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.
Highlights
The mechanistic target of rapamycin is a serine/threonine kinase that plays critical roles in the regulation of growth, metab‐ olism, and aging
While it has long been presumed that inhibition of mTOR complex 1 (mTORC1) by rapamycin mediates its beneficial effects on longevity, we and oth‐ ers have found that prolonged treatment with rapamycin in‐ hibits mTOR complex 2 (mTORC2), both in cell culture and in vivo in mice (Lamming et al, 2012; Sarbassov et al, 2004; Schreiber et al, 2015)
Disruption of mTORC2 signaling via deletion of Rictor, which encodes an essential protein component, in the liver, adipose tissue, or skeletal muscle leads to insulin resistance (Bentzinger et al, 2008; Kumar et al, 2008, 2010; Lamming, Demirkan, et al, 2014; Lamming, Mihaylova, et al, 2014; Polak et al, 2008; Tang et al, 2016)
Summary
The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that plays critical roles in the regulation of growth, metab‐ olism, and aging. The role of brain mTORC2 signaling in the regulation of metabolism, health, and lon‐ gevity has been less studied This knowledge gap has recently begun to narrow, with recent work showing that deletion of Rictor in male mice using the neuron‐specific Nestin‐Cre recombinase decreases energy expenditure and increases adiposity without affecting food intake, lowers body temperature, and disrupts glucose homeostasis (Kocalis et al, 2014). We observed increased phosphorylation of the mTORC2 target AKT S473 in whole brain lysates from 22‐ and 26‐month‐old females and 30‐month‐old males relative to young control mice (Figure 1a and Figure S1a) This effect was specific to mTORC2 and not representative of a generalized in‐ crease in insulin/IGF‐1 signaling, as phosphorylation of AKT T308, an mTORC2‐independent site downstream of insulin signaling, was not increased in aged mice of either sex. Beam break analysis revealed decreased locomotor activity in 6‐ and 10‐month‐old RictorNkx2.1−/− mice (Figure S5a–c), a phenotype that has not been previously associated with the mTORC2 signaling pathway
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