Autotaxin-LPA signaling contributes to obesity-induced insulin resistance in muscle and impairs mitochondrial metabolism.
Kenneth D'SouzaCarine NziroreraAndrew M CowieGeena P VarghesePurvi TrivediThomas O EichmannDipsikha BiswasMohamed TouaibiaAndrew J MorrisVassilis AidinisDaniel A KaneThomas PulinilkunnilPetra C KienesbergerPublished in: Journal of lipid research (2018)
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.
Keyphrases
- insulin resistance
- skeletal muscle
- type diabetes
- high fat diet induced
- glycemic control
- adipose tissue
- high fat diet
- metabolic syndrome
- polycystic ovary syndrome
- oxidative stress
- high glucose
- blood glucose
- diabetic rats
- gene expression
- hydrogen peroxide
- heart failure
- weight loss
- early onset
- atrial fibrillation
- risk assessment
- machine learning
- fatty acid
- big data
- blood pressure
- municipal solid waste
- nitric oxide