Autotaxin-LPA signaling contributes to obesity-induced insulin resistance in muscle and impairs mitochondrial metabolism
Autotaxin (ATX) is an adipokine that generates the bioactive lipid, lysophosphatidic acid (LPA). ATX-LPA signaling has been implicated in diet-induced obesity and systemic insulin resistance. However, it remains unclear whether the ATX-LPA pathway influences insulin function and energy metabolism in...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-10-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520341742 |
| _version_ | 1818420104672575488 |
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| author | Kenneth D'Souza Carine Nzirorera Andrew M. Cowie Geena P. Varghese Purvi Trivedi Thomas O. Eichmann Dipsikha Biswas Mohamed Touaibia Andrew J. Morris Vassilis Aidinis Daniel A. Kane Thomas Pulinilkunnil Petra C. Kienesberger |
| author_facet | Kenneth D'Souza Carine Nzirorera Andrew M. Cowie Geena P. Varghese Purvi Trivedi Thomas O. Eichmann Dipsikha Biswas Mohamed Touaibia Andrew J. Morris Vassilis Aidinis Daniel A. Kane Thomas Pulinilkunnil Petra C. Kienesberger |
| author_sort | Kenneth D'Souza |
| collection | DOAJ |
| description | Autotaxin (ATX) is an adipokine that generates the bioactive lipid, lysophosphatidic acid (LPA). ATX-LPA signaling has been implicated in diet-induced obesity and systemic insulin resistance. However, it remains unclear whether the ATX-LPA pathway influences insulin function and energy metabolism in target tissues, particularly skeletal muscle, the major site of insulin-stimulated glucose disposal. The objective of this study was to test whether the ATX-LPA pathway impacts tissue insulin signaling and mitochondrial metabolism in skeletal muscle during obesity. Male mice with heterozygous ATX deficiency (ATX+/−) were protected from obesity, systemic insulin resistance, and cardiomyocyte dysfunction following high-fat high-sucrose (HFHS) feeding. HFHS-fed ATX+/− mice also had improved insulin-stimulated AKT phosphorylation in white adipose tissue, liver, heart, and skeletal muscle. Preserved insulin-stimulated glucose transport in muscle from HFHS-fed ATX+/− mice was associated with improved mitochondrial pyruvate oxidation in the absence of changes in fat oxidation and ectopic lipid accumulation. Similarly, incubation with LPA decreased insulin-stimulated AKT phosphorylation and mitochondrial energy metabolism in C2C12 myotubes at baseline and following palmitate-induced insulin resistance. Taken together, our results suggest that the ATX-LPA pathway contributes to obesity-induced insulin resistance in metabolically relevant tissues. Our data also suggest that LPA directly impairs skeletal muscle insulin signaling and mitochondrial function. |
| first_indexed | 2024-12-14T12:49:10Z |
| format | Article |
| id | doaj.art-a7d0f675a50149038c6e8eb316042478 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-14T12:49:10Z |
| publishDate | 2018-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-a7d0f675a50149038c6e8eb3160424782022-12-21T23:00:43ZengElsevierJournal of Lipid Research0022-22752018-10-01591018051817Autotaxin-LPA signaling contributes to obesity-induced insulin resistance in muscle and impairs mitochondrial metabolismKenneth D'Souza0Carine Nzirorera1Andrew M. Cowie2Geena P. Varghese3Purvi Trivedi4Thomas O. Eichmann5Dipsikha Biswas6Mohamed Touaibia7Andrew J. Morris8Vassilis Aidinis9Daniel A. Kane10Thomas Pulinilkunnil11Petra C. Kienesberger12Dalhousie Medicine New Brunswick, Department of Biochemistry and Molecular Biology, Dalhousie University, Saint John, New Brunswick E2L 4L5, CanadaDalhousie Medicine New Brunswick, Department of Biochemistry and Molecular Biology, Dalhousie University, Saint John, New Brunswick E2L 4L5, CanadaDalhousie Medicine New Brunswick, Department of Biochemistry and Molecular Biology, Dalhousie University, Saint John, New Brunswick E2L 4L5, CanadaDalhousie Medicine New Brunswick, Department of Biochemistry and Molecular Biology, Dalhousie University, Saint John, New Brunswick E2L 4L5, CanadaDalhousie Medicine New Brunswick, Department of Biochemistry and Molecular Biology, Dalhousie University, Saint John, New Brunswick E2L 4L5, CanadaInstitute of Molecular Biosciences, University of Graz