Abstract
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.
Highlights
Autotaxin (ATX) is an adipokine that generates the bioactive lipid, lysophosphatidic acid (LPA)
Our study shows that: 1) partial ATX deficiency protects from impaired insulin signaling in white adipose tissue, liver, heart, and skeletal muscle following high-fat highsucrose (HFHS) feeding, as is reflected in reduced weight gain, improved glucose and insulin tolerance, and blunted cardiomyocyte dysfunction in male high-fat high-sucrose (HFHS)-fed ATX+/ mice; 2) HFHS-fed ATX+/ mice are resistant to impaired insulin-stimulated glucose transport in skeletal muscle and have improved mitochondrial pyruvate oxidation; and 3) in C2C12 myotubes, incubation with LPA reduces insulinstimulated AKT phosphorylation at baseline and exacerbates palmitate-induced insulin resistance, coincident with impaired mitochondrial respiration
It remained unclear whether changes in insulin signaling and mitochondrial function in metabolically relevant tissues contribute to the protective effect of ATX deficiency toward the obesity-induced impairment of glucose homeostasis
Summary
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. It remains unclear whether the ATX-LPA pathway influences insulin function and energy metabolism in target tissues, 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. HFHS-fed ATX+/ mice 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. Autotaxin-LPA signaling contributes to obesity-induced insulin resistance in muscle and impairs mitochondrial metabolism. Signaling effectors downstream of LPA receptors include PI3Kinase-AKT-Ras-related C3 botulinum toxin substrate 1 activation, modulation of adenylate cyclase, stimulation of the mitogen-activated protein kinase pathway, Rho and Rho kinase activation, and stimulation of the phospholipase C-protein kinase C pathway [7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
