Open AccessHypothalamic mTORC2 is essential for metabolic health and longevity
Author(s) -
Chellappa Karthikeyani,
Brinkman Jacqueline A.,
Mukherjee Sarmistha,
Morrison Mark,
Alotaibi Mohammed I.,
Carbajal Kathryn A.,
Alhadeff Amber L.,
Perron Isaac J.,
Yao Rebecca,
Purdy Cole S.,
DeFelice Denise M.,
Wakai Matthew H.,
Tomasiewicz Jay,
Lin Amy,
Meyer Emma,
Peng Yajing,
Arriola Apelo Sebastian I.,
Puglielli Luigi,
Betley J. Nicholas,
Paschos Georgios K.,
Baur Joseph A.,
Lamming Dudley W.
Publication year - 2019
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.13014
Subject(s) - mtorc2 , mtorc1 , longevity , biology , pi3k/akt/mtor pathway , mechanistic target of rapamycin , microbiology and biotechnology , signal transduction , cancer research , endocrinology , genetics
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.