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Phosphorus-31 Magnetic Resonance Spectroscopy: A Tool for Measuring In Vivo Mitochondrial Oxidative Phosphorylation Capacity in Human Skeletal Muscle
09:40

Phosphorus-31 Magnetic Resonance Spectroscopy: A Tool for Measuring In Vivo Mitochondrial Oxidative Phosphorylation Capacity in Human Skeletal Muscle

Published on: January 19, 2017

Tumor necrosis factor alpha-induced skeletal muscle insulin resistance involves suppression of AMP-kinase signaling

Gregory R Steinberg1, Belinda J Michell, Bryce J W van Denderen

  • 1St Vincent's Institute and Department of Medicine, University of Melbourne, Fitzroy, Vic, 3065, Australia. gsteinberg@svi.edu.au

Cell Metabolism
|December 5, 2006
PubMed

Insights

Tumor necrosis factor-alpha (TNFalpha) impairs skeletal muscle insulin sensitivity by suppressing AMPK activity, leading to reduced fatty-acid oxidation and increased lipid accumulation. Blocking TNFalpha signaling reverses these effects, highlighting AMPK as a key mediator.

Area of Science:

  • Molecular biology
  • Metabolic diseases
  • Endocrinology

Background:

  • Elevated tumor necrosis factor-alpha (TNFalpha) levels are linked to insulin resistance.
  • The precise mechanisms by which chronic TNFalpha exposure causes insulin resistance remain unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which TNFalpha signaling induces insulin resistance in skeletal muscle.
  • To investigate the role of AMP-activated protein kinase (AMPK) in TNFalpha-mediated insulin resistance.

Main Methods:

  • Investigated TNFalpha signaling pathways in skeletal muscle using in vitro and in vivo models.
  • Utilized genetic knockout models (TNFR1/2 null mice) and TNFalpha-neutralizing antibodies.
  • Assessed AMPK activity, protein phosphatase 2C (PP2C) expression, ACC phosphorylation, and intramuscular lipid accumulation.

Main Results:

  • TNFalpha signaling via TNF receptor 1 suppresses AMPK activity by upregulating PP2C transcription.
  • This suppression reduces acetyl-CoA carboxylase (ACC) phosphorylation, impairs fatty-acid oxidation, and increases intramuscular diacylglycerol.
  • These metabolic dysfunctions lead to insulin resistance in skeletal muscle.
  • The inhibitory effects of TNFalpha on AMPK signaling are reversible in TNFR1/2 knockout mice and upon TNFalpha blockade.

Conclusions:

  • AMPK is a critical molecular target of TNFalpha signaling in the context of insulin resistance.
  • TNFalpha-induced suppression of fatty-acid oxidation and lipid accumulation contributes to the development of insulin resistance, particularly in obesity.
  • Targeting TNFalpha signaling pathways may offer therapeutic strategies for metabolic disorders like insulin resistance.

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