Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Cell Metab. 2012 Jul 3;16(1):104-12. doi: 10.1016/j.cmet.2012.05.010. Epub 2012 Jun 21.
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.
PI3K-AKT、mTOR-p70S6 激酶和 AMPK 通路在代谢调节中发挥独特而关键的作用。每条通路对于瘦素在下丘脑的厌食作用都是必需的。在这里，我们表明这些通路在一个整合的磷酸化级联中汇聚，以介导瘦素在下丘脑的作用。我们确定 α2AMPK 上的丝氨酸(491)是汇聚的位点，并表明 p70S6 激酶与 α2AMPK 形成复合物，导致丝氨酸(491)磷酸化。阻断 α2AMPK-丝氨酸(491)磷酸化会增加下丘脑 AMPK 活性、食物摄入和体重。丝氨酸(491)磷酸化是瘦素对下丘脑 α2AMPK 活性、神经肽表达、食物摄入和体重的影响所必需的。这些结果确定了一种抑制 AMPK 激酶，即 p70S6 激酶，并证明 AMPK 是 mTOR-p70S6 激酶的底物。这一发现具有广泛的生物学意义，因为 mTOR-p70S6 激酶和 AMPK 具有多种基本的、通常相反的细胞效应，调节代谢、细胞生长和发育。
