Cytokine stimulation of energy expenditure through p38 MAP kinase activation of PPARgamma coactivator-1.
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.
Puigserver
P
P
Dana-Farber Cancer Institute, Department of Cell Biology, Boston, MA 02115, USA.
Rhee
J
J
Lin
J
J
Wu
Z
Z
Yoon
J C
JC
Zhang
C Y
CY
Krauss
S
S
Mootha
V K
VK
Lowell
B B
BB
Spiegelman
B M
BM
D000818:Animals; D002100:Cachexia / Q000503:physiopathology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D019069:Cell Respiration / Q000502:physiology; D016207:Cytokines / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004734:Energy Metabolism; D004789:Enzyme Activation / Q000502:physiology*; D017930:Genes, Reporter; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051264:Nuclear Respiratory Factors; D010100:Oxygen / Q000378:metabolism; D010766:Phosphorylation; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases
D016207:Cytokines; D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; D051264:Nuclear Respiratory Factors; D015534:Trans-Activators; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010100:Oxygen