Inhibition by amino acids

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Several reports have suggested a possible interplay between the mammalian target of rapamycin (mTOR) and AMPK signaling pathways coordinating amino acids- and energy-sensing. The mTOR pathway has recently emerged as a crucial point of convergence for signaling by amino acids, growth factors and cellular energy (Wullschleger et al., 2006). Whereas mTOR was presumed to be a direct cellular sensor for ATP levels, mounting evidence implicated AMPK in the regulation of mTOR activity. AMPK inhibits mTOR through direct phosphorylation of TSC2 tumor suppressor (Inoki et al., 2003) as well as critical mTOR-binding subunit raptor (Gwinn et al., 2008). Thus, mTOR activation and  AMPK activity are inversely related (Aguilar et al., 2007). Recent studies demonstrated that AMPK activity is suppressed by amino acids (Gleason et al., 2007; Leclerc and Rutter, 2004). Treatment of C2C12 myoblast cells with leucine enhanced the phosphorylation of mTOR and concomitantly reduced the phosphorylation of AMPK and inhibited its activity (Du et al., 2007). The ability of leucine to dramatically reduce AMPK activity is linked to a consequent drop in the level of AMP and a subsequent decrease in AMP/ATP ratio. In the liver, the increase of protein intake induces metabolic adaptation characterized by concomitant increase of mTOR phosphorylation and decrease of AMPK phosphorylation (Chotechuang et al., 2009). Similarly, high protein diet decreases AMPK and increases mTOR activity in the hypothalamus, leading to reduction in food intake (Ropelle et al., 2008). Consistent with a cross-regulation between AMPK and mTOR to control food intake, hypothalamic ATP levels are increased and AMP/ATP ratio reduced after high protein feeding.