title: Diacylglycerol kinase-δ regulates AMPK signaling, lipid metabolism, and skeletal muscle energetics.
abstract: Decrease of AMPK-related signal transduction and insufficient lipid oxidation contributes to the pathogenesis of obesity and type 2 diabetes. Previously, we identified that diacylglycerol kinase-δ (DGKδ), an enzyme involved in triglyceride biosynthesis, is reduced in skeletal muscle from type 2 diabetic patients. Here, we tested the hypothesis that DGKδ plays a role in maintaining appropriate AMPK action in skeletal muscle and energetic aspects of contraction. Voluntary running activity was reduced in DGKδ(+/-) mice, but glycogen content and mitochondrial markers were unaltered, suggesting that DGKδ deficiency affects skeletal muscle energetics but not mitochondrial protein abundance. We next determined the role of DGKδ in AMPK-related signal transduction and lipid metabolism in isolated skeletal muscle. AMPK activation and signaling were reduced in DGKδ(+/-) mice, concomitant with impaired lipid oxidation and elevated incorporation of free fatty acids into triglycerides. Strikingly, DGKδ deficiency impaired work performance, as evident by altered force production and relaxation dynamics in response to repeated contractions. In conclusion, DGKδ deficiency impairs AMPK signaling and lipid metabolism, thereby highlighting the deleterious role of excessive lipid metabolites in the development of peripheral insulin resistance and type 2 diabetes pathogenesis. DGKδ deficiency also influences skeletal muscle energetics, which may lead to low physical activity levels in type 2 diabetes.
authors.affiliation: Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden;
authors.forename: Lake Q
authors.initials: LQ
authors.lastname: Jiang
authors.affiliation: Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden;
authors.forename: Thais
authors.initials: T
authors.lastname: de Castro Barbosa
authors.affiliation: Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden;
authors.forename: Julie
authors.initials: J
authors.lastname: Massart
authors.affiliation: Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden;
authors.forename: Atul S
authors.initials: AS
authors.lastname: Deshmukh
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden; and.
authors.forename: Lars
authors.initials: L
authors.lastname: Löfgren
authors.affiliation: Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden;
authors.forename: Daniella E
authors.initials: DE
authors.lastname: Duque-Guimaraes
authors.affiliation: Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden;
authors.forename: Arda
authors.initials: A
authors.lastname: Ozilgen
authors.affiliation: Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden;
authors.forename: Megan E
authors.initials: ME
authors.lastname: Osler
authors.affiliation: Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden;
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Chibalin
authors.affiliation: Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden; Department of Physiology and Pharmacology, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden Juleen.zierath@ki.se.
authors.forename: Juleen R
authors.initials: JR
authors.lastname: Zierath
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D019852:Diacylglycerol Kinase / Q000235:genetics / Q000502:physiology*; D004734:Energy Metabolism / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism*; D010805:Physical Conditioning, Animal / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics
chemical_list: D019852:Diacylglycerol Kinase; D000263:Adenylate Kinase
keywords: AMPK; contraction; diacylglycerol kinase; lipid oxidation; skeletal muscle