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Autotaxin-Lysophosphatidic Acid Signaling Contributed to Obesity-Induced Insulin Resistance in Muscle and Impairs Mitochondrial Metabolism
Dalhousie Medicine New Brunswick, United States.
Dalhousie Medicine New Brunswick, United States.
Dalhousie Medicine New Brunswick, United States.
Dalhousie Medicine New Brunswick, United States. (Cardiovascular research center)ORCID-id: 0000-0002-4589-6440
Vise andre og tillknytning
2018 (engelsk)Inngår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 59, nr 10, s. 1805-1817Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

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. 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. 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. 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. 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.

sted, utgiver, år, opplag, sider
American Society for Biochemistry and Molecular Biology, 2018. Vol. 59, nr 10, s. 1805-1817
Emneord [en]
Metabolism, insulin resistance
HSV kategori
Forskningsprogram
Hälso- och sjukvårdsforskning
Identifikatorer
URN: urn:nbn:se:oru:diva-71323DOI: 10.1194/jlr.M082008ISI: 000445444500002PubMedID: 30072447Scopus ID: 2-s2.0-85054086353OAI: oai:DiVA.org:oru-71323DiVA, id: diva2:1277366
Merknad

Funding Agencies:

Natural Sciences and Engineering Research Council of Canada 

Canadian Institutes of Health Research Project 

Banting Research Foundation 

New Brunswick Health Research Foundation 

New Brunswick Innovation Foundation 

Heart and Stroke Foundation of Canada

Natural Sciences and Engineering Research Council of Canada

Canadian Diabetes Association 

Canada Foundation for Innovation 

Tilgjengelig fra: 2019-01-10 Laget: 2019-01-10 Sist oppdatert: 2019-01-11bibliografisk kontrollert

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Autotaxin-LPA signaling contributes to obesity-induced insulin resistance in muscle and impairs mitochondrial metabolism(1693 kB)112 nedlastinger
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