Autotaxin-LPA signaling contributes to obesity-induced insulin resistance in muscle and impairs mitochondrial metabolism

Journal of Lipid Research

Purvi Trivedi¹  Kenneth D'Souza¹  Carine Nzirorera¹  Andrew M. Cowie¹  Thomas Pulinilkunnil¹  Geena P. Varghese¹  Dipsikha Biswas¹  Mohamed Touaibia²  Daniel A. Kane³  Andrew J. Morris⁴  Vassilis Aidinis⁵  Thomas O. Eichmann⁶  Petra C. Kienesberger⁷ 

[1] Dalhousie Medicine New Brunswick, Department of Biochemistry and Molecular Biology, Dalhousie University, Saint John, New Brunswick E2L 4L5, Canada;Department of Chemistry and Biochemistry, Université de Moncton, Moncton, New Brunswick E1A 3E9, Canada;Department of Human Kinetics, St. Francis Xavier University, Antigonish, Nova Scotia B2G 2W5, Canada;Division of Cardiovascular Medicine, University of Kentucky, Lexington, KY 40536 and Lexington Veterans Affairs Medical Center, Lexington, KY 40511;Division of Immunology, Biomedical Sciences Research Center “Alexander Fleming”, 16672 Athens, Greece;Institute of Molecular Biosciences, University of Graz and Center for Explorative Lipidomics, BioTechMed-Graz, 8010 Graz, Austria;To whom correspondence should be addressed.;

关键词: diet effects/lipid metabolism;    glucose;    pyruvate;    skeletal muscle;    respiration;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown