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.
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This work was supported by Natural Sciences and Engineering Research Council of Canada Discovery Grant RGPIN-2014-04454, Canadian Institutes of Health Research Project Grant 156308, and grants from the Banting Research Foundation, the New Brunswick Health Research Foundation, the New Brunswick Innovation Foundation, and the Heart and Stroke Foundation of Canada to P.C.K. Additional support was provided by the Natural Sciences and Engineering Research Council of Canada, the Canadian Diabetes Association, the New Brunswick Health Research Foundation, the New Brunswick Innovation Foundation, and the Canada Foundation for Innovation to T.P.
The online version of this article (available at http://www.jlr.org) contains a supplement.
D'Souza, Kenneth; Nzirorera, Carine; Cowie, Andrew M.; Varghese, Geena P.; Trivedi, Purvi; Eichmann, Thomas O.; Biswas, Dipsikha; Touaibia, Mohamed; Morris, Andrew J.; Aidinis, Vassilis; Kane, Daniel A.; Pulinilkunnil, Thomas; and Kienesberger, Petra C., "Autotaxin-LPA Signaling Contributes to Obesity-Induced Insulin Resistance in Muscle and Impairs Mitochondrial Metabolism" (2018). Internal Medicine Faculty Publications. 159.