Leucine-mTOR signaling and nutrient stress in cell culture models

Leucine-induced activation of the mammalian target of rapamycin (mTOR) nutrient sensing signaling pathway and effects of nutritive modulation on adipocyte metabolism were studied in cell culture models. In human primary fibroblasts, crucial determinants (Leucine/glutamine-antiporter, amino acid sensor MAP4K3) of the leucine-induced mTOR signaling pathway were identified and its dependency on intracellular amino acid availability was shown. In defective leucine catabolism and nutrient starvation, regulation was dysfunctional consistent with sustaining a more efficient MAP4K3 and mTOR-S6K1 signaling. Such a regulatory circuit might serve to protect cells against detrimental consequences of reduced nutrient utilization in human conditions associated with disturbed leucine metabolism. In an adipocyte model, components of the “mTOR/PPARγ nutrient-sensing network” were identified and evaluated as indicators of “nutrient stress” modulation through alterations in nutrient composition.