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

Diabetes. 2017 Jul;66(7):1858-1870. doi: 10.2337/db16-0270. Epub 2017 Apr 12.


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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / drug effects
  • AMP-Activated Protein Kinases / metabolism*
  • Adenosine Monophosphate / metabolism
  • Animals
  • Antirheumatic Agents / pharmacology
  • Blotting, Western
  • Body Composition
  • Diet, High-Fat
  • Female
  • GTP Phosphohydrolases / genetics*
  • Glucose Clamp Technique
  • Immunoprecipitation
  • Infliximab / pharmacology
  • Insulin Resistance*
  • Lipid Metabolism / drug effects
  • Lipid Metabolism / genetics*
  • Locomotion
  • Mice
  • Mice, Knockout
  • Mitochondria, Muscle / drug effects
  • Mitochondria, Muscle / metabolism*
  • Muscle Fibers, Skeletal / drug effects
  • Muscle Fibers, Skeletal / metabolism*
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism*
  • Nerve Tissue Proteins / genetics*
  • Obesity / metabolism*
  • Oxidation-Reduction / drug effects
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / pharmacology


  • Antirheumatic Agents
  • Nerve Tissue Proteins
  • Tumor Necrosis Factor-alpha
  • Adenosine Monophosphate
  • Infliximab
  • AMP-Activated Protein Kinases
  • GTP Phosphohydrolases
  • PIKE protein, mouse