Tankyrase inhibition augments neuronal insulin sensitivity and glucose uptake via AMPK-AS160 mediated pathway

Tankyrase, a member of poly (ADP-ribose) polymerase (PARP) family, regulates various cellular pathways including wnt signaling, telomere maintenance and mitosis, has become a prime target for the development of cancer therapeutics. Inhibition of tankyrase, which leads to its increased cellular accumulation, reveal the role of tankyrase in the regulation of Glucose transporter type 4 (GLUT4) translocation and glucose homeostasis in peripheral insulin responsive tissues. While in adipocytes inhibition of tankyrase improves insulin sensitivity and glucose uptake, its inhibition in skeletal muscle leads to development of insulin resistance. Evidently further studies are required to determine the broader perspective of tankyrase in other cellular systems in regulating insulin signaling and insulin resistance. Role of tankyrase in neuronal tissues/cells has not been tested. In the present study, we investigated the effect of tankyrase inhibition in insulin-sensitive and insulin-resistant Neuro-2a cells. Here, we report that XAV939 treatment, a tankyrase inhibitor, improves insulin-stimulated glucose uptake in insulin-sensitive as well as in insulin-resistant neuronal cells via AMP-activated protein kinase (AMPK) - AKT Substrate of 160 kDa (AS160) mediated pathway without affecting the phosphorylation/activation of AKT. AMPK inhibition by Compound C repressed XAV939 treatment mediated increase in glucose uptake, confirming the role of tankyrase in glucose uptake via AMPK. We show for the first time that inhibition of tankyrase significantly improves glucose uptake and insulin sensitivity of insulin-resistant neuronal cells via AMPK-AS160 mediated pathway. Our study demonstrates new mechanistic insights of tankyrase mediated regulation of insulin sensitivity as well as glucose uptake in neuronal cells.