AUTOTAXIN IS NUTRITIONALLY REGULATED AND ALTERS MITOCHONDRIAL FUNCTION IN OBESITY-INDUCED INSULIN RESISTANCE

Abstract

The skeletal muscle is a major site of insulin stimulated glucose disposal. Skeletal muscle insulin sensitivity can be influenced by multiple circulating nutritional, hormonal, neuronal and bioactive factors, including adipose tissue secreted bioactive molecules known as adipokines. Autotaxin (ATX) is a novel adipokine that generates the bioactive lipid, lysophosphatidic acid (LPA). ATX-LPA signaling is increased in mouse models of diet-induced obesity and insulin resistance and clinically correlates with indices of insulin resistance. Prior studies have also suggested that the ATX-LPA pathway contributes to the development and/or exacerbation of systemic insulin resistance. However, it remained unclear how ATX is regulated in an obese-insulin resistant milieu and whether the ATX-LPA pathway influences insulin sensitivity in muscle under obese-insulin resistant conditions. ATX activity was demonstrated to be acutely and chronically nutritionally regulated by feeding/fasting and an obesogenic diet, respectively. We further identified glucose and insulin as novel regulators of ATX expression in adipocytes/adipose tissue. Glucose independently increased ATX expression in a time- and concentration-dependent manner. Insulin elicited a biphasic response; acute insulin stimulation increased ATX activity in a PI3Kinase-dependent and mTORC1-independent manner, whereas chronic insulin stimulation decreased ATX expression. Heterozygous whole body ATX knockout (ATX+/-) mice were partially protected from high fat high sucrose (HFHS) diet-induced obesity, insulin resistance and glucose intolerance. HFHS-fed ATX+/- mice also showed improved insulin-stimulated AKT phosphorylation and glucose uptake in the soleus muscle. Mechanistically, ATX deficiency improved palmitate-linked mitochondrial respiration in the soleus, which was independent of broad changes in myofiber reprogramming, mitochondrial content and ADP sensitivity. Interestingly, mitochondrial H2O2 generation was increased, concomitant with generally decreased antioxidant gene expression. Similarly, LPA directly inhibited insulin signaling, mitochondrial respiration and H2O2 secretion in C2C12 myotubes. Taken together, my thesis work identified glucose and insulin as novel, critical regulators of ATX expression. Furthermore, chronic ATX deficiency improves skeletal muscle insulin sensitivity, which may be linked to amelioration of mitochondrial dysfunction induced by an obesogenic diet. This work also suggests that targeting the ATX-LPA signaling pathway may be a therapeutic strategy for treating obesity-induced insulin resistance.