p70S6 Kinase Phosphorylates AMPK on Serine 491 to Mediate Leptin's Effect on Food Intake

SummaryThe 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 serine491 on α2AMPK as the site of convergence and show that p70S6 kinase forms a complex with α2AMPK, resulting in phosphorylation on serine491. Blocking α2AMPK-serine491 phosphorylation increases hypothalamic AMPK activity, food intake, and body weight. Serine491 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.

► p70S6 kinase is an inhibitory AMPK kinase that phosphorylates AMPK on serine485/491 ► Leptin inhibits hypothalamic α2AMPK activity by phosphorylating it on serine491 ► α2AMPK serine491 phosphorylation is necessary and sufficient for leptin action ► Hypothalamic PI3K-AKT, mTOR-p70S6 kinase, and AMPK converge to mediate leptin action