D'Souza 2018 J Lipid Res

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D'Souza K, Nzirorera C, Cowie AM, Varghese GP, Trivedi P, Eichmann TO, Biswas D, Touaibia M, Morris AJ, Aidinis V, Kane DA, Pulinilkunnil T, Kienesberger PC (2018) Autotaxin-LPA signaling contributes to obesity-induced insulin resistance in muscle and impairs mitochondrial metabolism. J Lipid Res 59:1805-17.

» PMID: 30072447 Open Access

D'Souza K, Nzirorera C, Cowie AM, Varghese GP, Trivedi P, Eichmann TO, Biswas D, Touaibia M, Morris AJ, Aidinis V, Kane DA, Pulinilkunnil T, Kienesberger PC (2018) J Lipid Res

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.

Keywords: Diet effects/lipid metabolism, Glucose, Pyruvate, Respiration, Skeletal muscle Bioblast editor: Plangger M O2k-Network Lab: CA Antigonish Kane DA, CA Saint John Pulinilkunnil T


Labels: MiParea: Respiration, Genetic knockout;overexpression, Exercise physiology;nutrition;life style  Pathology: Obesity 

Organism: Mouse  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue 


Coupling state: LEAK, OXPHOS  Pathway: F, N, S, ROX  HRR: Oxygraph-2k 

Labels, 2020-03