p70S6 kinase phosphorylates AMPK on serine 491 to mediate leptin's effect on food intake.
The PI3K-AKT, mTOR-p70S6 kinase and AMPK pathways play distinct and critical roles in metabolic regulation. Each pathway is necessary for leptin's anorexigenic effects in the hypothalamus. Here we show that these pathways converge in an integrated phosphorylation cascade to mediate leptin action in the hypothalamus. We identify serine(491) on α2AMPK as the site of convergence and show that p70S6 kinase forms a complex with α2AMPK, resulting in phosphorylation on serine(491). Blocking α2AMPK-serine(491) phosphorylation increases hypothalamic AMPK activity, food intake, and body weight. Serine(491) phosphorylation is necessary for leptin's effects on hypothalamic α2AMPK activity, neuropeptide expression, food intake, and body weight. These results identify an inhibitory AMPK kinase, p70S6 kinase, and demonstrate that AMPK is a substrate for mTOR-p70S6 kinase. This discovery has broad biologic implications since mTOR-p70S6 kinase and AMPK have multiple, fundamental and generally opposing cellular effects that regulate metabolism, cell growth, and development.
Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Yossi
Y
Dagon
Elizabeth
E
Hur
Bin
B
Zheng
Kerry
K
Wellenstein
Lewis C
LC
Cantley
Barbara B
BB
Kahn
D000263:Adenylate Kinase / Q000378:metabolism*; D054369:Agouti-Related Protein / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D002460:Cell Line; D004435:Eating; D007031:Hypothalamus / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D020738:Leptin / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D021122:Protein Subunits / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism*; D015398:Signal Transduction
D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D020738:Leptin; D021122:Protein Subunits; D012694:Serine; D011333:Pro-Opiomelanocortin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D000263:Adenylate Kinase