Cytokine stimulation of energy expenditure through p38 MAP kinase activation of PPARgamma coactivator-1

Mol Cell. 2001 Nov;8(5):971-82. doi: 10.1016/s1097-2765(01)00390-2.

Abstract

Cachexia is a chronic state of negative energy balance and muscle wasting that is a severe complication of cancer and chronic infection. While cytokines such as IL-1alpha, IL-1beta, and TNFalpha can mediate cachectic states, how these molecules affect energy expenditure is unknown. We show here that many cytokines activate the transcriptional PPAR gamma coactivator-1 (PGC-1) through phosphorylation by p38 kinase, resulting in stabilization and activation of PGC-1 protein. Cytokine or lipopolysaccharide (LPS)-induced activation of PGC-1 in cultured muscle cells or muscle in vivo causes increased respiration and expression of genes linked to mitochondrial uncoupling and energy expenditure. These data illustrate a direct thermogenic action of cytokines and p38 MAP kinase through the transcriptional coactivator PGC-1.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cachexia / physiopathology*
  • Calcium-Calmodulin-Dependent Protein Kinases / genetics
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cell Line
  • Cell Respiration / physiology
  • Cytokines / pharmacology*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Energy Metabolism*
  • Enzyme Activation / physiology*
  • Genes, Reporter
  • Humans
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mice, Transgenic
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitogen-Activated Protein Kinases / metabolism*
  • Models, Biological
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Nuclear Respiratory Factors
  • Oxygen / metabolism
  • Phosphorylation
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Cytokines
  • DNA-Binding Proteins
  • Lipopolysaccharides
  • Nuclear Respiratory Factors
  • Trans-Activators
  • Transcription Factors
  • peroxisome-proliferator-activated receptor-gamma coactivator-1
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Oxygen