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Hypothalamic mTORC2 is essential for metabolic health and longevity.
Authors Chellappa K, Brinkman JA, Mukherjee S, Morrison M, Alotaibi MI, Carbajal KA,
Alhadeff AL, Perron IJ, Yao R, Purdy CS, DeFelice DM, Wakai MH, Tomasiewicz J,
Lin A, Meyer E, Peng Y, Arriola Apelo SI, Puglielli L, Betley JN, Paschos GK,
Baur JA, Lamming DW
Submitted By Submitted Externally on 8/6/2019
Status Published
Journal Aging cell
Year 2019
Date Published 8/1/2019
Volume : Pages Not Specified : e13014
PubMed Reference 31373126
Abstract The mechanistic target of rapamycin (mTOR) is an evolutionarily conserved
protein kinase that regulates growth and metabolism. mTOR is found in two
protein complexes, mTORC1 and mTORC2, that have distinct components and
substrates and are both inhibited by rapamycin, a macrolide drug that robustly
extends lifespan in multiple species including worms and mice. Although the
beneficial effect of rapamycin on longevity is generally attributed to reduced
mTORC1 signaling, disruption of mTORC2 signaling can also influence the
longevity of worms, either positively or negatively depending on the temperature
and food source. Here, we show that loss of hypothalamic mTORC2 signaling in
mice decreases activity level, increases the set point for adiposity, and
renders the animals susceptible to diet-induced obesity. Hypothalamic mTORC2
signaling normally increases with age, and mice lacking this pathway display
higher fat mass and impaired glucose homeostasis throughout life, become more
frail with age, and have decreased overall survival. We conclude that
hypothalamic mTORC2 is essential for the normal metabolic health, fitness, and
lifespan of mice. Our results have implications for the use of mTORC2-inhibiting
pharmaceuticals in the treatment of brain cancer and diseases of aging.


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