title: Diacylglycerol kinase ε deficiency preserves glucose tolerance and modulates lipid metabolism in obese mice.
abstract: Diacylglycerol kinases (DGKs) catalyze the phosphorylation and conversion of diacylglycerol (DAG) into phosphatidic acid. DGK isozymes have unique primary structures, expression patterns, subcellular localizations, regulatory mechanisms, and DAG preferences. DGKε has a hydrophobic segment that promotes its attachment to membranes and shows substrate specificity for DAG with an arachidonoyl acyl chain in the sn-2 position of the substrate. We determined the role of DGKε in the regulation of energy and glucose homeostasis in relation to diet-induced insulin resistance and obesity using DGKε-KO and wild-type mice. Lipidomic analysis revealed elevated unsaturated and saturated DAG species in skeletal muscle of DGKε KO mice, which was paradoxically associated with increased glucose tolerance. Although skeletal muscle insulin sensitivity was unaltered, whole-body respiratory exchange ratio was reduced, and abundance of mitochondrial markers was increased, indicating a greater reliance on fat oxidation and intracellular lipid metabolism in DGKε KO mice. Thus, the increased intracellular lipids in skeletal muscle from DGKε KO mice may undergo rapid turnover because of increased mitochondrial function and lipid oxidation, rather than storage, which in turn may preserve insulin sensitivity. In conclusion, DGKε plays a role in glucose and energy homeostasis by modulating lipid metabolism in skeletal muscle.
authors.affiliation: Section of Integrative Physiology, Department of Molecular Medicine and Surgery and Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Louise
authors.initials: L
authors.lastname: Mannerås-Holm
authors.affiliation: Section of Integrative Physiology, Department of Molecular Medicine and Surgery and Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Milena
authors.initials: M
authors.lastname: Schönke
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Brozinick
authors.affiliation: Section of Integrative Physiology, Department of Molecular Medicine and Surgery and Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Laurène
authors.initials: L
authors.lastname: Vetterli
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN.
authors.forename: Hai-Hoang
authors.initials: HH
authors.lastname: Bui
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN.
authors.forename: Philip
authors.initials: P
authors.lastname: Sanders
authors.affiliation: Section of Integrative Physiology, Department of Molecular Medicine and Surgery and Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Emmani B M
authors.initials: EBM
authors.lastname: Nascimento
authors.affiliation: Section of Integrative Physiology, Department of Molecular Medicine and Surgery and Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Björnholm
authors.affiliation: Section of Integrative Physiology, Department of Molecular Medicine and Surgery and Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Chibalin
authors.affiliation: Section of Integrative Physiology, Department of Molecular Medicine and Surgery and Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden Juleen.zierath@ki.se.
authors.forename: Juleen R
authors.initials: JR
authors.lastname: Zierath
mesh_terms: D000818:Animals; D001823:Body Composition; D019852:Diacylglycerol Kinase / Q000172:deficiency* / Q000235:genetics; D004734:Energy Metabolism; D055786:Gene Knockout Techniques; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006706:Homeostasis; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008820:Mice, Obese; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D010084:Oxidation-Reduction
chemical_list: D019852:Diacylglycerol Kinase; D005947:Glucose
keywords: animal models; diabetes; insulin resistance; lipid kinase; lipidomics; muscle; obesity