Separation of the gluconeogenic and mitochondrial functions of PGC-1α through S6 kinase

PGC-1 alpha is a transcriptional coactivator that powerfully regulates many pathways linked to energy homeostasis. Specifically, PGC-1 alpha controls mitochondrial biogenesis in most tissues but also initiates important tissue-specific functions, including fiber type switching in skeletal muscle and gluconeogenesis and fatty acid oxidation in the liver. We show here that S6 kinase, activated in the liver upon feeding, can phosphorylate PGC-1 alpha directly on two sites within its arginine/serine-rich (RS) domain. This phosphorylation significantly attenuates the ability of PGC-1 alpha to turn on genes of gluconeogenesis in cultured hepatocytes and in vivo, while leaving the functions of PGC-1 alpha as an activator of mitochondrial and fatty acid oxidation genes completely intact. These phosphorylations interfere with the ability of PGC-1 alpha to bind to HNF4 alpha, a transcription factor required for gluconeogenesis, while leaving undisturbed the interactions of PGC-1 alpha with ERR alpha and PPAR alpha, factors important for mitochondrial biogenesis and fatty acid oxidation. These data illustrate that S6 kinase can modify PGC-1 alpha and thus allow molecular dissection of its functions, providing metabolic flexibility needed for dietary adaptation.