and Center for Explorative Lipidomics, BioTechMed-Graz, 8010 Graz, AustriaDalhousie Medicine New Brunswick, Department of Biochemistry and Molecular Biology, Dalhousie University, Saint John, New Brunswick E2L 4L5, CanadaDepartment of Chemistry and Biochemistry, Université de Moncton, Moncton, New Brunswick E1A 3E9, CanadaDivision of Cardiovascular Medicine, University of Kentucky, Lexington, KY 40536 and Lexington Veterans Affairs Medical Center, Lexington, KY 40511Division of Immunology, Biomedical Sciences Research Center “Alexander Fleming”, 16672 Athens, GreeceDepartment of Human Kinetics, St. Francis Xavier University, Antigonish, Nova Scotia B2G 2W5, CanadaDalhousie Medicine New Brunswick, Department of Biochemistry and Molecular Biology, Dalhousie University, Saint John, New Brunswick E2L 4L5, CanadaTo whom correspondence should be addressed.; Dalhousie Medicine New Brunswick, Department of Biochemistry and Molecular Biology, Dalhousie University, Saint John, New Brunswick E2L 4L5, Canada; To whom correspondence should be addressed.Autotaxin (ATX) is an adipokine that generates the bioactive lipid, lysophosphatidic acid (LPA). ATX-LPA signaling has been implicated in diet-induced obesity and systemic insulin resistance. However, it remains unclear whether the ATX-LPA pathway influences insulin function and energy metabolism in target tissues, particularly skeletal muscle, the major site of insulin-stimulated glucose disposal. The objective of this study was to test whether the ATX-LPA pathway impacts tissue insulin signaling and mitochondrial metabolism in skeletal muscle during obesity. Male mice with heterozygous ATX deficiency (ATX+/−) were protected from obesity, systemic insulin resistance, and cardiomyocyte dysfunction following high-fat high-sucrose (HFHS) feeding. HFHS-fed ATX+/− mice also had improved insulin-stimulated AKT phosphorylation in white adipose tissue, liver, heart, and skeletal muscle. Preserved insulin-stimulated glucose transport in muscle from HFHS-fed ATX+/− mice was associated with improved mitochondrial pyruvate oxidation in the absence of changes in fat oxidation and ectopic lipid accumulation. Similarly, incubation with LPA decreased insulin-stimulated AKT phosphorylation and mitochondrial energy metabolism in C2C12 myotubes at baseline and following palmitate-induced insulin resistance. Taken together, our results suggest that the ATX-LPA pathway contributes to obesity-induced insulin resistance in metabolically relevant tissues. Our data also suggest that LPA directly impairs skeletal muscle insulin signaling and mitochondrial function.http://www.sciencedirect.com/science/article/pii/S0022227520341742diet effects/lipid metabolismglucosepyruvateskeletal musclerespiration |
| spellingShingle | Kenneth D'Souza Carine Nzirorera Andrew M. Cowie Geena P. Varghese Purvi Trivedi Thomas O. Eichmann Dipsikha Biswas Mohamed Touaibia Andrew J. Morris Vassilis Aidinis Daniel A. Kane Thomas Pulinilkunnil Petra C. Kienesberger Autotaxin-LPA signaling contributes to obesity-induced insulin resistance in muscle and impairs mitochondrial metabolism Journal of Lipid Research diet effects/lipid metabolism glucose pyruvate skeletal muscle respiration |
| title | Autotaxin-LPA signaling contributes to obesity-induced insulin resistance in muscle and impairs mitochondrial metabolism |
| title_full | Autotaxin-LPA signaling contributes to obesity-induced insulin resistance in muscle and impairs mitochondrial metabolism |
| title_fullStr | Autotaxin-LPA signaling contributes to obesity-induced insulin resistance in muscle and impairs mitochondrial metabolism |
| title_full_unstemmed | Autotaxin-LPA signaling contributes to obesity-induced insulin resistance in muscle and impairs mitochondrial metabolism |
| title_short | Autotaxin-LPA signaling contributes to obesity-induced insulin resistance in muscle and impairs mitochondrial metabolism |
| title_sort | autotaxin lpa signaling contributes to obesity induced insulin resistance in muscle and impairs mitochondrial metabolism |
| topic | diet effects/lipid metabolism glucose pyruvate skeletal muscle respiration |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520341742 |
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