Inhibition by amino acids
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.
