin Sensitivity.
abstract: Accumulation of diacylglycerol (DG) in muscle is thought to cause insulin resistance. DG is a precursor for phospholipids, thus phospholipid synthesis could be involved in regulating muscle DG. Little is known about the interaction between phospholipid and DG in muscle; therefore, we examined whether disrupting muscle phospholipid synthesis, specifically phosphatidylethanolamine (PtdEtn), would influence muscle DG content and insulin sensitivity. Muscle PtdEtn synthesis was disrupted by deleting CTP:phosphoethanolamine cytidylyltransferase (ECT), the rate-limiting enzyme in the CDP-ethanolamine pathway, a major route for PtdEtn production. While PtdEtn was reduced in muscle-specific ECT knockout mice, intramyocellular and membrane-associated DG was markedly increased. Importantly, however, this was not associated with insulin resistance. Unexpectedly, mitochondrial biogenesis and muscle oxidative capacity were increased in muscle-specific ECT knockout mice and were accompanied by enhanced exercise performance. These findings highlight the importance of the CDP-ethanolamine pathway in regulating muscle DG content and challenge the DG-induced insulin resistance hypothesis.
authors.affiliation: Centre for Physical Activity and Nutrition (C-PAN) Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood, 3125 VIC, Australia.
authors.forename: Ahrathy
authors.initials: A
authors.lastname: Selathurai
authors.affiliation: Centre for Physical Activity and Nutrition (C-PAN) Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood, 3125 VIC, Australia.
authors.forename: Greg M
authors.initials: GM
authors.lastname: Kowalski
authors.affiliation: Department of Physiology, Monash University, Clayton, 3800 VIC, Australia.
authors.forename: Micah L
authors.initials: ML
authors.lastname: Burch
authors.affiliation: Department of Physiology, Monash University, Clayton, 3800 VIC, Australia.
authors.forename: Patricio
authors.initials: P
authors.lastname: Sepulveda
authors.affiliation: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Prahran, 3004 VIC, Australia.
authors.forename: Steve
authors.initials: S
authors.lastname: Risis
authors.affiliation: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Prahran, 3004 VIC, Australia.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Lee-Young
authors.affiliation: Centre for Physical Activity and Nutrition (C-PAN) Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood, 3125 VIC, Australia.
authors.forename: Severine
authors.initials: S
authors.lastname: Lamon
authors.affiliation: Metabolomics Laboratory, Baker IDI Heart and Diabetes Institute, Prahran, 3004 VIC, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Meikle
authors.affiliation: Metabolic Research Unit, Deakin University, Waurn Ponds, 3216 VIC, Australia.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Genders
authors.affiliation: Metabolic Research Unit, Deakin University, Waurn Ponds, 3216 VIC, Australia.
authors.forename: Sean L
authors.initials: SL
authors.lastname: McGee
authors.affiliation: Department of Physiology, Monash University, Clayton, 3800 VIC, Australia.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Watt
authors.affiliation: Centre for Physical Activity and Nutrition (C-PAN) Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood, 3125 VIC, Australia.
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Russell
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Frank
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Jackowski
authors.affiliation: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Prahran, 3004 VIC, Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Febbraio
authors.affiliation: Centre for Physical Activity and Nutrition (C-PAN) Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood, 3125 VIC, Australia. Electronic address: clinton.bruce@deakin.edu.au.
authors.forename: Clinton R
authors.initials: CR
authors.lastname: Bruce
mesh_terms: D000818:Animals; D003565:Cytidine Diphosphate / Q000031:analogs & derivatives* / Q000378:metabolism; D004075:Diglycerides / Q000378:metabolism*; D004983:Ethanolamines / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D001678:Organelle Biogenesis; D012316:RNA Nucleotidyltransferases / Q000235:genetics / Q000378:metabolism
chemical_list: C011439:1,2-diacylglycerol; D004075:Diglycerides; D004983:Ethanolamines; C006933:CDP ethanolamine; D003565:Cytidine Diphosphate; D012316:RNA Nucleotidyltransferases; C020126:Ethanolamine-phosphate cytidylyltransferase; D005947:Glucose