mTORC1 controls fasting-induced ketogenesis and its modulation by ageing

Abstract

The multi-component mechanistic target of rapamycin complex 1 (mTORC1) kinase is the central node of a mammalian pathway that coordinates cell growth with the availability of nutrients, energy and growth factors. Progress has been made in the identification of mTORC1 pathway components and in understanding their functions in cells, but there is relatively little known about the role of the pathway in vivo. Specifically, we have little knowledge regarding the role mTOCR1 has in liver physiology. In fasted animals, the liver performs numerous functions that maintain whole-body homeostasis, including the production of ketone bodies for peripheral tissues to use as energy sources. Here we show that mTORC1 controls ketogenesis in mice in response to fasting. We find that liver-specific loss of TSC1 (tuberous sclerosis 1), an mTORC1 inhibitor, leads to a fasting-resistant increase in liver size, and to a pronounced defect in ketone body production and ketogenic gene expression on fasting. The loss of raptor (regulatory associated protein of mTOR, complex 1) an essential mTORC1 component, has the opposite effects. In addition, we find that the inhibition of mTORC1 is required for the fasting-induced activation of PPARα (peroxisome proliferator activated receptor α), the master transcriptional activator of ketogenic genes, and that suppression of NCoR1 (nuclear receptor co-repressor 1), a co-repressor of PPARα, reactivates ketogenesis in cells and livers with hyperactive mTORC1 signalling. Like livers with activated mTORC1, livers from aged mice have a defect in ketogenesis, which correlates with an increase in mTORC1 signalling. Moreover, we show that the suppressive effects of mTORC1 activation and ageing on PPARα activity and ketone production are not additive, and that mTORC1 inhibition is sufficient to prevent the ageing-induced defect in ketogenesis. Thus, our findings reveal that mTORC1 is a key regulator of PPARα function and hepatic ketogenesis and suggest a role for mTORC1 activity in promoting the ageing of the liver.

Sex‐ and tissue‐specific changes in mTOR signaling with age in C57 BL /6J mice

“…1A) and skeletal muscle (Fig. 1B), due to the conflicting previous reports (Sengupta et al ., 2010; Houtkooper et al ., 2011; Leontieva et al ., 2014). In agreement with the results seen by Houtkooper et al ., we observed a 30% decrease in S6 S240/S244 phosphorylation in the livers of Middle‐aged males and females compared to Young (Fig.…”

“…The question of what happens to mTORC1 signaling during normal aging has therefore received significant attention. As reported in Table 1, numerous studies have reported increased mTORC1 signaling with age in HSCs (hematopoietic stem cells), hypothalamic POMC neurons, and in the liver and lung of mice (Chen et al ., 2009; Sengupta et al ., 2010; Yang et al ., 2012; Leontieva et al ., 2014; Calhoun et al ., 2015). …”

Chronic mTOR inhibition in mice with rapamycin alters T, B, myeloid, and innate lymphoid cells and gut flora and prolongs life of immune‐deficient mice

“…Rapamycin is considered primarily an mTORC1 inhibitor (Laplante & Sabatini, 2012) but can also inhibit mTORC2. Recent studies distinguish mTORC1 versus mTORC2 effects on lifespan (Selman et al ., 2009) in addition to effects on cell proliferation (Dowling et al ., 2010), metabolism (Sengupta et al ., 2010; Lamming et al ., 2012), protein translation (Thoreen et al ., 2012), immunity (Chi, 2012), and other processes (Yu et al ., 2010; Shimobayashi & Hall, 2014). …”

Ketone body 3‐hydroxybutyrate mimics calorie restriction via the Nrf2 activator, fumarate, in the retina

“…Although the relationship between CR and health benefits has been empirically demonstrated (Walford, Harris, & Gunion, 1992), the mechanisms underlying this process are multifactorial and still under intensive investigation. Complex association among nutrition‐sensing networks, mammalian target of rapamycin (mTOR; Sengupta, Peterson, Laplante, Oh, & Sabatini, 2010), AMP‐activated protein kinase (AMPK; Canto & Auwerx, 2011), peroxisome proliferator‐activated receptor co‐activator 1α (PGC‐1α; Finley et al., 2012), and sirtuin (Sirt) pathways (Imai, Armstrong, Kaeberlein, & Guarente, 2000) have recently been proposed as possible underlying mechanisms in rodents and nonrodent lower animals.…”

“…Recently, apart from its role as a metabolic fuel, the effects of 3HB associated with the benefits of CR were reported. The activity of a limiting enzyme of 3HB synthesis, mitochondrial hydroxymethylglutaryl‐CoA synthase (mHMG‐CoAS), is regulated through deacetylation by Sirt3 (Shimazu et al., 2010) and mTOR (Sengupta et al., 2010), master regulators of energy metabolic homeostasis signaling, and these activities have been linked to ameliorating diseases associated with oxidative stress. A more recent finding also showed that 3HB is an endogenous histone diacetyl‐lase inhibitor that helps cells resist oxidative stress (Shimazu et al., 2013).…”