Tumor Necrosis Factor-{alpha} Promotes Phosphoinositide 3-Kinase Enhancer A and AMP-Activated Protein Kinase Interaction to Suppress Lipid Oxidation in Skeletal Muscle

We report in this study that phosphoinositide 3-kinase enhancer A (PIKE-A) is a novel effector of TNF-α to facilitate its metabolic modulation in the skeletal muscle. Depletion of PIKE-A in C2C12 myotubes diminished the inhibitory activities of TNF-α on mitochondrial respiration and lipid oxidation, whereas PIKE-A overexpression exacerbated these cellular responses. We also found that TNF-α promoted the interaction between PIKE-A and AMP-activated protein kinase (AMPK) to suppress its kinase activity in vitro and in vivo. As a result, animals with PIKE ablation in the skeletal muscle per se display an upregulation of AMPK phosphorylation and a higher preference to use lipid as the energy production substrate under high-fat diet feeding, which mitigates the development of diet-induced hyperlipidemia, ectopic lipid accumulation, and muscle insulin resistance. Hence, our data reveal PIKE-A as a new signaling factor that is important for TNF-α–initiated metabolic changes in skeletal muscle.

Source: Diabetes - June 21, 2017 Category: Endocrinology Authors: Tse, M. C. L.; Herlea-Pana, O.; Brobst, D.; Yang, X.; Wood, J.; Hu, X.; Liu, Z.; Lee, C. W.; Zaw, A. M.; Chow, B. K. C.; Ye, K.; Chan, C. B. Tags: Signal Transduction Source Type: research