Trends in Endocrinology & Metabolism
ReviewmTOR couples cellular nutrient sensing to organismal metabolic homeostasis
Section snippets
mTOR complex 1: sensing local and systemic nutrient status
The ability of organisms to adapt to fluctuations in nutrient availability is fundamental to the fitness of a species. Organisms respond to nutrient fluctuations by altering the balance between energy-producing catabolic processes and energy-consuming anabolic processes. In eukaryotes, the metabolic response to nutrients is tightly coordinated by nutrient- and energy-sensing signaling pathways. Much progress has been made in our understanding of the cell-intrinsic wiring of these key signaling
Downstream of mTORC1: protein synthesis and beyond
In mammals, two main classes of direct mTORC1 substrates have emerged [13]: the ribosomal S6 kinases (S6K1 and S6K2) and the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4EBP1 and 4EBP2). mTORC1 phosphorylates the hydrophobic motif on the S6Ks (T389 on the 70-kDa isoform of S6K1), which is essential for subsequent activating phosphorylation events. The S6Ks phosphorylate a number of downstream targets, the best characterized of which is the ribosomal protein S6. Although our
mTORC1-dependent feedback mechanisms and cell intrinsic insulin resistance
A crucial element of mTORC1 signaling is its feedback effects on upstream pathways. Both mTORC1 and its downstream target S6K1 can exert negative regulatory inputs into upstream signaling molecules (Figure 2). The best characterized of these are the insulin receptor substrate (IRS) proteins, which are required to activate the PI3K-Akt pathway downstream of the insulin receptor. There are a number of rapamycin-sensitive phosphorylation sites on IRS1, and several of these serine residues appear
Pharmacological versus genetic manipulation of mTORC1 signaling in rodent models
Given the defined roles of mTORC1 in nutrient sensing and control of cellular physiology, there is a real push to understand the functions of mTORC1 in regulating the physiological state of mammals. To this end, gain- and loss-of-function models have been developed to delineate the role of mTORC1 signaling in rodents. One limitation of these models comes from the finding that null alleles of the mTORC1 components (mTOR or RAPTOR 41, 42, 43) or its key upstream regulators (TSC1 and TSC2 44, 45)
Pancreas
The endocrine pancreas functions as a sensor and regulator of circulating glucose levels, and alterations in the physiological function of the pancreas often reflect changes in islet mass [52]. Given its function as both a nutrient sensor and a regulator of cell growth, it is not surprising that mTORC1 has been shown to play a major role in the pancreatic control of insulin secretion and glucose homeostasis, largely through the regulation of β-cell size. Mouse models with constitutive
Conclusions and outstanding questions
The function of mTORC1 as a nutrient sensor and regulator of anabolic processes has been well established in cell culture models. However, we are just beginning to understand how its cell-intrinsic regulation and function translate into the control of systemic metabolism. From the rodent models discussed here, it appears that in response to food intake, mTORC1 activation enhances nutrient mobilization into peripheral tissues through increased insulin secretion from the pancreas, while also
Acknowledgments
Research on the regulation and metabolic function of mTORC1 in the Manning laboratory is supported by grants to B.D.M. from the National Institutes of Health (CA122617) and the American Diabetes Association.
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