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Aberrant mTOR Signaling Impairs Whole Body Physiology

The protein mTOR (see image of mTOR activating mutations) is a central controller of growth and metabolism. Deregulation of mTOR signaling increases the risk of developing metabolic diseases such as diabetes, obesity, and cancer. Online on July 31, 2014 in PNAS, researchers from the Biozentrum of the University of Basel describe how aberrant mTOR signaling in the liver not only affects hepatic metabolism, but also whole body physiology. The protein mTOR regulates cell growth and metabolism and thus plays a key role in the development of human disorders. In the cell, this regulatory protein is found in two structurally and functionally distinct protein complexes called mTORC1 and mTORC2. In a recent study, the research group of Professor Michael Hall from the Biozentrum of the University of Basel has shed light on the role of hepatic mTORC1 in whole body physiology and the relevance for human liver cancers. In mammals, the liver is a key organ that controls whole body physiology in response to nutrients. Dr. Hall’s team investigated the role of the nutrient sensor mTORC1 in this process. The researchers were able to show that activation of mTORC1 in the liver of mice reduces not only hepatic lipid metabolism but also locomotor activity and body temperature. Upon investigating the underlying molecular mechanism, they observed that mTORC1 hyperactivation enhances the level of the stress hormone FGF21 by depletion of the amino acid glutamine. Treatment of animals with glutamine reduced the level of FGF21 and thus prevented the physiological impairments. Human cancers often exhibit aberrant mTORC1 signaling and glutamine addiction. “We were excited to see that in human liver tumors mTORC1 signaling correlates with FGF21 expression,” comments cell biologist Dr. Marion Cornu, the first author of the study. Moreover, mTORC1 inhibitors such as rapamycin are currently used as immunosuppressive agents and anti-cancer drugs. Thus, the novel findings of Dr. Hall’s team provide evidence that treatment of glutamine addicted human cancers with rapamycin might have beneficial effects by blocking tumor growth and by preventing deregulation of whole body physiology. [Press release] [PNAS abstract]