mTOR couples cellular nutrient sensing to organismal metabolic homeostasis

Abstract

The mammalian target of rapamycin complex 1 (mTORC1) has the ability to sense a variety of essential nutrients and respond by altering cellular metabolic processes. Hence, this protein kinase complex is poised to influence adaptive changes to nutrient fluctuations toward the maintenance of whole-body metabolic homeostasis. Defects in mTORC1 regulation, arising from either physiological or genetic conditions, are believed to contribute to the metabolic dysfunction underlying a variety of human diseases, including type 2 diabetes. We are just now beginning to gain insights into the complex tissue-specific functions of mTORC1. In this review, we detail the current knowledge of the physiological functions of mTORC1 in controlling systemic metabolism, with a focus on advances obtained through genetic mouse models.

Figure 1. Nutrient sensing and upstream regulation of mTORC1

The presence of extracellular (or systemic) and intracellular nutrients are sensed by mTORC1 and stimulate its activation. In response to insulin, Akt inhibits TSC2, thereby allowing Rheb-GTP to accumulate and activate mTORC1. Nutrients and other factors influencing the energy status of the cell affect intracellular levels of AMP, which activates AMPK. AMPK exerts inhibitory effects on mTORC1 through activation of TSC2 and phosphorylation of Raptor. In addition, the presence of intracellular amino acids is sensed by mTORC1 through an undefined pathway affecting the Rag GTPases. Finally, the two best-characterized direct downstream targets of mTORC1, S6K1/2 and 4E-BP1, are shown.

Figure 2. mTORC1 signaling attenuates AKT activation through negative feedback mechanisms

Inhibitory phosphorylation events on IRS1 and the mTORC2 component Rictor by mTORC1 and/or S6K1 suppress the ability of insulin to stimulate Akt, a major metabolic effector of insulin signaling. Through such mechanisms, mTORC1 signaling can decrease insulin sensitivity. Importantly, this feedback effect on AKT signaling has been observed in all metabolic tissues examined (summarized in Table 1).