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Publication
Tumor Necrosis Factor-a Promotes Phosphoinositide 3-Kinase Enhancer A and
AMP-Activated Protein Kinase Interaction to Suppress Lipid Oxidation in Skeletal
Muscle.
Authors Tse MCL, Herlea-Pana O, Brobst D, Yang X, Wood J, Hu X, Liu Z, Lee CW, Zaw AM,
Chow BKC, Ye K, Chan CB
Submitted By Submitted Externally on 10/19/2017
Status Published
Journal Diabetes
Year 2017
Date Published 7/1/2017
Volume : Pages 66 : 1858 - 1870
PubMed Reference 28404596
Abstract Tumor necrosis factor-a (TNF-a) is an inflammatory cytokine that plays a central
role in obesity-induced insulin resistance. It also controls cellular lipid
metabolism, but the underlining mechanism is poorly understood. We report in
this study that phosphoinositide 3-kinase enhancer A (PIKE-A) is a novel
effector of TNF-a to facilitate its metabolic modulation in the skeletal muscle.
Depletion of PIKE-A in C2C12 myotubes diminished the inhibitory activities of
TNF-a on mitochondrial respiration and lipid oxidation, whereas PIKE-A
overexpression exacerbated these cellular responses. We also found that TNF-a
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-a-initiated metabolic changes in skeletal muscle.




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