Tumor necrosis factor-α promotes phosphoinositide 3-kinase enhancer A and AMP-activated protein kinase interaction to suppress lipid oxidation in skeletal muscle

Margaret Chui Ling Tse, Oana Herlea-Pana, Daniel Brobst, Xiuying Yang, John Wood, Xiang Hu, Zhixue Liu, Chi Wai Lee, Aung Moe Zaw, Billy K.C. Chow, Keqiang Ye, Chi Bun Chan*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

25 Citations (Scopus)

Abstract

Tumor necrosis factor-α (TNF-α) 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-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 AMPactivated 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.

Original languageEnglish
Pages (from-to)1858-1870
Number of pages13
JournalDiabetes
Volume66
Issue number7
DOIs
Publication statusPublished - 1 Jul 2017

Scopus Subject Areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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