Autotaxin-LPA signaling contributes to obesity-induced insulin resistance in muscle and impairs mitochondrial metabolism
| Autor: | Thomas Pulinilkunnil, Vassilis Aidinis, Dipsikha Biswas, Geena Paramel Varghese, Petra C. Kienesberger, Daniel A. Kane, Andrew J. Morris, Thomas O. Eichmann, Carine Nzirorera, Kenneth D'Souza, Purvi C. Trivedi, Andrew M. Cowie, Mohamed Touaibia |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment Muscle Fibers Skeletal pyruvate White adipose tissue Biochemistry chemistry.chemical_compound Mice 0302 clinical medicine Endocrinology Lysophosphatidic acid Homeostasis Insulin glucose Research Articles 2. Zero hunger biology Chemistry Myogenesis Mitochondria medicine.anatomical_structure Organ Specificity 030220 oncology & carcinogenesis lipids (amino acids peptides and proteins) Autotaxin Signal Transduction medicine.medical_specialty QD415-436 03 medical and health sciences Insulin resistance Internal medicine medicine Animals Obesity skeletal muscle Muscle Skeletal Phosphoric Diester Hydrolases Skeletal muscle Cell Biology medicine.disease Mice Inbred C57BL Insulin receptor 030104 developmental biology biology.protein Insulin Resistance Lysophospholipids diet effects/lipid metabolism respiration |
| Zdroj: | Journal of Lipid Research, Vol 59, Iss 10, Pp 1805-1817 (2018) |
| ISSN: | 0022-2275 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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