Separation of the gluconeogenic and mitochondrial functions of pgc-1α through s6 kinase

TY - JOUR

T1 - Separation of the gluconeogenic and mitochondrial functions of pgc-1α through s6 kinase

AU - Lustig, Y.

AU - Ruas, J.L.

AU - Estall, J.L.

AU - Lo, J.C.

AU - Devarakonda, S.

AU - Laznik, D.

AU - Choi, J.H.

AU - Spiegelman, B.M.

AU - Ono, H.

AU - Olsen, J.V.

PY - 2011/6/15

Y1 - 2011/6/15

N2 - PGC-1α is a transcriptional coactivator that powerfully regulates many pathways linked to energy homeostasis. Specifically, PGC-1α 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-1α directly on two sites within its arginine/serine-rich (RS) domain. This phosphorylation significantly attenuates the ability of PGC-1α to turn on genes of gluconeogenesis in cultured hepatocytes and in vivo, while leaving the functions of PGC-1α as an activator of mitochondrial and fatty acid oxidation genes completely intact. These phosphorylations interfere with the ability of PGC-1α to bind to HNF4α, a transcription factor required for gluconeogenesis, while leaving undisturbed the interactions of PGC-1α with ERRα and PPARα, factors important for mitochondrial biogenesis and fatty acid oxidation. These data illustrate that S6 kinase can modify PGC 1α and thus allow molecular dissection of its functions, providing metabolic flexibility needed for dietary adaptation.

AB - PGC-1α is a transcriptional coactivator that powerfully regulates many pathways linked to energy homeostasis. Specifically, PGC-1α 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-1α directly on two sites within its arginine/serine-rich (RS) domain. This phosphorylation significantly attenuates the ability of PGC-1α to turn on genes of gluconeogenesis in cultured hepatocytes and in vivo, while leaving the functions of PGC-1α as an activator of mitochondrial and fatty acid oxidation genes completely intact. These phosphorylations interfere with the ability of PGC-1α to bind to HNF4α, a transcription factor required for gluconeogenesis, while leaving undisturbed the interactions of PGC-1α with ERRα and PPARα, factors important for mitochondrial biogenesis and fatty acid oxidation. These data illustrate that S6 kinase can modify PGC 1α and thus allow molecular dissection of its functions, providing metabolic flexibility needed for dietary adaptation.

UR - http://www.scopus.com/inward/record.url?scp=79959635928&partnerID=8YFLogxK

U2 - 10.1101/gad.2054711

DO - 10.1101/gad.2054711

M3 - Journal article

C2 - 21646374

SN - 0890-9369

VL - 25

SP - 1232

EP - 1244

JO - Genes & Development

JF - Genes & Development

IS - 12

ER -