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

Cachexia is a chronic state of negative energy balance and muscle wasting t hat is a severe complication of cancer and chronic infection. While cytokin es such as IL-1 alpha, IL-1 beta, and TNF alpha can mediate cachectic state s, how these molecules affect energy expenditure is unknown. We show here t hat many cytokines activate the transcriptional PPAR gamma coactivator-1 (P GC-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 incre ased 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.